'); } else { $(".fotorama-caption").addClass("remove_caption"); } }) .fotorama();

MCLEAN, United States (AFP) When a person's immune system is impaired by a genetic disease a bone marrow transplant can be a powerful therapeutic tool, but with a major downside during the first few months the recipient's defences against viruses are severely weakened. The slightest infection can lead to a hospital trip.

A still-experimental type of treatment known as T-cell therapy aims to assist during this vulnerable period the months during which the body is rebuilding its natural defences. After two decades of clinical trials, the technology has been refined and is being used to treat more and more patients, many of them children.

A boy named Johan is one of them.

Today he is a mischievous, smiling toddler, with a thick shock of light-brown hair, who never tires, playfully tormenting the family's puppy, Henry.

There is no sign of the three-year-long medical and emotional roller coaster ride he and his family, who live in an affluent Washington suburb, have been on.

The first traumatic surprise came with the results of a pregnancy test Johan was not planned.

That was a huge shock. I cried, said his mother, 39-year-old Maren Chamorro.

Risky procedure

She had known since childhood that she carried a gene that can be fatal in a child's first 10 years, chronic granulomatous disease (CGD).

Her brother died of it at the age of seven. The inexorable laws of genetics meant that Maren had a one in four chance of transmitting it to her child.

For their first children, she and her husband Ricardo had chosen invitro fertilisation, allowing the embryos to be genetically tested before implantation.

Their twins Thomas and Joanna were born both disease-free seven and a half years ago.

But in Johan's case, a post-birth genetic test quickly confirmed the worst: He had CGD.

After conferring with experts at Children's National Hospital in Washington, the couple took one of the most important decisions of their lives, Johan would receive a bone marrow transplant a risky procedure but one that would give him a chance of a cure.

Obviously, the fact that Maren had lost a sibling at a young age from the disease played a big role, Ricardo confided.

Bone marrow, the spongy tissue inside bones, serves as the body's factory for the production of blood cells both red and white.

His brother's immune system

Johan's white blood cells were incapable of fighting off bacteria and fungal infections. A simple bacterial infection, of negligible concern in a healthy child, could spread out of control in his young body.

Luckily, Johan's brother Thomas, six years old at the time, was a perfect match. In April 2018, doctors first cleansed Johan's marrow using chemotherapy. They then took a small amount of marrow from Thomas's hip bones using a long, thin needle.

From that sample they extracted supercells, as Thomas calls them stem cells, which they reinjected into Johan's veins. Those cells would eventually settle in his bone marrow and begin producing normal white blood cells.

The second step was preventive cell therapy, under an experimental programme led by immunologist Michael Keller at Children's National Hospital.

The part of the immune system that protects against bacteria can be rebuilt in only a matter of weeks; but for viruses, the natural process takes at least three months.

Hurdles remain

From Thomas's blood, doctors extracted specialised white blood cells T-cells that had already encountered six viruses.

Keller grew them for 10 days in an incubator, creating an army of hundreds of millions of those specialised T-cells. The result: A fluffy white substance contained in a small glass vial.

Those T-cells were then injected into Johan's veins, immediately conferring protection against the six viruses.

He has his brother's immune system, said Keller, an assistant professor at Children's National.

Johan's mother confirmed as much: Today, when Thomas and Johan catch a cold they have the same symptoms, and for nearly the same amount of time.

I think it's pretty cool to have immunity from your big brother, Maren Chamorro said.

This therapeutic approach boosting the body's immune system using cells from a donor or one's own genetically modified cells is known as immunotherapy.

Its main use so far has been against cancer, but Keller hopes it will soon become available against viruses for patients, like Johan, who suffer from depressed immune systems.

The chief obstacles to that happening are the complexity of the process and the costs, which can run to many thousands of dollars. These factors currently restrict the procedure to some 30 medical centres in the United States.

For Johan, a year and a half after his bone marrow transplant, everything points to a complete success.

It's neat to see him processing things, and especially play outside in the mud, his mother said.

You know, what a gift!

Her only concern now is the same as any mother would have that when her son does fall ill, others in the family might catch the same bug.

Now you can read the Jamaica Observer ePaper anytime, anywhere. The Jamaica Observer ePaper is available to you at home or at work, and is the same edition as the printed copy available at http://bit.ly/epaperlive

See the rest here:
The supercells' that cured an infants genetic illness - Jamaica Observer

Bone Marrow Stem Cells Comments Off on The supercells’ that cured an infants genetic illness – Jamaica Observer | January 5th, 2020

Tator CH, Fehlings MG. Review of the secondary injury theory of acute spinal cord trauma with emphasis on vascular mechanisms. J Neurosurg. 1991;75:1526.

Guertin PA. A central pattern generator in the spinal cord for the central control of micturition: an opportunity for first-in-class drug treatments. Asia Pac J Clin Trials Nerv Syst Dis. 2019;4:12.

Silver J, Miller JH. Regeneration beyond the glial scar. Nat Rev Neurosci. 2004;5:14656.

Donnelly DJ, Popovich PG. Inflammation and its role in neuroprotection, axonal regeneration and functional recovery after spinal cord injury. Exp Neurol. 2008;209:37888.

Badner A, Siddiqui AM, Fehlings MG. Spinal cord injuries: how could cell therapy help? Expert Opin Biol Ther. 2017;17:52941.

Nagoshi N, Okano H. Applications of induced pluripotent stem cell technologies in spinal cord injury. J Neurochem. 2017;141:84860.

Orlic D, Kajstura J, Chimenti S, Bodine DM, Leri A, Anversa P. Bone marrow stem cells regenerate infarcted myocardium. Pediatr Transplant. 2003;7(Suppl 3):868.

Lovell-Badge R. The future for stem cell research. Nature. 2001;414:8891.

Neves J, Sousa-Victor P, Jasper H. Rejuvenating strategies for stem cell-based therapies in aging. Cell Stem Cell. 2017;20:16175.

Dang PN, Dwivedi N, Phillips LM, Yu X, Herberg S, Bowerman C, Solorio LD, Murphy WL, Alsberg E. Controlled dual growth factor delivery from microparticles incorporated within human bone marrow-derived mesenchymal stem cell aggregates for enhanced bone tissue engineering via endochondral ossification. Stem Cells Transl Med. 2016;5:20617.

Silva NA, Sousa N, Reis RL, Salgado AJ. From basics to clinical: a comprehensive review on spinal cord injury. Prog Neurobiol. 2014;114:2557.

Vismara I, Papa S, Rossi F, Forloni G, Veglianese P. Current options for cell therapy in spinal cord injury. Trends Mol Med. 2017;23:83149.

Dasari VR, Veeravalli KK, Dinh DH. Mesenchymal stem cells in the treatment of spinal cord injuries: a review. World J Stem Cells. 2014;6:12033.

Honmou O, Houkin K, Matsunaga T, Niitsu Y, Ishiai S, Onodera R, Waxman SG, Kocsis JD. Intravenous administration of auto serum-expanded autologous mesenchymal stem cells in stroke. Brain. 2011;134:1790807.

Cofano F, Boido M, Monticelli M, Zenga F, Ducati A, Vercelli A, Garbossa D. Mesenchymal stem cells for spinal cord injury: current options, limitations, and future of cell therapy. Int J Mol Sci. 2019;20(11).

Lee MW, Yang MS, Park JS, Kim HC, Kim YJ, Choi J. Isolation of mesenchymal stem cells from cryopreserved human umbilical cord blood. Int J Hematol. 2005;81:12630.

Evans MJ, Kaufman MH. Establishment in culture of pluripotential cells from mouse embryos. Nature. 1981;292:1546.

Shroff G, Dhanda Titus J, Shroff R. A review of the emerging potential therapy for neurological disorders: human embryonic stem cell therapy. Am J Stem Cells. 2017;6:112.

Harper JM, Krishnan C, Darman JS, Deshpande DM, Peck S, Shats I, Backovic S, Rothstein JD, Kerr DA. Axonal growth of embryonic stem cell-derived motoneurons in vitro and in motoneuron-injured adult rats. Proc Natl Acad Sci U S A. 2004;101:71238.

Iwai H, Shimada H, Nishimura S, Kobayashi Y, Itakura G, Hori K, Hikishima K, Ebise H, Negishi N, Shibata S, Habu S, Toyama Y, Nakamura M, Okano H. Allogeneic neural stem/progenitor cells derived from embryonic stem cells promote functional recovery after transplantation into injured spinal cord of nonhuman primates. Stem Cells Transl Med. 2015;4:70819.

Yang JR, Liao CH, Pang CY, Huang LL, Chen YL, Shiue YL, Chen LR. Transplantation of porcine embryonic stem cells and their derived neuronal progenitors in a spinal cord injury rat model. Cytotherapy. 2013;15:2018.

Johnson PJ, Tatara A, Shiu A, Sakiyama-Elbert SE. Controlled release of neurotrophin-3 and platelet-derived growth factor from fibrin scaffolds containing neural progenitor cells enhances survival and differentiation into neurons in a subacute model of SCI. Cell Transplant. 2010;19:89101.

Keirstead HS, Nistor G, Bernal G, Totoiu M, Cloutier F, Sharp K, Steward O. Human embryonic stem cell-derived oligodendrocyte progenitor cell transplants remyelinate and restore locomotion after spinal cord injury. J Neurosci. 2005;25:4694705.

Tetzlaff W, Okon EB, Karimi-Abdolrezaee S, Hill CE, Sparling JS, Plemel JR, Plunet WT, Tsai EC, Baptiste D, Smithson LJ, Kawaja MD, Fehlings MG, Kwon BK. A systematic review of cellular transplantation therapies for spinal cord injury. J Neurotrauma. 2011;28:161182.

Nakamura M, Okano H. Cell transplantation therapies for spinal cord injury focusing on induced pluripotent stem cells. Cell Res. 2013;23:7080.

Iyer NR, Wilems TS, Sakiyama-Elbert SE. Stem cells for spinal cord injury: strategies to inform differentiation and transplantation. Biotechnol Bioeng. 2017;114:24559.

Sabelstrom H, Stenudd M, Frisen J. Neural stem cells in the adult spinal cord. Exp Neurol. 2014;260:449.

Gregoire CA, Goldenstein BL, Floriddia EM, Barnabe-Heider F, Fernandes KJ. Endogenous neural stem cell responses to stroke and spinal cord injury. Glia. 2015;63:146982.

Lu P, Wang Y, Graham L, McHale K, Gao M, Wu D, Brock J, Blesch A, Rosenzweig ES, Havton LA, Zheng B, Conner JM, Marsala M, Tuszynski MH. Long-distance growth and connectivity of neural stem cells after severe spinal cord injury. Cell. 2012;150:126473.

Kerr CL, Letzen BS, Hill CM, Agrawal G, Thakor NV, Sterneckert JL, Gearhart JD, All AH. Efficient differentiation of human embryonic stem cells into oligodendrocyte progenitors for application in a rat contusion model of spinal cord injury. Int J Neurosci. 2010;120:30513.

Hofstetter CP, Holmstrom NA, Lilja JA, Schweinhardt P, Hao J, Spenger C, Wiesenfeld-Hallin Z, Kurpad SN, Frisen J, Olson L. Allodynia limits the usefulness of intraspinal neural stem cell grafts; directed differentiation improves outcome. Nat Neurosci. 2005;8:34653.

Gabel BC, Curtis EI, Marsala M, Ciacci JD. A review of stem cell therapy for spinal cord injury: large animal models and the frontier in humans. World Neurosurg. 2017;98:43843.

Ahuja CS, Wilson JR, Nori S, Kotter MRN, Druschel C, Curt A, Fehlings MG. Traumatic spinal cord injury. Nat Rev Dis Primers. 2017;3:17018.

Pereira IM, Marote A, Salgado AJ, Silva NA. Filling the gap: neural stem cells as a promising therapy for spinal cord injury. Pharmaceuticals (Basel). 2019;12(2).

Yousefifard M, Rahimi-Movaghar V, Nasirinezhad F, Baikpour M, Safari S, Saadat S, Moghadas Jafari A, Asady H, Razavi Tousi SM, Hosseini M. Neural stem/progenitor cell transplantation for spinal cord injury treatment; a systematic review and meta-analysis. Neuroscience. 2016;322:37797.

Deng J, Zhang Y, Xie Y, Zhang L, Tang P. Cell transplantation for spinal cord injury: tumorigenicity of induced pluripotent stem cell-derived neural stem/progenitor cells. Stem Cells Int. 2018;2018:5653787.

Kanatsu-Shinohara M, Shinohara T. Spermatogonial stem cell self-renewal and development. Annu Rev Cell Dev Biol. 2013;29:16387.

Glaser T, Opitz T, Kischlat T, Konang R, Sasse P, Fleischmann BK, Engel W, Nayernia K, Brustle O. Adult germ line stem cells as a source of functional neurons and glia. Stem Cells. 2008;26:243443.

Streckfuss-Bomeke K, Vlasov A, Hulsmann S, Yin D, Nayernia K, Engel W, Hasenfuss G, Guan K. Generation of functional neurons and glia from multipotent adult mouse germ-line stem cells. Stem Cell Res. 2009;2:13954.

Kossack N, Meneses J, Shefi S, Nguyen HN, Chavez S, Nicholas C, Gromoll J, Turek PJ, Reijo-Pera RA. Isolation and characterization of pluripotent human spermatogonial stem cell-derived cells. Stem Cells. 2009;27:13849.

Yang H, Liu Y, Hai Y, Guo Y, Yang S, Li Z, Gao WQ, He Z. Efficient conversion of spermatogonial stem cells to phenotypic and functional dopaminergic neurons via the PI3K/Akt and P21/Smurf2/Nolz1 pathway. Mol Neurobiol. 2015;52:165469.

Yang H, Liu C, Chen B, An J, Zhang R, Zhang Q, Zhao J, He B, Hao DJ. Efficient generation of functionally active spinal cord neurons from spermatogonial stem cells. Mol Neurobiol. 2017;54:788803.

Nazm Bojnordi M, Movahedin M, Tiraihi T, Javan M, Ghasemi Hamidabadi H. Oligoprogenitor cells derived from spermatogonia stem cells improve remyelination in demyelination model. Mol Biotechnol. 2014;56:38793.

Nomura H, Kim H, Mothe A, Zahir T, Kulbatski I, Morshead CM, Shoichet MS, Tator CH. Endogenous radial glial cells support regenerating axons after spinal cord transection. Neuroreport. 2010;21:8716.

Panayiotou E, Malas S. Adult spinal cord ependymal layer: a promising pool of quiescent stem cells to treat spinal cord injury. Front Physiol. 2013;4:340.

Liu Y, Tan B, Wang L, Long Z, Li Y, Liao W, Wu Y. Endogenous neural stem cells in central canal of adult rats acquired limited ability to differentiate into neurons following mild spinal cord injury. Int J Clin Exp Pathol. 2015;8:383542.

Ahuja CS, Fehlings M. Concise review: bridging the gap: novel neuroregenerative and neuroprotective strategies in spinal cord injury. Stem Cells Transl Med. 2016;5:91424.

Xue PXZF, Kou YH, Han S, Wang TB, Zhang DY, Jiang BG. Pre-hospital and in-hospital first aid programs and specifications for spine and spinal cord injury in Beijing, China: study protocol for a prospective, multicenter, nonrandomized controlled trial. Asia Pac J Clin Trials Nerv Syst Dis. 2017;2:5865.

Mukaino M, Nakamura M, Yamada O, Okada S, Morikawa S, Renault-Mihara F, Iwanami A, Ikegami T, Ohsugi Y, Tsuji O, Katoh H, Matsuzaki Y, Toyama Y, Liu M, Okano H. Anti-IL-6-receptor antibody promotes repair of spinal cord injury by inducing microglia-dominant inflammation. Exp Neurol. 2010;224:40314.

Anwar MA, Al Shehabi TS, Eid AH. Inflammogenesis of secondary spinal cord injury. Front Cell Neurosci. 2016;10:98.

Gao L, Zhang Z, Xu W, Li T, Ying G, Qin B, Li J, Zheng J, Zhao T, Yan F, Zhu Y, Chen G. Natrium benzoate alleviates neuronal apoptosis via the DJ-1-related anti-oxidative stress pathway involving Akt phosphorylation in a rat model of traumatic spinal cord injury. Front Mol Neurosci. 2019;12:42.

Sugawara T, Chan PH. Reactive oxygen radicals and pathogenesis of neuronal death after cerebral ischemia. Antioxid Redox Signal. 2003;5:597607.

Wang X, Wu X, Liu Q, Kong G, Zhou J, Jiang J, Wu X, Huang Z, Su W, Zhu Q. Ketogenic metabolism inhibits histone deacetylase (HDAC) and reduces oxidative stress after spinal cord injury in rats. Neuroscience. 2017;366:3643.

Zhou L, Ouyang L, Lin S, Chen S, Liu Y, Zhou W, Wang X. Protective role of beta-carotene against oxidative stress and neuroinflammation in a rat model of spinal cord injury. Int Immunopharmacol. 2018;61:929.

Shimizu EN, Seifert JL, Johnson KJ, Romero-Ortega MI. Prophylactic riluzole attenuates oxidative stress damage in spinal cord distraction. J Neurotrauma. 2018;35:131928.

Zhang L, Kaneko S, Kikuchi K, Sano A, Maeda M, Kishino A, Shibata S, Mukaino M, Toyama Y, Liu M, Kimura T, Okano H, Nakamura M. Rewiring of regenerated axons by combining treadmill training with semaphorin3A inhibition. Mol Brain. 2014;7:14.

Tashiro S, Nishimura S, Iwai H, Sugai K, Zhang L, Shinozaki M, Iwanami A, Toyama Y, Liu M, Okano H, Nakamura M. Functional recovery from neural stem/progenitor cell transplantation combined with treadmill training in mice with chronic spinal cord injury. Sci Rep. 2016;6:30898.

Assinck P, Duncan GJ, Hilton BJ, Plemel JR, Tetzlaff W. Cell transplantation therapy for spinal cord injury. Nat Neurosci. 2017;20:63747.

Emgard M, Piao J, Aineskog H, Liu J, Calzarossa C, Odeberg J, Holmberg L, Samuelsson EB, Bezubik B, Vincent PH, Falci SP, Seiger A, Akesson E, Sundstrom E. Neuroprotective effects of human spinal cord-derived neural precursor cells after transplantation to the injured spinal cord. Exp Neurol. 2014;253:13845.

Hawryluk GW, Mothe A, Wang J, Wang S, Tator C, Fehlings MG. An in vivo characterization of trophic factor production following neural precursor cell or bone marrow stromal cell transplantation for spinal cord injury. Stem Cells Dev. 2012;21:222238.

Kadoya K, Lu P, Nguyen K, Lee-Kubli C, Kumamaru H, Yao L, Knackert J, Poplawski G, Dulin JN, Strobl H, Takashima Y, Biane J, Conner J, Zhang SC, Tuszynski MH. Spinal cord reconstitution with homologous neural grafts enables robust corticospinal regeneration. Nat Med. 2016;22:47987.

Armstrong RJ, Hurelbrink CB, Tyers P, Ratcliffe EL, Richards A, Dunnett SB, Rosser AE, Barker RA. The potential for circuit reconstruction by expanded neural precursor cells explored through porcine xenografts in a rat model of Parkinsons disease. Exp Neurol. 2002;175:98111.

Bregman BS, Kunkel-Bagden E, Reier PJ, Dai HN, McAtee M, Gao D. Recovery of function after spinal cord injury: mechanisms underlying transplant-mediated recovery of function differ after spinal cord injury in newborn and adult rats. Exp Neurol. 1993;123:316.

Stenudd M, Sabelstrom H, Frisen J. Role of endogenous neural stem cells in spinal cord injury and repair. JAMA Neurol. 2015;72:2357.

Giusto E, Donega M, Cossetti C, Pluchino S. Neuro-immune interactions of neural stem cell transplants: from animal disease models to human trials. Exp Neurol. 2014;260:1932.

Volkman R, Offen D. Concise review: mesenchymal stem cells in neurodegenerative diseases. Stem Cells. 2017;35:186780.

Qu J, Zhang H. Roles of mesenchymal stem cells in spinal cord injury. Stem Cells Int. 2017;2017:5251313.

DeBrot A, Yao L. The combination of induced pluripotent stem cells and bioscaffolds holds promise for spinal cord regeneration. Neural Regen Res. 2018;13:167784.

Lee RH, Kim B, Choi I, Kim H, Choi HS, Suh K, Bae YC, Jung JS. Characterization and expression analysis of mesenchymal stem cells from human bone marrow and adipose tissue. Cell Physiol Biochem. 2004;14:31124.

Cho SR, Kim YR, Kang HS, Yim SH, Park CI, Min YH, Lee BH, Shin JC, Lim JB. Functional recovery after the transplantation of neurally differentiated mesenchymal stem cells derived from bone marrow in a rat model of spinal cord injury. Cell Transplant. 2016;25:1423.

Luo H, Xu C, Liu Z, Yang L, Hong Y, Liu G, Zhong H, Cai X, Lin X, Chen X, Wang C, Nanwen Z, Xu W. Neural differentiation of bone marrow mesenchymal stem cells with human brain-derived neurotrophic factor gene-modified in functionalized self-assembling peptide hydrogel in vitro. J Cell Biochem. 2019;120:282835.

Osaka M, Honmou O, Murakami T, Nonaka T, Houkin K, Hamada H, Kocsis JD. Intravenous administration of mesenchymal stem cells derived from bone marrow after contusive spinal cord injury improves functional outcome. Brain Res. 2010;1343:22635.

Ramalho BDS, Almeida FM, Sales CM, de Lima S, Martinez AMB. Injection of bone marrow mesenchymal stem cells by intravenous or intraperitoneal routes is a viable alternative to spinal cord injury treatment in mice. Neural Regen Res. 2018;13:104653.

Neirinckx V, Cantinieaux D, Coste C, Rogister B, Franzen R, Wislet-Gendebien S. Concise review: spinal cord injuries: how could adult mesenchymal and neural crest stem cells take up the challenge? Stem Cells. 2014;32:82943.

Nakajima H, Uchida K, Guerrero AR, Watanabe S, Sugita D, Takeura N, Yoshida A, Long G, Wright KT, Johnson WE, Baba H. Transplantation of mesenchymal stem cells promotes an alternative pathway of macrophage activation and functional recovery after spinal cord injury. J Neurotrauma. 2012;29:161425.

Salgado AJ, Reis RL, Sousa NJ, Gimble JM. Adipose tissue derived stem cells secretome: soluble factors and their roles in regenerative medicine. Curr Stem Cell Res Ther. 2010;5:10310.

Kim Y, Jo SH, Kim WH, Kweon OK. Antioxidant and anti-inflammatory effects of intravenously injected adipose derived mesenchymal stem cells in dogs with acute spinal cord injury. Stem Cell Res Ther. 2015;6:229.

Kolar MK, Kingham PJ, Novikova LN, Wiberg M, Novikov LN. The therapeutic effects of human adipose-derived stem cells in a rat cervical spinal cord injury model. Stem Cells Dev. 2014;23:165974.

Kokai LE, Marra K, Rubin JP. Adipose stem cells: biology and clinical applications for tissue repair and regeneration. Transl Res. 2014;163:399408.

Kim Y, Lee SH, Kim WH, Kweon OK. Transplantation of adipose derived mesenchymal stem cells for acute thoracolumbar disc disease with no deep pain perception in dogs. J Vet Sci. 2016;17:1236.

Zhou J, Lu P, Ren H, Zheng Z, Ji J, Liu H, Jiang F, Ling S, Heng BC, Hu X, Ouyang H. 17beta-estradiol protects human eyelid-derived adipose stem cells against cytotoxicity and increases transplanted cell survival in spinal cord injury. J Cell Mol Med. 2014;18:32643.

Hyun J, Grova M, Nejadnik H, Lo D, Morrison S, Montoro D, Chung M, Zimmermann A, Walmsley GG, Lee M, Daldrup-Link H, Wan DC, Longaker MT. Enhancing in vivo survival of adipose-derived stromal cells through Bcl-2 overexpression using a minicircle vector. Stem Cells Transl Med. 2013;2:690702.

Lee SH, Kim Y, Rhew D, Kuk M, Kim M, Kim WH, Kweon OK. Effect of the combination of mesenchymal stromal cells and chondroitinase ABC on chronic spinal cord injury. Cytotherapy. 2015;17:137483.

Hur JW, Cho TH, Park DH, Lee JB, Park JY, Chung YG. Intrathecal transplantation of autologous adipose-derived mesenchymal stem cells for treating spinal cord injury: a human trial. J Spinal Cord Med. 2016;39:65564.

Sanluis-Verdes A, Sanluis-Verdes N, Manso-Revilla MJ, Castro-Castro AM, Pombo-Otero J, Fraga-Marino M, Sanchez-Ibanez J, Domenech N, Rendal-Vazquez ME. Tissue engineering for neurodegenerative diseases using human amniotic membrane and umbilical cord. Cell Tissue Bank. 2017;18:115.

Caron I, Rossi F, Papa S, Aloe R, Sculco M, Mauri E, Sacchetti A, Erba E, Panini N, Parazzi V, Barilani M, Forloni G, Perale G, Lazzari L, Veglianese P. A new three dimensional biomimetic hydrogel to deliver factors secreted by human mesenchymal stem cells in spinal cord injury. Biomaterials. 2016;75:13547.

Bottai D, Scesa G, Cigognini D, Adami R, Nicora E, Abrignani S, Di Giulio AM, Gorio A. Third trimester NG2-positive amniotic fluid cells are effective in improving repair in spinal cord injury. Exp Neurol. 2014;254:12133.

Gao S, Ding J, Xiao HJ, Li ZQ, Chen Y, Zhou XS, Wang JE, Wu J, Shi WZ. Anti-inflammatory and anti-apoptotic effect of combined treatment with methylprednisolone and amniotic membrane mesenchymal stem cells after spinal cord injury in rats. Neurochem Res. 2014;39:154452.

Sankar V, Muthusamy R. Role of human amniotic epithelial cell transplantation in spinal cord injury repair research. Neuroscience. 2003;118:117.

Liu CB, Huang H, Sun P, Ma SZ, Liu AH, Xue J, Fu JH, Liang YQ, Liu B, Wu DY, Lu SH, Zhang XZ. Human umbilical cord-derived mesenchymal stromal cells improve left ventricular function, perfusion, and remodeling in a porcine model of chronic myocardial ischemia. Stem Cells Transl Med. 2016;5:100413.

Park SE, Jung NY, Lee NK, Lee J, Hyung B, Myeong SH, Kim HS, Suh YL, Lee JI, Cho KR, Kim DH, Choi SJ, Chang JW, Na DL. Distribution of human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) in canines after intracerebroventricular injection. Neurobiol Aging. 2016;47:192200.

Kang KS, Kim SW, Oh YH, Yu JW, Kim KY, Park HK, Song CH, Han H. A 37-year-old spinal cord-injured female patient, transplanted of multipotent stem cells from human UC blood, with improved sensory perception and mobility, both functionally and morphologically: a case study. Cytotherapy. 2005;7:36873.

Yao L, He C, Zhao Y, Wang J, Tang M, Li J, Wu Y, Ao L, Hu X. Human umbilical cord blood stem cell transplantation for the treatment of chronic spinal cord injury: electrophysiological changes and long-term efficacy. Neural Regen Res. 2013;8:397403.

Zhu H, Poon W, Liu Y, Leung GK, Wong Y, Feng Y, Ng SCP, Tsang KS, Sun DTF, Yeung DK, Shen C, Niu F, Xu Z, Tan P, Tang S, Gao H, Cha Y, So KF, Fleischaker R, Sun D, Chen J, Lai J, Cheng W, Young W. Phase I-II clinical trial assessing safety and efficacy of umbilical cord blood mononuclear cell transplant therapy of chronic complete spinal cord injury. Cell Transplant. 2016;25:192543.

Guo L, Rolfe AJ, Wang X, Tai W, Cheng Z, Cao K, Chen X, Xu Y, Sun D, Li J, He X, Young W, Fan J, Ren Y. Rescuing macrophage normal function in spinal cord injury with embryonic stem cell conditioned media. Mol Brain. 2016;9:48.

Salewski RP, Mitchell RA, Shen C, Fehlings MG. Transplantation of neural stem cells clonally derived from embryonic stem cells promotes recovery after murine spinal cord injury. Stem Cells Dev. 2015;24:3650.

Koch P, Opitz T, Steinbeck JA, Ladewig J, Brustle O. A rosette-type, self-renewing human ES cell-derived neural stem cell with potential for in vitro instruction and synaptic integration. Proc Natl Acad Sci U S A. 2009;106:322530.

Shin S, Mitalipova M, Noggle S, Tibbitts D, Venable A, Rao R, Stice SL. Long-term proliferation of human embryonic stem cell-derived neuroepithelial cells using defined adherent culture conditions. Stem Cells. 2006;24:12538.

Chang YW, Goff LA, Li H, Kane-Goldsmith N, Tzatzalos E, Hart RP, Young W, Grumet M. Rapid induction of genes associated with tissue protection and neural development in contused adult spinal cord after radial glial cell transplantation. J Neurotrauma. 2009;26:97993.

Moreno-Manzano V, Rodriguez-Jimenez FJ, Garcia-Rosello M, Lainez S, Erceg S, Calvo MT, Ronaghi M, Lloret M, Planells-Cases R, Sanchez-Puelles JM, Stojkovic M. Activated spinal cord ependymal stem cells rescue neurological function. Stem Cells. 2009;27:73343.

See more here:
Crosstalk between stem cell and spinal cord injury ...

Spinal Cord Stem Cells Comments Off on Crosstalk between stem cell and spinal cord injury … | January 5th, 2020

The reconstitution of the blood system in humans holds great therapeutic potential to treat many disorders, like blood cancers, sickle-cell anemia and others. Successful reconstitution requires the transplantation and engraftment of hematopoietic (or blood) stem cells (HSCs), which after reaching their niche, start producing all types of blood cells, including platelets, white and red blood cells.

In current clinical practice, this is carried out by infusing HSCs obtained from a matched donor who is immunologically compatible with the patient in need (allogeneic transplantation), or by the expansion of the patients own HSCs in the lab, and then re-infusing them back into the patient (ex-vivo, autologous transplantation).

However, the utility of both routes is currently limited by a number of factors. First, in the case of allogeneic transplantation, the scarcity of matched donors significantly increases the waiting time, which could be detrimental to the patient. Second, the ex vivo expansion of HSCs, whether allogeneic or autologous, has been a challenging task, due to the limited proliferative potential these cells exhibit in culture. These limitations have raised the need for other sources of HSCs that would alleviate the need for matched donors and yield functional HSCs in large quantities.

In 2007, Professor Shinya Yamanaka and colleagues demonstrated that somatic cells, like skin fibroblasts, could be reprogrammed back to a cellular state that resembled human embryonic stem cells (hESCs), which are a group of cells found in the blastocyst-stage human embryo and contribute solely to the development of the human fetus during pregnancy. The reprogrammed cells were termed, Induced Pluripotent Stem Cells (iPSCs).

In addition to their developmental potential, human ESCs and iPS cells display unlimited proliferative potential in culture, which makes them an ideal source of cells for regenerative medicine in general and for hematopoietic differentiation to obtain possibly unlimited quantities of HSCs. Therefore, there has been a growing interest to harness the potential of these cells for treating blood disorders.

However, advancement in deriving functional HSCs from human pluripotent stem cells has been slow. This has been attributed to incomplete understanding of the molecular mechanisms underlying normal hematopoiesis. In this review, the authors discuss the latest efforts to generate HSCs capable of long-term engraftment and reconstitution of the blood system from human pluripotent stem cells. Stem cell research has witnessed milestone achievements in this area in the last couple of years, the significance of which are discussed and analyzed in detail.

The authors additionally discuss two highly important families of transcription factors in the context of hematopoiesis and hematopoietic differentiation, the Homeobox (HOX) and GATA proteins. These are thought of as master regulators, in the sense of having numerous transcriptional targets, which upon activation, could elicit significant changes in cell identity. The authors hypothesize that precise temporal control of the levels of certain members of these families during hematopoietic differentiation could yield functional HSCs capable of long-term engraftment.

The authors conclude the review with a summary of future perspectives, in which they discuss how newly developed techniques, like the deactivated-Cas9 (dCas9) gene-expression control system, can be utilized during the course of hematopoietic differentiation of pluripotent stem cells for precise temporal control of the aforementioned master regulators to achieve functional HSCs.

Please Donate Today Did you enjoy this article? Then please consider donating today to ensure that Eurasia Review can continue to be able to provide similar content.

Read the original here:
Making Blood On Demand: How Far Have We Come? - Eurasia Review

Skin Stem Cells Comments Off on Making Blood On Demand: How Far Have We Come? – Eurasia Review | January 5th, 2020

There was a head-scratching moment when Martin Swales answered his front door and a priest handed him a letter.

The mystery was quickly solved. It contained a thank you note from someone whose life Martin had saved.

He knew his bone marrow had been given to someone called Jan and imagined it was a woman in Britain.

In fact the recipient was dad Jan Zemek 4,500 miles away in the US.

And Martins gift of life has led to an extraordinary 30-year bond between the pair, who are like blood brothers.

Jan named his second daughter Martina in honour of his hero and Martin is godfather to his third girl.

Retired welder Martin, 58, of Guisborough, North Yorks, said: Donating bone marrow didnt just save Jans life, it changed mine as well.

The first time I met Jan, I put my arms around him and he hugged me back.

It felt natural, like I was welcoming my brother. It feels like our two families have become one.

They each have three grown-up children and have visited each other for baptisms, graduations, and weddings.

Martin recently went to Switzerland, where Jan lives with his family, to celebrate 30 years since the transplant and present his blood brother with a Walk of Fame plaque.

It includes the touching message: Stood strong, fought hard, and won. You are a survivor.

The mens amazing and heart-warming story dates from 1986 when Martin joined the Anthony Nolan stem cell register after an appeal to save two girls living in the North East.

He was not a match for the girls but in 1989 was called by the register because he could be for Jan.

Martin said: It was quite a shock because Id pretty much forgotten about the register. They told me I was a possible match for someone and what was involved. I said yes straight away. I wanted to help if I could.

Despite the discomfort, Martin gave bone marrow from his hip at a clinic in Harley Street that August. Doctors extracted it from inside his hip using a long needle. Today most donations are no more invasive than giving blood.

Martin spent two nights in hospital. He said: It doesnt take long but at the time I was suffering from sciatica so I think I found it a bit more painful than most. It was an uncomfortable journey home on the train.Anthony Nolan covered the cost of the trip.

Jan, a 27-year-old dad, was diagnosed with leukaemia in 1987. Initially doctors kept the news from him as no treatment was available in the Czech Republic, where he lived.

Jan said: I was diagnosed one year after the Chernobyl tragedy, weve never known if that radiation was to blame for my cancer. I suddenly grew very tired, nobody knew the reason.

I didnt know how sick I was because the doctors wouldnt tell me.

My wife, who was then my girlfriend, went to the same doctors and they told her, Dont marry this guy, dont have children with him. He is going to die in two years.

But Radka ignored their warning and insisted on marrying Jan in 1987.

His only hope was a bone marrow transplant. Weeks later he left for the US with his dad, who planned to be his donor.

Jan said: A few months earlier, I read in the paper the opera singer Jos Carreras was diagnosed with a similar blood disease and was going to the same US centre for a transplant.

They arrived with less than 40 in their pockets and discovered a transplant from his dad would give Jan only a 15 per cent chance of survival.

Instead doctors advised them to find a donor. It took two years and 10,000 to test potential donors before they found a perfect match in Martin.

By then Jan and Radka had become parents to their first daughter, Jana.

Jan needed to raise more than 100,000 to fund the transplant.

He said: It was such a huge amount of money to raise but when you are dying you have no choice.

There were 12 rival local radio stations but they all got together to run a joint appeal, which they broadcast at the same time. It was incredible.

Jan did a sponsored run, gave talks about his ordeal to church congregations to request donations, and wrote to celebrities, especially those with links to the Czech Republic.

Donald Trump s ex-wife Ivana gave 1,000, as did One Flew Over the Cuckoos Nest director Milos Forman. Jan said: The response was crazy. So many people donated 20 dollars or 50.

Martins bone marrow was flown to the Fred Hutchinson Cancer Research Center in Seattle, where Jan was waiting in an isolation room.

He had been blasted with chemo and radiotherapy so his immune system would not attack Martins transplanted cells.

Normally, under strict anonymity rules to protect donor and recipient, Martin and Jan would have been unable to contact each other for years.

But a priest from the North East of England working at the hospital recognised Martins address when the bag of bone marrow arrived.

He offered to take a photo of Jan, a thank you letter, and a Czech garnet stone to Martin when he returned home in 1990.

Martin said: I was stunned. I had no idea my bone marrow had travelled so far. Knowing Id helped a young father, just like me, brought home how important it was and how easily it could have been me waiting for a stranger to save my life.

I wrote straight back. The priest also brought a letter from a couple whose daughter was in the same hospital.

Her transplant didnt work. Sadly she died, but they wrote to thank me for saving Jan. Responding to them was much harder. How do you find the right words?

Martin and Jan kept in touch. When Jans second daughter was born in 1991, he and Radka named her after Martin.

Jan said: How do you repay someone who saved your life? Naming our daughter after Martin was our way of showing him we would never forget what he did for us.

Hes not just the man who saved my life. He is a nice guy. Thats why were so close.

Video Unavailable

Click to playTap to play

Play now

Jan, 59, and his family moved to Switzerland, where he landed a job with a sports marketing firm that works with World Athletics.

In 1992 his job brought him to Crystal Palace in South London and he spent a few days with Martin and family.

Jans youngest daughter Michaela was born in 1995 and he invited Martin and his family to Switzerland for the baptism and asked him to be godfather.

The two families continued to visit each other and holidayed together in the Czech capital Prague. When Jans eldest, Jana, was studying at Newcastle University, she regularly spent weekends with Martin and his wife Tracey.

Martin said: It meant so much to visit Jan for the 30 anniversary of his transplant earlier this year.

"They showed us the sights and we went up the mountains. It was brilliant. I could never have imagined this when I joined the stem cell register all those years ago.

He added: I hope Martin and I will be able to celebrate another anniversary together in ten years.

The Anthony Nolan register matches potential donors to patients needing stem cell transplants and does vital research. To join, donate or find out more, see anthonynolan.org .

Read the original:
Bone marrow donor's amazing 30 year bond with man he saved - Mirror Online

Bone Marrow Stem Cells Comments Off on Bone marrow donor’s amazing 30 year bond with man he saved – Mirror Online | January 5th, 2020

IN the summer of 2019, a mother in Nashville, Tennessee in the United States, with a seemingly incurable genetic disorder finally found an end to her suffering by editing her genome.

Victoria Grays recovery from sickle cell disease, which had caused her painful seizures, came in a year of breakthroughs in one of the hottest areas of medical research gene therapy.

I have hoped for a cure since I was about 11, the 34-year-old said.

Since I received the new cells, I have been able to enjoy more time with my family without worrying about pain or an out-of-the-blue emergency.

Over several weeks, Grays blood was drawn so that doctors could get to the cause of her illness stem cells from her bone marrow that were making deformed red blood cells.

The stem cells were sent to a Scottish laboratory, where their DNA was modified using Crispr/Cas9 pronounced Crisper a new tool informally known as a molecular scissors.

The genetically-edited cells were transfused back into Grays veins and bone marrow. A month later, she was producing normal blood cells.

Medics warn that caution is necessary, but theoretically, she has been cured.

This is one patient. This is early results. We need to see how it works out in other patients, said her doctor, Haydar Frangoul, at the Sarah Cannon Research Institute in Nashville.

But these results are really exciting.

In Germany, a 19-year-old woman was treated with a similar method for a different blood disease beta thalassemia.

She had previously needed 16 blood transfusions per year. Nine months later, she is completely free of that burden.

For decades, the DNA of living organisms such as corn and salmon has been modified. But Crispr, invented in 2012, made gene editing more widely accessible.

It is much simpler than preceding technology, cheaper and easy to use in small labs.

The technique has given new impetus to the perennial debate over the wisdom of humanity manipulating life itself.

Its all developing very quickly, said French geneticist Emmanuelle Charpentier, one of Crisprs inventors and the co-founder of Crispr Therapeutics, the biotech company conducting the clinical trials involving Gray and the German patient.

Gene cures

Crispr was the latest breakthrough in a year of great strides in gene therapy, a medical adventure that started three decades ago, when the first TV telethons were raising money for children with muscular dystrophy.

Scientists practising the technique insert a normal gene into cells containing a defective gene.

It does the work the original could not, such as making normal red blood cells in Grays case or making tumour-killing super white blood cells for a cancer patient.

Crispr goes even further: instead of adding a gene, the tool edits the genome itself.

After decades of research and clinical trials on a genetic fix to genetic disorders, 2019 saw a historic milestone: approval to bring to market the first gene therapies for a neuromuscular disease in the US and a blood disease in the European Union.

They join several other gene therapies bringing the total to eight approved in recent years to treat certain cancers and an inherited blindness.

Serge Braun, the scientific director of the French Muscular Dystrophy Association, sees 2019 as a turning point that will lead to a medical revolution.

Twenty-five, 30 years, thats the time it had to take, he said. It took a generation for gene therapy to become a reality. Now, its only going to go faster.

Just outside Washington, at the US National Institutes of Health (NIH), researchers are also celebrating a breakthrough period.

We have hit an inflection point, said US NIHs associate director for science policy Carrie Wolinetz.

These therapies are exorbitantly expensive, however, costing up to US$2 million (RM8.18 million) meaning patients face grueling negotiations with their insurance companies.

They also involve a complex regimen of procedures that are only available in wealthy countries.

Gray spent months in hospital getting blood drawn, undergoing chemotherapy, having edited stem cells reintroduced via transfusion and fighting a general infection.

You cannot do this in a community hospital close to home, said her doctor.

However, the number of approved gene therapies will increase to about 40 by 2022, according to Massachusetts Institute of Technology (MIT) researchers.

They will mostly target cancers and diseases that affect muscles, the eyes and the nervous system.

In this Oct 10, 2018, photo, He speaks during an interview at his laboratory in Shenzhen, China. The scientist was recently sentenced to three years in prison for practicing medicine illegally and fined 3 million yuan (RM1.76 million). AP

Bioterrorism potential

Another problem with Crispr is that its relative simplicity has triggered the imaginations of rogue practitioners who dont necessarily share the medical ethics of Western medicine.

In 2018 in China, scientist He Jiankui triggered an international scandal and his excommunication from the scientific community when he used Crispr to create what he called the first gene-edited humans.

The biophysicist said he had altered the DNA (deoxyribonucleic acid) of human embryos that became twin girls Lulu and Nana.

His goal was to create a mutation that would prevent the girls from contracting HIV (human immunodeficiency virus), even though there was no specific reason to put them through the process.

That technology is not safe, said Kiran Musunuru, a genetics professor at the University of Pennsylvania, explaining that the Crispr scissors often cut next to the targeted gene, causing unexpected mutations.

Its very easy to do if you dont care about the consequences, he added.

Despite the ethical pitfalls, restraint seems mainly to have prevailed so far.

The community is keeping a close eye on Russia, where biologist Denis Rebrikov has said he wants to use Crispr to help deaf parents have children without the disability.

There is also the temptation to genetically edit entire animal species, e.g. malaria-causing mosquitoes in Burkina Faso or mice hosting ticks that carry Lyme disease in the US.

The researchers in charge of those projects are advancing carefully however, fully aware of the unpredictability of chain reactions on the ecosystem.

Charpentier doesnt believe in the more dystopian scenarios predicted for gene therapy, including American biohackers injecting themselves with Crispr technology bought online.

Not everyone is a biologist or scientist, she said.

And the possibility of military hijacking to create soldier-killing viruses or bacteria that would ravage enemies crops?

Charpentier thinks that technology generally tends to be used for the better.

Im a bacteriologist -- weve been talking about bioterrorism for years, she said. Nothing has ever happened. AFP Relaxnews

We're sorry, this article is unavailable at the moment. If you wish to read this article, kindly contact our Customer Service team at 1-300-88-7827. Thank you for your patience - we're bringing you a new and improved experience soon!

Article type: metered

User Type: anonymous web

User Status:

Campaign ID: 7

Cxense type: free

User access status: 3

See the original post:
Gene editing breakthroughs that cured genetic diseases in 2019 - The Star Online

Bone Marrow Stem Cells Comments Off on Gene editing breakthroughs that cured genetic diseases in 2019 – The Star Online | January 5th, 2020

DURHAM Hemophilia. Cystic fibrosis. Duchenne muscular dystrophy. Huntingtons disease. These are just a few of the thousands of disorders caused by mutations in the bodys DNA. Treating the root causes of these debilitating diseases has become possible only recently, thanks to the development of genome editing tools such as CRISPR, which can change DNA sequences in cells and tissues to correct fundamental errors at the source but significant hurdles must be overcome before genome-editing treatments are ready for use in humans.

Enter the National Institutes of Health Common FundsSomatic Cell Genome Editing (SCGE)program, established in 2018 to help researchers develop and assess accurate, safe and effective genome editing therapies for use in the cells and tissues of the body (aka somatic cells) that are affected by each of these diseases.

Todaywith three ongoing grants totaling more than $6 million in research fundingDuke University is tied with Yale University, UC Berkeley and UC Davis for the most projects supported by the NIH SCGE Program.

In the 2019 SCGE awards cycle, Charles Gersbach, the Rooney Family Associate Professor of Biomedical Engineering, and collaborators across Duke and North Carolina State University received two grants: the first will allow them to study how CRISPR genome editing affects engineered human muscle tissues, while the second project will develop new CRISPR tools to turn genes on and off rather than permanently alter the targeted DNA sequence. This work builds on a 2018 SCGE grant, led by Aravind Asokan, professor and director of gene therapy in the Department of Surgery, which focuses on using adeno-associated viruses to deliver gene editing tools to neuromuscular tissue.

Duke engineers improve CRISPR genome editing with biomedical tails

There is an amazing team of engineers, scientists and clinicians at Duke and the broader Research Triangle coalescing around the challenges of studying and manipulating the human genome to treat diseasefrom delivery to modeling to building new tools, said Gersbach, who with his colleagues recently launched the Duke Center for Advanced Genomic Technologies (CAGT), a collaboration of the Pratt School of Engineering, Trinity College of Arts and Sciences, and School of Medicine. Were very excited to be at the center of those efforts and greatly appreciate the support of the NIH SCGE Program to realize this vision.

For their first grant, Gersbach will collaborate with fellow Duke biomedical engineering faculty Nenad Bursac and George Truskey to monitor how genome editing affects engineered human muscle tissue. Through their new project, the team will use human pluripotent stem cells to make human muscle tissues in the lab, specifically skeletal and cardiac muscle, which are often affected by genetic diseases. These systems will then serve as a more accurate model for monitoring the health of human tissues, on-target and off-target genome modifications, tissue regeneration, and possible immune responses during CRISPR-mediated genome editing.

Duke researchers: Single CRISPR treatment provides long-term benefits in mice

Currently, most genetic testing occurs using animal models, but those dont always accurately replicate the human response to therapy, says Truskey, the Goodson Professor of Biomedical Engineering.

Bursac adds, We have a long history of engineering human cardiac and skeletal muscle tissues with the right cell types and physiology to model the response to gene editing systems like CRISPR. With these platforms, we hope to help predict how muscle will respond in a human trial.

Gersbach will work with Tim Reddy, a Duke associate professor of biostatistics and bioinformatics, and Rodolphe Barrangou, the Todd R. Klaenhammer Distinguished Professor in Probiotics Research at North Carolina State University, on the second grant. According to Gersbach, this has the potential to extend the impact of genome editing technologies to a greater diversity of diseases, as many common diseases, such as neurodegenerative and autoimmune conditions, result from too much or too little of certain genes rather than a single genetic mutation. This work builds on previous collaborations between Gersbach, Barrangou and Reddy developing bothnew CRISPR systems for gene regulationandto regulate the epigenome rather than permanently delete DNA sequences.

Aravind Asokan leads Dukes initial SCGE grant, which explores the the evolution of next generation of adeno-associated viruses (AAVs), which have emerged as a safe and effective system to deliver gene therapies to targeted cells, especially those involved in neuromuscular diseases like spinal muscular atrophy, Duchenne muscular dystrophy and other myopathies. However, delivery of genome editing tools to the stem cells of neuromuscular tissue is particularly challenging. This collaboration between Asokan and Gersbach builds on their previous work in usingAAV and CRISPR to treat animal models of DMD.

We aim to correct mutations not just in the mature muscle cells, but also in the muscle stem cells that regenerate skeletal muscle tissue, explainsAsokan. This approach is critical to ensuring long-term stability of genome editing in muscle and ultimately we hope to establish a paradigm where our cross-cutting viral evolution approach can enable efficient editing in multiple organ systems.

Click through to learn more about theDuke Center for Advanced Genomic Technologies.

(C) Duke University

Link:
Duke researchers land $6M in federal grants to advance gene editing - WRAL Tech Wire

Cardiac Stem Cells Comments Off on Duke researchers land $6M in federal grants to advance gene editing – WRAL Tech Wire | January 5th, 2020

If your new year's resolutions includeorganizingthe skincare products taking over your medicine cabinet, checking the expiration dates on your makeup, and tossing those almostempty shampoo and conditioner bottles that have been taking up space in your shower since 2018, I've got some bad news for you:You're probably going to hit pause on reassessing your beauty routineuntil February.Thanks to January'snew beauty product launches, your collection is definitelygoing to grow this month.

Tatcha'sinnovative, travel-friendly serum stick will be the one skincare product you pack for every trip you take, while OLEHENRIKSEN'scleanseris like a refreshing fruit juice for your face. As for makeup, IT Cosmetics has created an uber-comfortable matte lipstick, and Hourglass' concealer is a long-wear formula that doesnotcrease.

Get exclusive discounts, celeb inspo, & more.

RELATED:All the Products Our Beauty Editors Loved Using in December

When it comes to haircare, the drugstore is the place to be. Celebrity hairstylist Kristin Ess has added fragrance-free products to her affordable namesake haircare line, and Pantenejust expanded its Gold Series Collection for natural hair with a hydrating, protective cream specifically formulated for braided styles.

While thesenew haircare, skincare, and makeup products are exciting, there's no question that having so many options can be overwhelming. That's why we've done the work topickout the top 20 worth spending your hard-earned coin on.

VIDEO:What Every Beginner Needs to Have in Their Makeup Kit

Read more from the original source:
The 20 Best New Beauty Products That'll Help You Kick 2020 Off Right - InStyle

Skin Stem Cells Comments Off on The 20 Best New Beauty Products That’ll Help You Kick 2020 Off Right – InStyle | January 4th, 2020

Fertility expert Marcelle Cedars discusses the future of reproductive medicine.

By Ariel Bleicher UCSF Magazine

Advances in medicine and public health have dramatically extended the human lifespan. Our hearts, lungs, and other vital organs now last 79 years on average. For women, however, the ovaries which stop functioning at an average 51 years remain a stubborn exception. That may soon change, says fertility expert Marcelle Cedars, MD, during a conversation on the future of reproductive medicine.

There are two aspects. One is qualitative. As a woman ages, the quality of her eggs meaning their capacity to make a healthy baby declines. We understand very little about what causes this decline. If we understood that process better, we could dramatically impact fertility success rates.

The other aspect is quantitative. Women are born with a finite number of eggs, and they lose those eggs throughout their lifetime. In fact, that rapid decline in egg numbers starts even before birth. Theres a peak in utero of five to six million eggs. At birth, a woman has only about 1.5 million eggs; at the time of puberty, about 500,000. Through genetics research, were learning that the rate of this decline and the variability from woman to woman is largely driven by ones genes.

Exactly. But what if we could use your genetics and other biological data to understand your unique fertility risks and develop therapies specifically for you or for groups of women like you? This approach is called precision medicine. It has made a huge impact in the world of cancer in terms of improving survival rates. But in the field of reproductive health, precision medicine is still in its infancy.

Potentially. If we can pinpoint the mechanisms of ovarian aging, we could potentially develop a therapy that enables you to still have healthy eggs into your 50s, possibly your 60s. But just because we can do something doesnt always mean we should do it. We know that as women get older, pregnancies are more complicated. You have higher risk for things like high blood pressure, diabetes, and preterm labor. There are many downstream implications, both for the mothers health and the childs.

I dont think the goal should be to enable women to get pregnant into their 60s. Rather, we want women to have the best reproductive lifespan possible to be able to have children when they want to and to not have children when they don't want to and to have a society that supports women across that spectrum.

Were starting to believe that some of the same cellular mechanisms that underlie general aging might also control ovarian aging. This revelation makes the ovary even more interesting to study because its early demise could be a unique window into the bodys aging process. If we can identify cases of accelerated ovarian aging and understand the underlying causes, we might be able to improve not only reproductive function in individual women but also overall health and longevity for all women.

Samesex couples having genetically related children is probably on the horizon. Scientists are learning how to take skin cells or blood cells and turn them into stem cells, which can then be turned into eggs or sperm. Thats not science fiction; its already happening. We just need to figure out how to do it well and safely in humans.

Well probably also see germline engineering. Thats the process of editing genes in reproductive cells or embryos. It has the potential to cure disease before birth. This technology is here. But will society be ready to accept it? A lot of questions need to be answered before its put to use. In addition to technical hurdles, there are innumerable social issues. For instance, if we can eliminate a certain disease, will there be less focus on treatments for people who still have the disease? And what about access to care and social equity? Who would be able to afford these procedures? How will they be applied?

Restrictions are currently preventing the U.S. government from funding research that involves the manipulation of human embryos. As a result, funding for reproductive science is low, which has driven a lot of experts out of academia. If we want to see a revolution in reproductive health, like whats happening with precision cancer medicine, we need to invest in the development of scientific knowledge that will move this field forward.

Original post:
Research Jan. 2, 2020 The End of Infertility Is in Sight - UCSF News Services

Skin Stem Cells Comments Off on Research Jan. 2, 2020 The End of Infertility Is in Sight – UCSF News Services | January 4th, 2020

The reconstitution of the blood system in humans holds great therapeutic potential to treat many disorders, like blood cancers, sickle-cell anemia and others. Successful reconstitution requires the transplantation and engraftment of hematopoietic (or blood) stem cells (HSCs), which after reaching their niche, start producing all types of blood cells, including platelets, white and red blood cells.

In current clinical practice, this is carried out by infusing HSCs obtained from a matched donor who is immunologically compatible with the patient in need (allogeneic transplantation), or by the expansion of the patient's own HSCs in the lab, and then re-infusing them back into the patient (ex-vivo, autologous transplantation). However, the utility of both routes is currently limited by a number of factors. First, in the case of allogeneic transplantation, the scarcity of matched donors significantly increases the waiting time, which could be detrimental to the patient. Second, the ex vivo expansion of HSCs, whether allogeneic or autologous, has been a challenging task, due to the limited proliferative potential these cells exhibit in culture. These limitations have raised the need for other sources of HSCs that would alleviate the need for matched donors and yield functional HSCs in large quantities.

In 2007, Professor Shinya Yamanaka and colleagues demonstrated that somatic cells, like skin fibroblasts, could be reprogrammed back to a cellular state that resembled human embryonic stem cells (hESCs), which are a group of cells found in the blastocyst-stage human embryo and contribute solely to the development of the human fetus during pregnancy. The reprogrammed cells were termed, Induced Pluripotent Stem Cells (iPSCs). In addition to their developmental potential, human ESCs and iPS cells display unlimited proliferative potential in culture, which makes them an ideal source of cells for regenerative medicine in general and for hematopoietic differentiation to obtain possibly unlimited quantities of HSCs. Therefore, there has been a growing interest to harness the potential of these cells for treating blood disorders.

However, advancement in deriving functional HSCs from human pluripotent stem cells has been slow. This has been attributed to incomplete understanding of the molecular mechanisms underlying normal hematopoiesis. In this review, the authors discuss the latest efforts to generate HSCs capable of long-term engraftment and reconstitution of the blood system from human pluripotent stem cells. Stem cell research has witnessed milestone achievements in this area in the last couple of years, the significance of which are discussed and analyzed in detail.

The authors additionally discuss two highly important families of transcription factors in the context of hematopoiesis and hematopoietic differentiation, the Homeobox (HOX) and GATA proteins. These are thought of as master regulators, in the sense of having numerous transcriptional targets, which upon activation, could elicit significant changes in cell identity. The authors hypothesize that precise temporal control of the levels of certain members of these families during hematopoietic differentiation could yield functional HSCs capable of long-term engraftment.

The authors conclude the review with a summary of future perspectives, in which they discuss how newly developed techniques, like the deactivated-Cas9 (dCas9) gene-expression control system, can be utilized during the course of hematopoietic differentiation of pluripotent stem cells for precise temporal control of the aforementioned master regulators to achieve functional HSCs.

More:
Making blood on demand: How far have we come? - Science Codex

Skin Stem Cells Comments Off on Making blood on demand: How far have we come? – Science Codex | January 4th, 2020

Victoria Beckham aims to "create a brand of the future" with Victoria Beckham Beauty.

The former Spice Girl launched her eponymous beauty brand last year, later expanding her label to include skincare, and the 45-year-old fashion designer says her intention was to create products that are sustainable and not made from toxic formulas, whilst being "inclusive" for all skin tones.

The mother-of-four told the February issue of Harper's Bazaar UK: "I've been obsessed with make-up and skincare and wellness for longer than I can remember."But I couldn't find what I wanted - clean beauty.

"What is that, even? It's a real grey area.

"I wanted to create a brand of the future - focusing on what's in the formulas but then also sustainability.

"The other thing that was key was making sure it was very inclusive - whether it's make-up or skincare, this is for every skin type and tone, and for both women and men."

In November, Victoria - who has Brooklyn, 20, Romeo, 17, Cruz, 14 and Harper, eight, with retired soccer star husband David Beckham - released her Cell Rejuvenating Priming Moisturiser in collaboration with Professor Augustinus Bader, the German stem-cell scientist behind The Cream, which was named as one of 2019's most popular skincare products.

Bader's product features a patented Trigger Factor Complex that works to jumpstart your skin's repair and renewal functions to heal skin faster and in turn, improve the appearance of fine lines and wrinkles, and as a fan of the cream herself, Victoria was thrilled to work with the scientist.

She said: "It's been a dream to develop, with Augustinus, a priming moisturiser that works to improve the health of my skin and gives me that fresh, natural glow that I love."

The priming moisturiser is a hybrid product that combines primer with moisturiser, and is inspired by Victoria's own skincare routine.

Victoria's product implements Bader's Trigger Factor Complex technology, as well as the lipids, vitamins, and amino acids found in his original cream, but with the added benefit of also smoothing skin so it's prepped for make-up application.

Bader explained: "It's the first priming moisturiser of its kind to care for your skin cells while also preparing your skin for makeup application."

The cream has a lightweight texture that can be work alone to give skin a radiant finish or under make-up, which according to Victoria, "will enhance your products."

Read the original:
Victoria Beckham Dreams That her Beauty Line Will Become 'Brand of the Future' - Al Bawaba

Skin Stem Cells Comments Off on Victoria Beckham Dreams That her Beauty Line Will Become ‘Brand of the Future’ – Al Bawaba | January 4th, 2020

HUNTINGTON Serucell Corporation, a cosmeceutical company based in Huntington, has developed the worlds only dual-cell technology to create and produce anti-aging skincare products, and they did it in Huntington.

Serucell KFS Cellular Protein Complex Serum is made start to finish at Serucells laboratory on the south side of Huntington.

This has been one of the best kept secrets in West Virginia, said Cortland Bohacek, executive chairman and a co-founder of Serucell Corporation.

The company soft launch was in September 2018 at The Greenbrier Spas. The Official online launch was April 2019 and is getting exposure with some well known sellers like Neiman Marcus, local dermatologist and plastic surgeons offices and several other retail locations from New York to California. It is also sold online at serucell.com.

One person that has tried the product is Jennifer Wheeler, who is also a Huntington City Council member.

As a consumer I have an appreciation of the quality of the product and the results Ive seen using it, she said. It has been transformative for my skin and seems like its success will be transformative for our city as well.

She said Serucell and the people behind it are impressive on every level.

In my role on council, Im especially grateful for the companys conscious effort to stay and grow in our city, Wheeler said.

A one-ounce bottle of the serum costs $225. The recommended usage is twice per day and it will last on average of about six weeks.

Serucells active ingredient is called KFS (Keratinocyte Fibroblast Serum), which is made up of more than 1,500 naturally derived super proteins, collagens, peptides and signaling factors that support optimal communication within the cellular makeup of your skin.

This is the first and only dual-cell technology that optimizes hydration and harnesses the power of both keratinocytes and fibroblasts, two essential contributors to maintaining healthy skin by supporting natural rejuvenation of aging skin from the inside out, said Jennifer Hessel, president and CEO of the company.

When applied to the skin, KFS helps boost the skins natural ability to support new collagen and elastin, strengthen the connection and layer of support between the upper and lower layers of your skin. The result, over time is firmer, plumper and smoother skin, according to Hessel.

Why it works so naturally with your skin is because it is natural, Hessel said. These proteins play an important role in strengthening the bond between the layers of your skin, and thats where the re-boot happens.

KFS is the creation of Dr. Walter Neto, Serucells chief science officer and co-founder of the company. Neto is both a physician and a research scientist, specializing in the field of regenerative medicine with an emphasis on skin healing and repair.

Neto said Serucells technology unlocks the key to how our cells communicate and harnesses the signaling power actions to produce the thousands of bioactive proteins necessary to support the skins natural rejuvenation.

Originally from Brazil, Neto studied at Saint Matthews University and completed his clinical training in England. His clinical research on stem-cell cancer therapies, bone and tissue engineering and wound and burn healing led to his discovery in cell-to-cell communication, and ultimately the creation of Serucells KFS Cellular Protein Complex Serum.

Neto received multiple patents for the production method of Serucell KFS Serum.

Neto lives in Huntington with his wife and four golden retrievers.

Neto works alongside his longtime friend, Dr. Brett Jarrell.

I have known Brett since I was 18 years old, Neto said.

Jarrell practices emergency medicine in Ashland, Kentucky, and oversees all aspects of quality control for Serucell. He received his bachelors degree in biology from Wittenberg University, his masters degree in biology from Marshall University and his medical degree from the Marshall University School of Medicine. Jarrell completed his residency at West Virginia University and is board certified by the American Board of Emergency Medicine.

Jarrell has served as a clinical instructor of emergency medicine at the Marshall School of Medicine, president of the West Virginia chapter of the American College of Emergency Medicine and he has published a number of peer-reviewed journal articles on stroke research.

Jarrell also lives in Huntington.

Another co-founder of the company is Dr. Tom McClellan.

McClellan is Serucells chief medical officer and director of research and is a well-respected plastic and reconstructive surgeon with a private practice, McClellan Plastic Surgery, in Morgantown.

McClellan completed his plastic and reconstructive surgery training at the world-renowned Lahey Clinic Foundation, a Harvard Medical School and Tufts Medical School affiliate in Boston, Massachusetts. While in Boston, he worked at Lahey Medical Center, Brigham and Womens Hospital, as well as at the Boston Childrens Hospital. McClellan is board certified by the American Board of Plastic Surgery.

In addition to his practice and role at Serucell, McClellan utilizes his surgical skills through pro bono work with InterplastWV, a non-profit group that provides comprehensive reconstructive surgery to the developing world. He has participated in surgical missions to Haiti, Peru and the Bahamas.

McClellan lives in Morgantown with his family.

All three doctors here have strong connections to West Virginia and we didnt want to leave, Neto said. We all want to give back to West Virginia, so that is the main reason we have our business here in Huntington.

We are building a company we believe can make a difference in the community, Hessel added. Our goal is to grow Serucell and build our brand right here in Huntington. There is a pool of untapped talent here in Huntington. When we expand our business here, we can provide another reason for young people to be able to stay and grow their careers, whether it is in science, operations or manufacturing. The team is a pretty excited to make an impact in the community where it all started.

Hessel decline to give sales numbers, but said the business has been growing each year since the product was introduced. She also declined to give the number of employees at the facility, but did say it has sales representatives across the country.

For more information, visit serucell.com.

Original post:
Local firm adds a new wrinkle to anti-aging products - The Coal Valley News

Skin Stem Cells Comments Off on Local firm adds a new wrinkle to anti-aging products – The Coal Valley News | January 4th, 2020

Gene editing Researchers will work frenzied to evaluate the potential of a new version of the Crispr technique, known as Prime editing, unveiled in October to a lot of fanfare. Prime editing was proposed to have the ability to rectify about 89 percent of the 75,000 adverse genetic mutations that lay behind hereditary diseases, such as cystic fibrosis and sickle cell disease of the blood disorder.

3D rockets Last year, major steps in rocket science were made, with successful testing of a number of 3D-printed engine prototypes.

Stem cells Scientists around the world are collaborating on trials of potential stem cell treatments for blindness, spinal cord injury, heart failure, diabetes, Parkinsons disease and lung cancer, and some of the first findings are expected to be available later this year. Embryonic or pluripotent stem cells have immense therapeutic promise because they can grow into any of the bodys roughly 220 adult, specialized cells, from insulin-making pancreatic cells to the brains nerve cells.

Mars The ExoMars programs 2020 mission, if all goes to plan, will bring to the surface of Mars a European rover and a Russian vehicle. ExoMars will be the first mission to incorporate the ability to move across the planets surface and reach into the ability to study Mars.

Nasa is setting up a separate mission to research Mars habitability and prepare for future human missions. Smart needle Researchers are hoping to get an early indication as to whether a new smart needle they have developed can detect cancer successfully in seconds.

The researchers have so far concentrated on lymphoma, but said the procedure could also be used later down the line to treat other aspects of the disease, such as breast and prostate cancer. The smart needle uses light to near-instantly classify cancerous tissues. Using a Raman spectroscopy procedure, the Optical Biopsy tests the tissue-scattered light when a laser embedded in the needle shines on it.

The light scatters slightly from healthy tissues than from diseased tissues, which ensures that doctors will immediately make a decision. Developed by Toyota, the Human Support Robot and Delivery Support Robot will be used in tandem.

The new plant is designed to handle 5,000 tons of waste a day, burning the waste.

Excerpt from:
It can be difficult to forecast technological and scientific changes, but this is what will happen in 2020 - Medical Herald

Spinal Cord Stem Cells Comments Off on It can be difficult to forecast technological and scientific changes, but this is what will happen in 2020 – Medical Herald | January 4th, 2020

In theglobalstem cells marketa sizeable proportion of companies are trying to garner investments from organizations based overseas. This is one of the strategies leveraged by them to grow their market share. Further, they are also forging partnerships with pharmaceutical organizations to up revenues.

In addition, companies in the global stem cells market are pouring money into expansion through multidisciplinary and multi-sector collaboration for large scale production of high quality pluripotent and differentiated cells. The market, at present, is characterized by a diverse product portfolio, which is expected to up competition, and eventually growth in the market.

Some of the key players operating in the global stem cells market are STEMCELL Technologies Inc., Astellas Pharma Inc., Cellular Engineering Technologies Inc., BioTime Inc., Takara Bio Inc., U.S. Stem Cell, Inc., BrainStorm Cell Therapeutics Inc., Cytori Therapeutics, Inc., Osiris Therapeutics, Inc., and Caladrius Biosciences, Inc.

Request PDF Sample of Stem Cells Market Report @https://www.transparencymarketresearch.com/sample/sample.php?flag=S&rep_id=132

As per a report by Transparency Market Research, the global market for stem cells is expected to register a healthy CAGR of 13.8% during the period from 2017 to 2025 to become worth US$270.5 bn by 2025.

Depending upon the type of products, the global stem cell market can be divided into adult stem cells, human embryonic stem cells, induced pluripotent stem cells, etc. Of them, the segment of adult stem cells accounts for a leading share in the market. This is because of their ability to generate trillions of specialized cells which may lower the risks of rejection and repair tissue damage.

Depending upon geography, the key segments of the global stem cells market are North America, Latin America, Europe, Asia Pacific, and the Middle East and Africa. At present, North America dominates the market because of the substantial investments in the field, impressive economic growth, rising instances of target chronic diseases, and technological progress. As per the TMR report, the market in North America will likely retain its dominant share in the near future to become worth US$167.33 bn by 2025.

Enquiry for Discount on Stem Cells Market Report @https://www.transparencymarketresearch.com/sample/sample.php?flag=D&rep_id=132

Investments in Research Drives Market

Constant thrust on research to broaden the utility scope of associated products is at the forefront of driving growth in the global stem cells market. Such research projects have generated various possibilities of different clinical applications of these cells, to usher in new treatments for diseases.Since cellular therapies are considered the next major step in transforming healthcare, companies are expanding their cellular therapy portfolio to include a range of ailments such as Parkinsons disease, type 1 diabetes, spinal cord injury, Alzheimers disease, etc.

The growing prevalence of chronic diseases and increasing investments of pharmaceutical and biopharmaceutical companies in stem cell research are the key driving factors for the stem cells therapeutics market. The growing number of stem cell donors, improved stem cell banking facilities, and increasing research and development are other crucial factors serving to propel the market, explains the lead analyst of the report.

More here:
Stem Cells Market Key Opportunities and Forecast up to 2025 - AnalyticSP

Spinal Cord Stem Cells Comments Off on Stem Cells Market Key Opportunities and Forecast up to 2025 – AnalyticSP | January 4th, 2020

There is also another option on the table: a technology called haplo-identical, where they could use the stem cells from my brother, who is a 50 per cent match.

But it shouldnt have been this hard to find a match, and thats whyI started my campaign to sign more people up to the transplant list.I want to make a difference for other people who have to go through this.

If I dont make it, I want to leave a legacy that the children can look at when theyre older and know that Mummy did everything she could to fight this thing. There can only be one winner with this disease, and it needs to be me.

As told to Jessica Salter

Leukaemia Care is one of three charities supported by this years Telegraph Christmas Charity Appeal. Our others are Wooden Spoon, which works with the rugby community to raise money for disabled and disadvantaged children,and The Silver Line, a telephone support service for lonely elderly people. To donate,visit telegraph.co.uk/charity or call 0151 284 1927 before the end of January

Read more:
My agonising two-year wait for a stem-cell donor after being diagnosed with leukaemia - The Telegraph

Bone Marrow Stem Cells Comments Off on My agonising two-year wait for a stem-cell donor after being diagnosed with leukaemia – The Telegraph | January 4th, 2020

Colleen LeCours lay in a hospital bed at the General campus of The Ottawa Hospital on August 12, 2016, waiting for the only thing that could save her life a stem cell transplant from a stranger.

The donor could be anywhere in the world if a related blood donor cant be found, the call to find a match goes out to registries all over the globe and the donated stem cells are rushed across international borders.

What LeCours didnt know is that her donor, an 18-year-old Carleton University student named Timothy White, was just one floor below. Similarly, White didnt know that his recipient was in the same hospital.

There are currently more than 450,000 people on the Canadian Blood Services Stem Cell Registry formerly known as OneMatch and 36 million on affiliated international registries. Still, some people never find a match. There are more than 900 Canadians in need of a transplant who have not found a match anywhere in the world.

What were the odds that the match for LeCours, now 57, would be found in the same city?

Astronomical, she said.

The chances that White would even ever be asked to donate were also very low only about one in a thousand. After he agreed to donate, he was not told where the recipient might be. I was told the recipient could be anywhere. They could be in Africa, said White, now 22 and a recent graduate in computer science.

White had signed up for the registry through a cheek swab booth at ComiCon less than six months earlier. A smart place to recruit would-be stem cell donors, he notes. The optimal donor is a male between the age of 17 and 35 and thats the ComiCon demographic.

He decided to register as a potential donor because he grew up in the scouting movement. One of the main philosophies is to do a good turn every day, he said.

The donation was a non-surgical procedure in which Whites blood was removed though a needle, the stem cells were separated from his blood and the remaining blood components returned to his body through another needle. The procedure started at about 8 a.m. and was over by about 5 p.m.

I figured if I gave someone a day for a thousand more days (of life) then I felt it was a fair trade. I have many years of life. Why not spend one day? said White.

LeCourss medical journey started in 2009 with an emergency room visit for abdominal pain. She was eventually diagnosed with Stage 4 follicular lymphoma, a blood cancer that affects infection-fighting white blood cells. At the time, LeCours was working for Gov.-Gen. Michalle Jean and was able to stay on the job most of the time during her six months of treatment.

Four years later, the lymphoma returned. It was back again two years after that, in a more aggressive form. The only treatment was stem cell transplant.

There are two main kinds of stem cell transplants autologous and allogenic. In an autologous transplant, stem cells are collected from a patients own blood and reintroduced after being treated to remove cancer cells. In an allogenic stem cell transplant, the stem cells come from a donor.

At this point, LeCours was a candidate for an autologous transplant. Once again, she underwent aggressive chemotherapy. A year later, the cancer returned.

Doctors told LeCours there wasnt much else they could do and advised her to get her affairs in order. But the hospitals transplant team felt she could be a candidate for an allogenic transplant. Theres risk rejecting donated stem cells can be fatal to the patient.

LeCours learned that her brother was a match. But the medical work-up would last about three months and she couldnt wait that long.

I wasnt sure I wanted to do it but I didnt have much choice, she said. They said, We have someone waiting in the wings.

And I said, He probably has wings.

After the transplant, LeCours recovered as an outpatient in the home of her brother and sister-in-law. It took three months to rebuild her immune system. Her only rejection symptoms were a bit of skin irritation.

In January 2018, LeCours received an email asking if she would like to exchange contact information with her donor. She replied that she would.

A few months later, she got a message with Whites co-ordinates and was astonished to find that her donor was in Ottawa. It took her a few weeks to formulate an email.

I didnt want to scare him. I just wanted him to know how incredibly grateful I was. And I wanted to pay it forward, said LeCours.

After careful consideration, she sent White an email on Oct. 8, 2018.

Today, being Thanksgiving, I have so much to be thankful for, namely you giving your stem cells and saving my life and the success of the stem cells grafting to my bone marrow, LeCours wrote. I cant thank you enough for your wonderful selfless act.

Stem cell donor 18-year-old Carleton University student Timothy White at The Ottawa Hospital, General campus, donating stem cells for Colleen LeCours in August 2016. At the time he did not know that LeCours would be the recipient. Courtesy Timothy White.jpg

She added that she didnt know anything about him except for his name and email address, and asked if they could meet. They got together for the first time over lunch in a burger restaurant.

As soon as I saw him, I broke down, said LeCours.

It has been three and a half years since the transplant and LeCours remains in remission. She invited White to her familys Thanksgiving this year, and the two meet to catch up every few months. Its one of the quirks of stem cell donation that the recipient assumes the blood type of the donor. LeCours, once O-positive, now has blood type A-negative, like White.

Im a grandmother. The fact that my grandson has his moma is huge.

ALSO IN THE NEWS

Ottawa police chief lifts suspension of police union boss Matt Skof

Reduce the burden: Inuit healing centre reopens after funding lapse forced shut down

RTG wasnt on top of it : New Years Eve light rail issues attributed to dirt, grit buildup on trains

Read more:
ASTRONOMICAL ODDS: Stem cell recipient and her donor both from Ottawa - Ottawa Sun

Bone Marrow Stem Cells Comments Off on ASTRONOMICAL ODDS: Stem cell recipient and her donor both from Ottawa – Ottawa Sun | January 4th, 2020

For its promising investigational therapeutic approach to neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), BrainStorm Cell Therapeutics is theBuzz of BIO 2020 winnerin the Public Therapeutic Biotech category.

The Buzz of BIO contest identifies U.S. companies with groundbreaking, early-stage potential to improve lives. The event also is anopportunity to make investor connections that could take products to the next phase.

Ten biotechnology companies are nominated in each of the three categories ofBuzz of BIO: Public Therapeutic Biotech, Private Therapeutic Biotech, and Diagnostics and Beyond. In the Public Therapeutic Biotech category that BrainStorm won, nominated companies must be actively developing a publicly traded human treatment intended for review by theU.S. Food and Drug Administration (FDA).

As a developer of autologous cellular therapies treatments that use a patients own cells and tissues for debilitating neurodegenerative diseases, BrainStorm is now testing its NurOwn therapy for safety and effectiveness. The treatment involves extracting, from human bone, marrow-derived mesenchymal stem cells (MSCs), which are capable of differentiating into other cell types. The MSCs are then matured into a specific cell type that produces neurotrophic factors compounds that promote nervous tissue growth and survival. They are then reintroduced to the body via injection into muscles and/or the spinal canal.

Backed by a California Institute for Regenerative Medicine grant, Brainstorm has fully enrolledits randomized, double-blind, placebo-controlled Phase 3 clinical trial (NCT03280056) at six U.S. sites in California, Massachusetts, and Minnesota. Some 200 ALS patients are participating. A secondary safety analysis by the trials independent Data Safety Monitoring Board (DSMB) revealed no new concerns. Every two months, study subjects will be given three injections into the spinal canal of either NurOwn or placebo.

The trial is expected to conclude late this year. Results will be announced shortly afterward.

In a Phase 2 study (NCT02017912), which included individuals with rapidly progressing ALS, NurOwn demonstrated a positive safety profile as well as prospective efficacy.

The use of autologous MSC cells to potentially treat ALS was given orphan drug status by both the FDA and the European Medicines Agency.

Thanks to everyone who voted for BrainStorm during the Buzz of BIO competition,Chaim Lebovits, BrainStorm president and CEO, said in a press release. The entire management team at BrainStorm was very pleased with the results of this competition, and we look forward to presenting to an audience of accredited investors who may benefit from the companys story. We thank the BIO[Biotechnology Innovation Organization] team for singling out BrainStorms NurOwn as a key technology with the potential to improve lives.

As a contest winner, BrainStorm is invited to givea presentation at theBio CEO & Investor Conference, to be held Feb. 1011 in New York City, along with exposure to multiple industry elites and potential investors.

NurOwn cells also are being tested in a Phase 2 clinical study (NCT03799718) in patients with progressive multiple sclerosis.

Mary M. Chapman began her professional career at United Press International, running both print and broadcast desks. She then became a Michigan correspondent for what is now Bloomberg BNA, where she mainly covered the automotive industry plus legal, tax and regulatory issues. A member of the Automotive Press Association and one of a relatively small number of women on the car beat, Chapman has discussed the automotive industry multiple times of National Public Radio, and in 2014 was selected as an honorary judge at the prestigious Cobble Beach Concours dElegance. She has written for numerous national outlets including Time, People, Al-Jazeera America, Fortune, Daily Beast, MSN.com, Newsweek, The Detroit News and Detroit Free Press. The winner of the Society of Professional Journalists award for outstanding reporting, Chapman has had dozens of articles in The New York Times, including two on the coveted front page. She has completed a manuscript about centenarian car enthusiast Margaret Dunning, titled Belle of the Concours.

Total Posts: 6

Ins holds a PhD in Biomedical Sciences from the University of Lisbon, Portugal, where she specialized in blood vessel biology, blood stem cells, and cancer. Before that, she studied Cell and Molecular Biology at Universidade Nova de Lisboa and worked as a research fellow at Faculdade de Cincias e Tecnologias and Instituto Gulbenkian de Cincia. Ins currently works as a Managing Science Editor, striving to deliver the latest scientific advances to patient communities in a clear and accurate manner.

Link:
BrainStorm Cell Therapeutics Wins 2020 'Buzz of BIO' Award for ALS Investigational Therapy - ALS News Today

Bone Marrow Stem Cells Comments Off on BrainStorm Cell Therapeutics Wins 2020 ‘Buzz of BIO’ Award for ALS Investigational Therapy – ALS News Today | January 4th, 2020

Military personnel walk past the Raytheon Missile stand.

Carl De Souza | AFP | Getty Images

Check out the companies making headlines in midday trading:

Raytheon, Lockheed Martin, L3Harris Equity of major aircraft and weapons manufacturers Raytheon, Lockheed Martin and L3Harris rose 1.6%, 3.8% and 3.3%, respectively, in midday trading as U.S.-Iranian tensions flare in the Middle East. The U.S. confirmed it was responsible for a drone strike in Baghdad on Friday that killed Iranian Gen. Qasem Soleimani, Tehran's top military commander and a prominent political fixture in the region.

Incyte Shares of Incyte plunged 10% Friday after the company announced that a Phase III study showed one of its developmental drugs failed to show results that were statistically superior to a placebo. The drug was aimed at treating a disease that arises when donated bone marrow or stem cells attack their new host.

Tesla Tesla's stock climbed 3.8% on Friday after the automaker reported better-than-expected deliveries for its most recent quarter. The electric car company delivered 112,000 vehicles during the fourth quarter, topping consensus estimates of 106,000. Tesla delivered roughly 367,500 vehicles for the full year, a 50% increase from 2018 and within the range that it had given as guidance.

Bank of America Shares of the top U.S. bank fell 1.5% in afternoon trading after BMO Capital Markets downgraded the equity to market perform from outperform, telling clients its valuation re-rating has "run its course." Analyst James Fotheringham added that Bank of America shares now trade at a premium to their long-term average and suggested investors look to cheaper names like Citi and Morgan Stanley in the big-bank space.

Concho Resources, Apache, Devon Energy Shares of Concho, Apache and Devon all traded higher, following crude prices, after the U.S. killed a top Iranian military leader in an airstrike. Concho and Apache each traded higher by more than 1% while Devon advanced 0.8%.

L Brands Shares of L Brands rose nearly 8% after Bank of America upgraded the retail and apparel company to buy from neutral. The bank's analysts cited a strong Bath & Body Works business, potential for a more stable Victoria's Secret and a high dividend yield as reasons for the upgrade. The bank also raised its price target on the stock to $25 per share from $21, which would be a 49% increase from where the stock closed on Thursday.

Humana Humana rose 1.5% after Goldman Sachs added the health care company to its "Conviction Buy" list and told clients it sees sizable upward revisions to earnings estimates due to the recent repeal of a fee on health insurers.

CNBC's Fred Imbert and Jesse Pound contributed to this report.

Excerpt from:
Stocks making the biggest moves midday: L3Harris, Tesla, Apache & more - CNBC

Bone Marrow Stem Cells Comments Off on Stocks making the biggest moves midday: L3Harris, Tesla, Apache & more – CNBC | January 4th, 2020

INTRODUCTION

Programmed cell death protein 1 (PD-1) is a major inhibitor of T cell responses expressed on activated T cells. It is also expressed on natural killer cells, B cells, regulatory T cells, T follicular helper cells, and myeloid cells (1). The current model supports that a key mechanism dampening antitumor immune responses is the up-regulation of PD-1 ligands in cancer cells and antigen-presenting cells (APCs) of the tumor microenvironment (TME), which mediate ligation of PD-1 on tumor-infiltrating CD8+ T cells, leading to the development of T incapable of generating antitumor responses (2). Therapeutic targeting of the PD-1 pathway with antibodies blocking the PD-1 receptor or its ligands induces expansion of oligoclonal CD8+ tumor-infiltrating lymphocytes that recognize tumor neoantigens (3). Thus, in the context of cancer, PD-1 is considered a major inhibitor of T effector cells, whereas on APC and cancer cells, emphasis has been placed on the expression of PD-1 ligands. PD-1 ligand-1 expression in the TME is often a prerequisite for patient enrollment to clinical trials involving blockade of the PD-1 pathway. However, responses do not always correlate with PD-L1 expression, and it remains incompletely understood how the components of the PD-1:PD-L1/2 pathway suppress antitumor immunity.

Recent studies indicated that PD-1 can be induced by Toll-like receptor (TLR) signaling in macrophages (M) and negatively correlates with M1 polarization (4). PD-1 expression in macrophages plays a pathologic role by suppressing the innate inflammatory response to sepsis (5) and inhibiting Mycobacterium tuberculosis phagocytosis in active tuberculosis (6). Our knowledge about the function of PD-1 on myeloid cells in the context of cancer is very limited. However, similar to its role in infections, PD-1 expression inversely correlates with M1 polarization and phagocytic potency of tumor-associated M (TAM) against tumor (7, 8). The mechanisms of PD-1 expression in myeloid cells and the role of PD-1expressing myeloid cells in tumor immunity remain unknown.

The rapid increase in myeloid cell output in response to immunologic stress is known as emergency myelopoiesis. Terminally differentiated myeloid cells are essential innate immune cells and are required for the activation of adaptive immunity. Strong activation signals mediated by pathogen-associated molecular pattern or danger-associated molecular pattern molecules lead to a transient expansion and subsequent differentiation of myeloid progenitors to mature monocytes and granulocytes to protect the host. In contrast, during emergency myelopoiesis mediated by continuous low-level stimulation mediated by cancer-derived factors and cytokines, bone marrow common myeloid progenitors (CMPs) but, predominantly, granulocyte/macrophage progenitors (GMPs) undergo modest expansion with hindered differentiation, and a fraction of myeloid cells with immunosuppressive and tumor-promoting properties, named myeloid-derived suppressor cells (MDSCs), accumulates. MDSCs suppress CD8+ T cell responses by various mechanisms (9). In the mouse, MDSCs consist of two major subsets, CD11b+Ly6ChiLy6G (thereafter named CD11b+Ly6C+) monocytic (M-MDSC) and CD11b+Ly6CloLy6G+ (hereafter named CD11b+Ly6G+) polymorphonuclear (PMN-MDSC) (10). These cells have similar morphology and phenotype to normal monocytes and neutrophils but distinct genomic and biochemical profiles (9). In humans, in addition to M-MDSC and PMN-MDSC, a small subset of early-stage MDSC has been identified (10).

Although PMN-MDSCs represent the major subset of circulating MDSC, they are less immunosuppressive than M-MDSC when assessed on a per cell basis (1113). Current views support the two-signal requirement for MDSC function. The first signal controls MDSC generation, whereas the second signal controls MDSC activation, which depends on cues provided by the TME and promotes MDSC differentiation to TAM (14). Proinflammatory cytokines and endoplasmic reticulum stress response in the TME contribute to pathologic myeloid cell activation that manifests as weak phagocytic activity, increased production of reactive oxygen species and nitric oxide (NO) and expression of arginase-1 (ARG1), and convert myeloid cells to MDSC (9). MDSCs are associated with poor outcomes in many cancer types in patients and negatively correlate with response to chemotherapy, immunotherapy, and cancer vaccines (1519).

In the present study, we examined how PD-1 regulates the response of myeloid progenitors to cancer-driven emergency myelopoiesis and its implications on antitumor immunity. We determined that myeloid progenitors, which expand during cancer-driven emergency myelopoiesis, express PD-1 and PD-L1. PD-L1 was constitutively expressed on CMPs and GMPs, whereas PD-1 expression displayed a notable increase on GMPs that arose during tumor-driven emergency myelopoiesis. PD-1 was also expressed on tumor-infiltrating myeloid cellsincluding M-MDSCs and PMN-MDSCs, CD11b+F4/80+ M, and CD11c+major histocompatibility complex class II-positive (MHCII+) dendritic cells (DCs) in tumor-bearing miceand on MDSCs in patients with refractory lymphoma. Ablation of PD-1 signaling in PD-1 knockout (KO) mice prevented GMP accumulation and MDSC generation and resulted in increase of Ly6Chi effector monocytes, M and DC. We generated mice with conditional targeting of the Pdcd1 gene (PD-1f/f) and selectively eliminated PD-1 in myeloid cells or T cells. Compared with T cellspecific ablation of PD-1, myeloid-specific PD-1 ablation more effectively decreased tumor growth in various tumor models. At a cellular level, only myeloid-specific PD-1 ablation skewed the myeloid cell fate commitment from MDSC to effector Ly6Chi monocytes M and DC and induced T effector memory (TEM) cells with improved functionality. Our findings reveal a previously unidentified role of the PD-1 pathway and suggest that skewing of myeloid cell fate during emergency myelopoiesis and differentiation to effector APCs, thereby reprogramming T cell responses, might be a key mechanism by which PD-1 blockade mediates antitumor function.

For our studies, we selected the murine B16-F10 melanoma tumor model because it has been informative in dissecting mechanisms of resistance to checkpoint immunotherapy (20). First, we examined whether B16-F10 induces tumor-driven emergency myelopoiesis similarly to the MC17-51 fibrosarcoma, a mouse tumor model well established to induce cancer-driven emergency myelopoiesis (21). We assessed the expansion of myeloid progenitors in the bone marrow and the increase of CD11b+CD45+ myeloid cells in the spleen and tumor (figs. S1 and S2). Both tumor types induced increase of myeloid progenitors in the bone marrow and systemic increase of CD45+CD11b+ myeloid cells (fig. S3), providing evidence that B16-F10 melanoma is an appropriate tumor model to study tumor-driven emergency myelopoiesis and its consequences in tumor immunity. In the spleen of nontumor-bearing mice, few myeloid cells constitutively expressed very low levels of PD-L1, whereas PD-1 was very low to undetectable (Fig. 1, A and B). In B16-F10 tumor-bearing mice, expression of PD-1 and PD-L1 was up-regulated on myeloid cells of the spleen (Fig. 1, C to F). PD-1 and PD-L1 were also expressed on myeloid cells at the tumor site (Fig. 1, G to I). All subsets of myeloid cells expanding in tumor-bearing mice including M-MDSCs, PMN-MDSCs, CD11b+F4/80+ Ms, and CD11c+MHCII+ DCs expressed PD-1 (Fig. 1, D and G). Kinetics studies of PD-1 expression on myeloid cells in the spleen of tumor-bearing mice showed a gradual increase over time (Fig. 1, J to M).

(A and B) Expression of PD-1 and PD-L1 on CD11b+Ly6C+ monocytes and CD11c+MHCII+ DC in the spleen of nontumor-bearing C57BL/6 mice. FMO, fluorescence minus one. (C) C57BL/6 mice were inoculated with B16-F10 mouse melanoma, and at the indicated time points, expression of PD-1 was examined by flow cytometry in the spleen after gating on the indicated myeloid populations; contour plots depicting the percentage of positive cells are shown. On day 16 after tumor inoculation, expression of PD-1 and PD-L1 was assessed in the spleen (D) and the tumor site (G) after gating on the indicated myeloid populations. (D and G) Fluorescence-activated cell sorting (FACS) histograms and contour plots depicting the percentage of positive cells and bar graphs (E, F, H, and I) of mean SEM positive cells. Results are representative of 12 independent experiments with six mice per group. (J to M) Kinetics of PD-1 up-regulation on CD11b+Ly6C+, CD11b+Ly6G+, CD11b+F4/80+, and CD11c+MHCII+ of the spleen after tumor inoculation. **P < 0.01, ***P < 0.005, ****P < 0.001.

Because myeloid cells that give rise to MDSC and TAM are generated from myeloid progenitors in the bone marrow during tumor-driven emergency myelopoiesis, we examined PD-1 and PD-L1 expression in these myeloid progenitors. In nontumor-bearing mice, PD-1 was detected at very low levels on GMPs (Fig. 2A), whereas PD-L1 was constitutively expressed in CMPs but mostly on GMPs (Fig. 2B). In tumor-bearing mice, PD-L1 was up-regulated in CMPs and GMPs, and its expression levels remained elevated during all assessed time points (Fig. 2, F to J). PD-1 expression was induced on CMPs but more prominently on GMPs (Fig. 2, C to I). Kinetics studies showed that PD-1 expression on GMPs peaked early after tumor inoculation (Fig. 2, C, E, and I), at a time point when tumor growth was not yet measurable. Thus, induction of PD-1 expression in myeloid progenitors is an early event during tumor development.

(A and B) Expression of PD-1 and PD-L1 on CMPs and GMPs of nontumor-bearing mice. (C to J) C57BL/6 mice were inoculated with B16-F10 mouse melanoma, and expression of PD-1 and PD-L1 on CMPs and GMPs was examined on days 9, 12, 14, and 16 after implantation. FACS histograms (C and F) and contour plots (D, E, G, and H) indicating the percentage of positive cells and bar graphs of mean SEM positive cells (I and J) are shown. Results are representative of four independent experiments with six mice per group. (K and L) Kinetics of PD-1 (K) and PD-L1 (L) expression on CMPs (blue) and GMPs (orange) during tumor-driven emergency myelopoiesis. Results are representative of four separate experiments with six mice per group. *P < 0.05, ***P < 0.005, ****P < 0.001.

To determine whether PD-1 expression on GMPs was mediated by growth factors regulating emergency myelopoiesis, we cultured bone marrow cells from nontumor-bearing mice with granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony growth factor (GM-CSF), and the TLR4 ligand lipopolysaccharide. PD-1 that was constitutively expressed at low levels in GMPs was up-regulated by culture with each of these factors (fig. S4A), consistent with our findings that PD-1 expression was rapidly induced on GMPs of tumor-bearing mice in vivo (Fig. 2, C, E, and I). Quantitative polymerase chain reaction (qPCR) in purified Linneg bone marrow cells showed that PD-1 mRNA was constitutively expressed in myeloid progenitors and was up-regulated by culture with G-CSF or GM-CSF (fig. S4B). Together, these in vivo and in vitro studies provide evidence that PD-1 expression on myeloid progenitors is regulated by a direct cell-intrinsic effect of factors driving cancer-mediated emergency myelopoiesis.

To examine whether PD-1 was expressed in MDSCs in humans, we used samples from healthy donors and patients with malignant non-Hodgkins lymphoma (NHL) (figs. S5 and S6). A high level of PD-1expressing M-MDSCs was detected in the peripheral blood of three patients with treatment-refractory NHL but not in two patients who responded to treatment or five healthy donors (fig. S6). These results show that PD-1 expression is detected in human MDSCs and serve as a paradigm, suggesting that PD-1 expression in MDSCs of patients with cancer might be a clinically relevant event.

To examine whether PD-1 might have an active role in tumor-induced stress myelopoiesis, we used PD-1deficient (PD-1/) mice. PD-1 deletion, which resulted in decreased tumor growth (Fig. 3, A and B), substantially altered tumor-induced stress myelopoiesis (Fig. 3, C to E). Although accumulation of CMPs was comparable, accumulation of GMPs was significantly diminished in PD-1/ mice (Fig. 3, C and D), indicating that GMPs might be a key target on which PD-1 mediated its effects on myeloid progenitors (Fig. 3E). Kinetics studies showed sustained GMP expansion in wild-type (WT) tumor-bearing mice. In contrast, in PD-1/ tumor-bearing mice, GMPs displayed a rapid expansion and subsequent decline (fig. S7). In parallel, in PD-1/ mice, there was an increase of differentiated CD11b+Ly6Chi monocytic cells not only in the tumor (Fig. 3H) but also in the spleen and the small intestine, which also displayed an increase in CD11c+MHCII+ DCs (Fig. 3, F and G). Moreover, at these sites, there was a significant increase of the CD11b+Ly6C+/CD11b+Ly6G+ ratio (Fig. 3, I to K), indicating a shift of myelopoiesis output toward monocytic lineage dominance. These Ly6Chi monocytes, CD11b+F4/80+ Ms, and CD11c+MHCII+ DCs in PD-1/ tumor-bearing mice expressed interferon (IFN) regulatory factor 8 (IRF8), and all myeloid subsets had elevated expression of the retinoic acid receptor-related orphan receptor (RORC or ROR) (Fig. 3, L to N, and fig. S8). Similar results were observed in two additional tumor models, the MC38 colon adenocarcinoma and the MC17-51 fibrosarcoma model (fig. S9), both of which induced cancer-driven emergency myelopoiesis (fig. S3).

(A and B) WT and PD-1/ mice were inoculated with B16-F10 melanoma, and tumor size was monitored daily (A). Mice were euthanized on day 16, and tumor weight was measured (B). Data shown are means SEM of six mice per group and are representative of six independent experiments. (C) Mean percentages SEM of LSK (Linneg, Sca1pos, CD127neg, c-kitpos) and LK (Linneg, Sca1neg, CD127neg, c-kitpos) hematopoietic precursors, CMP, and GMP in the bone marrow of nontumor-bearing and tumor-bearing WT and PD-1/ mice. GMPs in PD-1/ mice were significantly lower compared with GMPs in WT mice (**P < 0.01). (D) Representative contour plots of FACS analysis for CMP and GMP in the bone marrow of tumor-bearing WT and PD-1/ mice. (E) Schematic presentation of myeloid lineage differentiation. The arrowhead indicates GMP, the key target population of PD-1 during emergency myelopoiesis. HSC, hematopoietic stem cells; MPP, multi-potent progenitor; MDP, monocyte/macrophages and DC precursors; CDP, common dendritic cell progenitors; CLP, common lymphoid progenitors. (F to H) Mean percentages of CD45+CD11b+, CD11b+Ly6C+, CD11b+Ly6G+, and CD11c+MHCII+ in the spleen (F), small intestine (G), and B16-F10 site (H) of tumor-bearing WT and PD-1/ mice. (I to K) Representative plots of FACS analysis for CD11b+Ly6Chi and CD11b+Ly6C+/CD11b+Ly6G+ ratio in the spleen (I), small intestine (J), and B16-F10 site (K). (L to N) Mean percentages SEM of RORC and IRF8 expressing CD11b+Ly6C+, CD11b+Ly6G+, CD11b+F4/80+, and CD11c+MHCII+ myeloid cells within the CD45+CD11b+ gate in the spleen (L), small intestine (M), and B16-F10 site (N). Data from one representative experiment of three independent experiments with six mice per group are shown. (O and P) Diminished suppressive activity (O) and NO production (P) of CD11b+Ly6C+ cells isolated from PD-1/ tumor-bearing mice. CD11b+Ly6C+ cells were isolated from tumor-bearing WT and PD-1/ mice and cultured at various ratios with OTI splenocytes stimulated with OVA257264. Data show means SEM of one representative of two experiments (*P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.001).

IRF8 regulates myeloid cell fate to monocyte/macrophage and DC differentiation versus granulocyte differentiation (22, 23), explaining the increase of CD11b+Ly6C+/CD11b+Ly6G+ ratio that we observed in tumor-bearing PD-1 KO mice. IRF8 is designated as one of the terminal selectors that control the induction and maintenance of the terminally differentiated state of these myeloid cells (22, 23). Moreover, IRF8 shifts the fate of myeloid cells away from immature MDSC, which are characterized by a restriction in IRF8 expression (24, 25). Retinoid-related orphan nuclear receptors not only are required for myelopoiesis and are mediators of the inflammatory response of effector Ly6Chi monocytes and macrophages (21, 26) but also can be expressed by MDSC (21). For these reasons, we examined the functional properties of CD11b+Ly6C+ cells in PD-1/ tumor-bearing mice. A key mechanism by which CD11b+Ly6C+ M-MDSCs mediate suppression of T cell responses involves the production of NO (27). We assessed the immunosuppressive function and found diminished NO production and diminished suppressor capacity of CD11b+Ly6C+ myeloid cells isolated from tumor-bearing PD-1/ mice compared with their counterparts isolated from tumor-bearing WT control mice (Fig. 3, O and P). Thus, PD-1 ablation switches the fate and function of myeloid cells away from immunosuppressive MDSC and promotes the generation of differentiated monocytes, M, and DC. The expansion of CD11b+Ly6Chi monocytes, the increase of the CD11b+Ly6C+/CD11b+Ly6G+ ratio, and the up-regulation of RORC in myeloid cells of the spleen of PD-1/ mice were already observed on day 9 after tumor inoculation, when tumors were not yet measurable, and on day 12, when tumors in WT and PD-1/ mice had comparable size (fig. S10). These results indicate that the effects of PD-1 ablation on the myeloid compartment of PD-1/ tumor-bearing mice preceded the differences in tumor growth.

To determine the potential therapeutic relevance of these findings, we examined whether changes in the myeloid compartment might be detected during treatment with PD-1blocking antibody. Compared with the control treatment group, mice receiving antiPD-1 antibody (fig. S11A) had diminished accumulation of GMP in the bone marrow (fig. S11B) and increased expansion of Ly6C+ monocytes and DC in the tumor site (fig. S11D), with effector features characterized by the expression of RORC, IRF8, and IFN- (fig. S11, E to G and I). In contrast, cells expressing interleukin-4 receptor (IL-4Ra), a marker of MDSC (10, 28), were significantly decreased (fig. S11H). Thus, treatment with antiPD-1blocking antibody promotes the differentiation of myeloid cells with effector features while suppressing expansion of MDSC in tumor-bearing mice.

To determine whether these changes on myeloid cell fate in PD-1/ mice were mediated by myeloid cellintrinsic effects of PD-1 ablation or by the effects of PD-1neg T cells on myeloid cells, we generated mice with conditional targeting of Pdcd1 gene (PD-1f/f) (fig. S12A) and crossed them with mice expressing cre recombinase under the control of the lysozyme (LysM) promoter to induce selective ablation of the Pdcd1 gene in myeloid cells (PD-1f/fLysMcre) or with mice expressing cre recombinase under the control of the CD4 promoter to induce selective ablation of the Pdcd1 gene in T cells (PD-1f/fCD4cre) (fig. S12, B and C). In PD-1f/fLysMcre mice, tumor growth was significantly diminished (Fig. 4, A and B), indicating that despite the preserved PD-1 expression in T cells, myeloid-specific PD-1 ablation in PD-1f/fLysMcre mice was sufficient to inhibit tumor growth. Tumor-driven emergency myelopoiesis was selectively affected in PD-1f/fLysMcre mice. Although myeloid-specific PD-1 ablation resulted in expansion of CMPs, accumulation of GMPs was prevented (Fig. 4C). In contrast, no change on cancer-driven emergency myelopoiesis was detected in PD-1f/fCD4cre mice, which had comparable expansion of CMP and GMP to PD-1f/f control mice (Fig. 5A).

(A and B) PD-1f/f, PD-1f/fLysMcre, and PD-1/ mice were inoculated with B16-F10 melanoma, and tumor size was monitored daily (A). After mice were euthanized, tumor weight was measured (B). (C) Mean percentages SEM of CMP and GMP in the bone marrow of tumor-bearing PD-1f/f and PD-1f/fLysMcre mice. (D) Mean percentages SEM of CD11b+CD45+ cells and CD11b+Ly6C+, CD11b+Ly6G+, CD11b+F4/80+, and CD11c+MHCII+ myeloid subsets in the spleen of tumor-bearing mice. (E) Mean percentages SEM of CD11b+CD45+, CD11b+Ly6C+, and CD11b+Ly6G+ cells and (F) representative contour plots of FACS analysis for CD11b+CD45+ and CD11b+Ly6C+ cells at the tumor site in PD-1f/f, PD-1f/fLysMcre, and PD-1/ mice. (G) Mean percentages SEM of CD16/CD32+, CD86+, CD88+, and CD80+ cells and IFN-expressing myeloid cell subsets within the CD45+CD11b+ gate in B16-F10 tumors from PD-1f/f, PD-1f/fLysMcre, and PD-1/ mice. (H) Mean percentages SEM and (I) FACS histograms of IL-4Ra, CD206, and ARG1 expression in CD11b+Ly6C+, CD11b+Ly6G+, CD11b+F4/80+, and CD11c+MHCII+ myeloid cells within the CD11b+CD45+ gate in the spleen of tumor-bearing PD-1f/f, PD-1f/fLysMcre, and PD-1/ mice. Data are from one representative of three independent experiments with six mice per group are shown in all the panels (*P < 0.05, **P < 0.01, ***P < 0.005, and ****P < 0.001).

PD-1f/f and PD-1f/fCD4cre mice were inoculated with B16-F10 melanoma. (A) On day 16, mice were euthanized, and bone marrow CMPs and GMPs were examined by flow cytometry. Mean percentages SEM of CMP or GMP are shown. (B and C) Tumor size was assessed every other day from inoculation (B). On the day of euthanasia, tumor weight was measured (C). (D) Mean percentages SEM of CD11b+CD45+ cells and CD11b+Ly6C+ and CD11b+Ly6G+ populations within the CD11+CD45+ gate in the spleen. (E) Mean percentages SEM of CD11b+CD45+ cells and CD11b+Ly6C+, CD11b+Ly6G+, CD11b+F4/80+, and CD11c+MHCII+ cells within the CD11b+CD45+ gate in the tumor site. (F) Mean percentages SEM of CD16/CD32+, CD86+, CD88+, CD80+, and IFN- expression in the indicated myeloid subsets (CD11b+Ly6C+, CD11b+Ly6G+, CD11b+F4/80+, and CD11c+MHCII+) within the CD11b+CD45+ gate in the tumor site. (G to J) Mean percentages SEM of CD4+ and CD8+ TCM and TEM (G), as well as IFN-, IL-2, and IL-17 (H to J) expression in CD4+ and CD8+ TEM and TCM at the tumor site, and respective contour plots (K to M). Results are from one representative of two independent experiments with six mice per group are shown (*P < 0.05 and **P < 0.01).

Myeloid-specific PD-1 ablation in PD-1f/fLysMcre mice not only shifted the differentiation of CD11b+Ly6C+ and CD11b+Ly6G+ myeloid subsets and increased the CD11b+Ly6C+/CD11b+Ly6G+ ratio in the spleen and tumor site as in PD-1/ mice (Fig. 4, D to F) but also resulted in a notably different immunological profile of CD11b+Ly6C+ monocytic myeloid cells, consistent with effector myeloid function as indicated by the expression of effector myeloid cell markers including CD80, CD86, CD16/32 (Fc receptor II/III), and CD88 (C5aR) (Fig. 4G). Consistent with the improved function of myeloid cells, PD-1f/fLysMcre mice also had higher levels of IFN-expressing CD11b+Ly6Chi monocytes and CD11b+F4/80+ Ms (Fig. 4G and fig. S13, A and B) and increase of IRF8+ and RORC+ CD11b+Ly6Chi monocytes (fig. S13, C and D). In contrast, cells expressing IL-4Ra, CD206, and ARG1which are markers of MDSC, immunosuppressive neutrophils, and tolerogenic DCs (2933)were diminished (Fig. 4, H and I). Thus, myeloid-intrinsic PD-1 ablation skews the fate of myeloid cells away from immunosuppressive MDSCs; promotes the differentiation of functional effector monocytes, Ms, and DCs; and has a decisive role in systemic antitumor immunity despite PD-1 expression in T cells.

We studied antitumor responses in mice with T cellspecific PD-1 ablation and found that PD-1f/fCD4cre mice had diminished antitumor protection (Fig. 5, B and C). Consistent with the causative role of myeloid cellspecific PD-1 targeting in the differentiation and function of myeloid cells, T cellspecific PD-1 ablation did not induce expansion of CD11b+CD45+ leukocytes, CD11b+F4/80+ Ms, and CD11c+MHCII+ DCs and increase of CD11b+Ly6C+/CD11b+Ly6G+ ratio (Fig. 5, D and E) or immunological features of functional effector myeloid cells (Fig. 5F) in PD-1f/fCD4cre tumor-bearing mice, compared with control tumor-bearing mice. Moreover, despite PD-1 ablation, tumor-bearing PD-1f/fCD4cre mice did not have quantitative differences in tumor-infiltrating TEM cells compared with control tumor-bearing mice (Fig. 5G) or features of enhanced effector function as determined by assessment of cytokine-producing cells (Fig. 5, H to M).

Similar outcomes to those observed with B16-F10 tumor in the differentiation of myeloid cells toward myeloid effectors versus MDSC were obtained when PD-1f/fLysMcre and PD-1f/fCD4cre mice were inoculated with MC38 colon adenocarcinoma cells (Fig. 6, B to I). Moreover, PD-1f/fLysMcre but not PD-1f/f CD4cre mice inoculated with MC38 had functional differences in tumor-infiltrating TEM and T central memory (TCM) cells compared with control tumor-bearing mice (Fig. 6, J to L). In the context of this highly immunogenic tumor, PD-1 ablation in myeloid cells resulted in complete tumor eradication, whereas mice with PD-1 ablation in T cells showed progressive tumor growth (Fig. 6A). Together, these results suggest that by preventing the differentiation of effector myeloid cells and promoting generation of MDSC, myeloid-specific PD-1 expression has a decisive role on T cell function. Thus, although PD-1 is an inhibitor of T cell responses (2, 34, 35), ablation of PD-1 signaling in myeloid cells is an indispensable requirement for induction of systemic antitumor immunity in vivo.

(A) PD-1f/f, PD-1f/fCD4cre, and PD-1f/fLysMcre mice were inoculated with MC38 colon adenocarcinoma, and tumor size was monitored daily. Mice were euthanized on day 21, and mean percentages SEM of CD45+CD11b+ cells and CD11b+Ly6C+, CD11b+Ly6G+, CD11b+F4/80+, and CD11c+MHCII+ myeloid subsets in the spleen (B) and tumor site (C) were determined. (D) Mean percentages SEM of RORC- and IRF8-expressing CD11b+Ly6C+, CD11b+Ly6G+, CD11b+F/480+, and CD11c+MHCII+ myeloid cells and (E) mean percentages SEM of ARG1, IL-4Ra, CD88, and CD80 cells within the same myeloid subsets in the spleen. (F and G) Representative flow cytometry plots for RORC and IRF8 expression. (H) Mean percentages SEM and (I) representative flow cytometry plots of IFN- and ARG1-expressing CD11b+Ly6C+ and CD11b+Ly6G+ myeloid cells at the tumor site. (J to L) Mean percentages SEM of CD4+ and CD8+ TCM and TEM cells (J) and IFN-expressing CD4+ and CD8+ TEM and TCM at the tumor site (K) and respective contour plots (L). Data are from one representative of three experiments with six mice per group (*P < 0.05, **P < 0.01, and ***P < 0.001).

To further investigate the direct effects of PD-1 on myeloid cell fate in the absence of T cells, we used recombination activating gene 2 (RAG2) KO mice (lacking mature T cells and B cells). Treatment of RAG2 KO tumor-bearing mice with antiPD-1blocking antibody resulted in decreased accumulation of GMPs during tumor-driven emergency myelopoiesis (fig. S14A), myeloid cell expansion in the spleen and tumor site (fig. S14, B and C), and enhanced generation of effector myeloid cells (fig. S14, D to G), providing evidence that blockade of PD-1mediated signals skews myeloid lineage fate to myeloid effector cells in a myeloid cellintrinsic and T cellindependent manner. In RAG2 KO mice treated with antiPD-1 antibody, despite the absence of T cells, a decrease of tumor growth was also observed (fig. S14, H and I), suggesting that ablation of PD-1 signaling promotes myeloid-specific mechanisms that induce tumor suppression, one of which might involve increased phagocytosis (8).

To understand mechanisms that might be responsible for the significant differences of myeloid cell fate commitment induced by myeloid-specific PD-1 targeting, we examined whether PD-1deficient bone marrow myeloid progenitors might have distinct signaling responses to the key hematopoietic growth factors that mediate cancer-driven emergency myelopoiesis, which also induced PD-1 expression in GMP during in vitro culture. To avoid any potential impact of bone marrowresiding PD-1/ T cells or mature myeloid cells on the signaling responses of myeloid progenitors, we used Linneg bone marrow from PD-1f/fLysMcre mice because LysMcre is expressed in CMPs and GMPs (36), allowing us to take advantage of the selective deletion of PD-1 in these myeloid progenitors. PD-1deficient GMPs (fig. S15) had enhanced activation of extracellular signalregulated kinase 1/2 (Erk1/2), mammalian target of rapamycin complex 1 (mTORC1), and signal transducer and activator of transcription 1 (STAT1) in response to G-CSF, a main mediator of emergency myelopoiesis (37, 38). These results are notable because each of these signaling targets has a decisive role in the differentiation and maturation of myeloid cells while preventing the generation of immature immunosuppressive MDSC (3942). These findings indicate that PD-1 might affect the differentiation of myeloid cells by regulating the fine tuning of signaling responses of myeloid progenitors to hematopoietic growth factors that induce myeloid cell differentiation and lineage fate determination during emergency myelopoiesis.

Metabolism has a decisive role in the fate of hematopoietic and myeloid precursors. Stemness and pluripotency are regulated by maintenance of glycolysis (43). Switch from glycolysis to mitochondrial metabolism and activation of oxidative phosphorylation and trichloroacetic acid (TCA) cycle are associated with differentiation (44). This is initiated by glycolysis-mediated mitochondrial biogenesis and epigenetic regulation of gene expression (43). The structural remodeling of the mitochondrial architecture during differentiation is characterized by increased replication of mitochondrial DNA to support production of TCA cycle enzymes and electron transport chain subunits, linking mitochondrial metabolism to differentiation (45).

We examined whether PD-1 ablation, which promoted the differentiation of myeloid cells in response to tumor-mediated emergency myelopoiesis, might affect the metabolic properties of myeloid precursors. Linneg bone marrow myeloid precursors were cultured with the cytokines G-CSF/GM-CSF/IL-6 that drive tumor-mediated emergency myelopoiesis in cocktail (Fig. 7, A and B) or individually (Fig. 7, C and D). Hematopoietic stem cell differentiation was documented by decrease of Linneg, which was more prominent in the cultures of PD-1deficient bone marrow cells, and coincided with increase of CD45+CD11b+ cells (Fig. 7, A and B). Ly6C+ monocytic cells dominated in the PD-1f/fLysMcre cultures, whereas Ly6G+ granulocytes were decreasing compared with PD-1f/f control cultures (Fig. 7, C and D), providing evidence for a cell-intrinsic mechanism of PD-1deficient myeloid precursors for monocytic lineage commitment. Glucose uptake, but more prominently, mitochondrial biogenesis, was elevated in PD-1deficient CMP and GMP (Fig. 7, E and F). Bioenergetics studies showed that PD-1deficient cells developed robust mitochondrial activity (Fig. 7G) and increase of oxygen consumption rate (OCR)/extracellular acidification rate (ECAR) ratio during culture (Fig. 7H), indicating that mitochondrial metabolism progressively dominated over glycolysis. This bioenergetic profile is consistent with metabolism-driven enhanced differentiation of hematopoietic and myeloid precursors (45, 46).

(A and B) Linneg bone marrow from PD-1f/f and PD-1f/fLysMcre mice was cultured with GM-CSF, G-CSF, and IL-6 for the indicated time intervals. Mean percentages SEM of CD11b+CD45+ (A) and Linneg cells (B) are shown. (C and D) Bone marrow cells purified as in (A) and (B) were cultured with the indicated growth factors, and mean percentages SEM of CD11b+Ly6C+ and CD11b+Ly6G+ cells were examined after 48 hours of culture. (E to H) Bone marrow cells were prepared and cultured as in (A) and (B), and at 48 hours of culture, glucose uptake was assessed using 2-[N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)Amino]-2-Deoxyglucose (2-NBDG) (E), and mitochondrial biogenesis was assessed by MitoGreen staining and flow cytometry (F). (G) At 24, 48, and 72 hours of culture, OCR and ECAR were measured by a Seahorse extracellular flux analyzer, and mitostress responses at each time point of culture were examined. (H) OCR/ECAR ratio was measured at these time points, and the increase of OCR/ECAR ratio during stimulation was calculated. (I) Linneg bone marrow cells from PD-1f/f and PD-1f/fLysMcre mice were cultured with G-CSF and GM-CSF for 48 hours, and metabolite analysis was performed by mass spectrometry. The unsupervised hierarchical clustering heat map of the top 50 metabolites is shown. (J) At 24, 48, and 72 hours of culture with G-CSF and GM-CSF, mRNA was extracted and analyzed for the expression of the indicated genes by qPCR. Results of the 48-hour culture are shown and are presented as the fold increase over the mRNA level expressed by PD-1f/f cells. Results are from one of three independent experiments. (K to M) At 24 hours of culture with GM-CSF, G-CSF, or IL-6, the content of neutral lipid droplets, including triglycerides and cholesterol esters, was assessed by flow cytometry using boron-dipyrromethene (BODIPY) 493/503. Mean percentages SEM (K) of BODIPY 493/503positive cells within the CD11b+CD45+ gate, representative contour plots (L), and histograms of FACS analysis (M) are shown. (N) PD-1f/f and PD-1f/fLysMcre DC were differentiated in the presence of B16-F10 tumor supernatant, and the content of neutral lipids was assessed. Mean percentage SEM of BODIPY 493/503positive DC within the CD45+CD11b+ gate is shown. Results are representative of three experiments. *P < 0.05, **P < 0.01, and ***P < 0.005.

We performed unbiased global metabolite analysis to determine whether PD-1deficient myeloid precursors developed a distinct metabolic program. Compared with control, PD-1deficient cells had elevated metabolic intermediates of glycolysis and pentose phosphate pathway (PPP), acetylcoenzyme A (coA), and the TCA cycle metabolites citrate and -ketoglutarate, but the most prominent difference was the elevated cholesterol (Fig. 7I, figs. S16 and S17, and table S1). Abundant cytosolic acetyl-coA can be used for fatty acid and cholesterol biosynthesis (fig. S17) (43). Moreover, mTORC1 activates de novo cholesterol synthesis via sterol regulatory element-binding protein 1 (SREBP1), which regulates transcription of enzymes involved in cholesterol synthesis (47, 48). Because acetyl-coA was elevated (Fig. 7I and fig. S17) and mTORC1 activation was enhanced in PD-1deficient myeloid progenitors in response to growth factors driving emergency myelopoiesis (fig. S15), we examined whether activation of the mevalonate pathway that induces cholesterol synthesis (fig. S18A) might be involved. In PD-1deficient myeloid progenitors cultured with growth factors of emergency myelopoiesis, mRNA of genes regulating cholesterol synthesis and uptake was increased, mRNA of genes promoting cholesterol metabolism was decreased (Fig. 7J and fig. S18B), whereas cellular cholesterol and neutral lipid content was elevated (Fig. 7, K to M). PD-1deficient DC not only differentiated in vitro in the presence of B16-F10 tumor supernatant but also had a significant increase of cholesterol and neutral lipids compared with similarly differentiated DC from control mice (Fig. 7N). Consistent with these in vitro findings, glucose uptake and content of cholesterol and neutral lipids were elevated in GMPs of tumor-bearing PD-1 KO mice compared with control mice at days 7 or 9 after tumor inoculation, respectively, when tumors were not yet detectable or tumors in WT and PD-1 mice had equal size (fig. S19). Thus, features associated with metabolism-driven differentiation of myeloid progenitors are enhanced early in tumor-bearing PD-1 KO mice.

In addition to cholesterol synthesis, mevalonate also leads to the synthesis of isoprenoids, including geranylgeranyl pyrophosphate (GGPP) (fig. S17), which is required for protein geranylgeranylation catalyzed by geranylgeranyltransferase and has an active role in the up-regulation of RORC expression (49). Our metabolite analysis showed increased GGPP (Fig. 7I), providing a mechanistic explanation for the up-regulation of RORC in PD-1deficient myeloid cells. Cholesterol accumulation is associated with skewing of hematopoiesis toward myeloid lineage and monocytosis, induces a proinflammatory program in monocytes/macrophages and DC, and amplifies TLR signaling (5052). Together, these results unravel a previously unidentified role of PD-1 targeting in regulating myeloid lineage fate commitment and proinflammatory differentiation of monocytes, macrophages, and DC during tumor-driven emergency myelopoiesis, through metabolic reprogramming.

Previously, it was determined that monocyte/macrophage terminal differentiation is controlled by the combined actions of retinoid receptors and the nuclear receptor peroxisome proliferatoractivated receptor (PPAR), which is regulated by cholesterol and promotes gene expression and lipid metabolic processes, leading to terminal macrophage differentiation (26, 53). Because our in vitro studies showed that PD-1deficient myeloid progenitors developed a distinct metabolic program with elevated cholesterol metabolism, we examined whether PD-1 ablation might alter the expression of PPAR in addition to RORC. We found that the expression of PPAR was elevated in CD11b+Ly6C+ monocytic cells and M isolated from tumors of PD-1/ and PD-1f/fLysMcre mice (Fig. 8, A to C). Because PD-1deficient myeloid progenitors developed robust mitochondrial activity during culture in vitro (Fig. 7, G and H) and PPAR is involved in mitochondrial function (53), we examined whether myeloid cells in tumor-bearing mice have improved mitochondrial metabolism, a feature that has an important role in supporting antitumor function of other immune cells (54). Monocytes, M, and DC isolated from tumor of PD-1/, and PD-1f/fLysMcre mice had increased mitochondrial membrane potential compared with myeloid cells from control tumor-bearing mice, consistent with enhanced mitochondrial metabolism (Fig. 8, D to G).

(A to C) Expression of PPAR in myeloid cells at the B16-F10 site in PD-1f/f, PD-1f/fLysMcre, and PD-1/ mice was examined by flow cytometry. Mean percentages SEM (A), representative histograms (B), and contour plots (C) of PPAR-expressing CD11b+Ly6C+, CD11b+F4/80+, and CD11c+MHCII+ subsets. (D to G) Mitochondrial metabolic activity of myeloid cells at the B16-F10 tumor site in PD-1f/f, PD-1f/fLysMcre, and PD-1/ mice was examined by assessing mitochondrial membrane potential using MitoRed. Mean fluorescence intensity (MFI) SEM of MitoRedpositive CD11b+Ly6C+, CD11b+F4/80+, and CD11c+MHCII+ subsets within the CD45+CD11b+ gate (D to F) and representative plots of FACS analysis (G) are shown. (H to L) In parallel, expression of IFN-, IL-17A, IL-2, IL-10, RORC, and ICOS in CD8+ TCM and TEM isolated from B16-F10bearing PD-1f/f and PD-1f/fLysMcre mice was assessed by flow cytometry. Representative histograms (H), contour plots (I and K), and mean percentages SEM (J, L, and M) within the CD44hiCD62Lhi gate (for TCM) and CD44hiCD62lo gate (for TEM) cells are shown. Data are from one representative of four independent experiments (*P < 0.05, **P < 0.01, and ***P < 0.005).

We investigated whether these significant immunometabolic changes of myeloid cells, induced by myeloid-specific PD-1 targeting, affected immunological properties of T cells that have key roles in their antitumor function. Compared with control PD-1f/f tumor-bearing mice, PD-1f/fLysMcre tumor-bearing mice had no quantitative differences in CD4+ or CD8+ TEM and TCM cells (fig. S20A) but had significant functional differences. There was an increase of IFN-, IL-17, and IL-10producing CD8+ TEM cells and IL-2producing CD8+ TCM cells (Fig. 8, H to J). Inducible T cell costimulator (ICOS) and lymphocyte-activation gene 3 (Lag3) were elevated in T cells from PD-1f/fLysMcre tumor-bearing mice but cytotoxic T-lymphocyte-associated protein 4 (CTLA4), T cell immunoglobulin and mucin domain 3 (Tim3), CD160, and PD-1/PD-L1 were comparable in T cells from PD-1f/f and PD-1f/fLysMcre tumor-bearing mice (Fig. 8, K to M, and fig. S20B). These findings are significant because IL-17producing T helper cell 17 (TH17)/ T cytotoxic cell 17 (Tc17) cells have enhanced antitumor function and mediate durable tumor growth inhibition (55). Moreover, T cells with a hybrid phenotype producing both IFN- and IL-17 might have superior antitumor properties by combining the enhanced effector function of TH1/Tc1 and the longevity and stemness of TH17/Tc17 cells (56). In our studies, these properties of TEM cells correlated with improved antitumor function in PD-1f/fLysMcre mice.

To examine experimentally whether PD-1deficient myeloid cells differentiated in tumor-bearing mice in vivo have improved capacity of inducing antigen-specific T cell responses, we assessed responses of the same primary CD4+ or CD8+ T cells to antigen-loaded DCs isolated from PD-1/ or control mice bearing B16-F10 tumors (fig. S21A). DCs isolated from the spleen of tumor-bearing WT and PD-1/ mice were pulsed with ovalbumin (OVA) and cocultured with OVA-specific CD4+ or CD8+ T cells from OTI or OTII T cell receptor (TCR)transgenic mice. DCs from tumor-bearing PD-1/ mice had superior ability to induce OTI and OTII T cell proliferation and IFN- expression (fig. S21, B and C). Together, our data provide evidence that myeloid cellintrinsic PD-1 ablation induces potent antitumor immunity by decreasing accumulation of MDSC and promoting proinflammatory and effector monocytic/macrophage and DC differentiation, thereby leading to enhanced effector T cell responses.

Our present studies reveal a previously unidentified role of the PD-1 pathway in regulating lineage fate commitment and function of myeloid cells that arise from tumor-driven emergency myelopoiesis. These outcomes are mediated by myeloid-intrinsic effects of PD-1 ablation, leading to altered signaling and metabolic reprogramming of myeloid progenitors characterized by enhanced differentiation and elevated cholesterol synthesis. Consequently, the accumulation of immature immunosuppressive and tumor-promoting MDSC is diminished, and the output of differentiated, inflammatory effector monocytes, M, and DC is enhanced. These immunometabolic changes of myeloid cells promote the differentiation of TEM cells and systemic antitumor immunity in vivo despite preserved PD-1 expression in T cells.

We found that PD-1deficient myeloid progenitors had enhanced activation of Erk1/2 and mTORC1 in response to G-CSF. These results indicate that Erk1/2 and mTORC1, a downstream mediator of phosphatidylinositol 3-kinase (PI3K)/Akt signaling, which are major targets of PD-1 in T cells (2), are subjected to PD-1mediated inhibition in myeloid cells. These results are revealing because Erk1/2 phosphorylation subverts MDSC-mediated suppression by inducing M-MDSCs differentiation to APC (39). Erk and PI3K regulate glycolysis in response to G-CSF (57). PI3K/Akt/mTORC1 signaling is critical in myeloid lineage commitment. Expression of constitutively active Akt in CD34+ cells induces enhanced monocyte and neutrophil development, whereas a dominant negative Akt has the opposite effect (58). mTORC1 is necessary for the transition of hematopoietic cells from a quiescent state to a prepared alert state in response to injury-induced systemic signals (59), for G-CSFmediated differentiation of myeloid progenitors (40), and for M-CSFmediated monocyte/macrophage generation (41). mTORC1 stimulates translation initiation through phosphorylation of 4E (eIF4E)binding protein 1 (4E-BP1) and ribosomal S6 kinases and has a decisive role in the expression of glucose transporters and enzymes of glycolysis and PPP (47). Consistent with these, our studies showed that PD-1deficient myeloid progenitors had elevated expression of glycolysis and PPP intermediates after culture with emergency cytokines in vitro and enhanced monocytic differentiation in tumor-bearing mice in vivo. Together, our findings indicate that PD-1 might affect the differentiation of myeloid cells by regulating the fine tuning of signaling responses of myeloid progenitors to hematopoietic growth factors that induce myeloid cell differentiation and lineage fate determination during emergency myelopoiesis. Further studies will identify how receptor-proximal signaling events mediated by hematopoietic growth factors are targeted by PD-1 in a manner comparable to PD-1mediated targeting of signaling pathways in T cells (2, 34, 35).

Our metabolite analysis showed that a notable difference of PD-1deficient myeloid progenitors was the increased expression of mevalonate metabolism enzymes and the elevated cholesterol. mTORC1 activates SREBP1, which induces transcription of enzymes involved in fatty acid and cholesterol synthesis (48), thereby leading to glycolysis-regulated activation of the mevalonate pathway. Our signaling studies showing enhanced mTORC1 activation and our metabolic studies showing enhanced mitochondrial metabolism and increased cholesterol content in PD-1deficient myeloid cells provide a mechanistic link between the altered differentiation of PD-1deficient myeloid progenitors and the altered immunophenotypic and functional program of PD-1deficient monocytes, M, and DC in tumor-bearing mice. Cholesterol drives myeloid cell expansion and differentiation of macrophages and DC (50, 51, 60) and promotes antigen-presenting function (61). These properties are consistent with the metabolic profile and the increased cholesterol of PD-1deficient myeloid progenitors; the inflammatory and effector features of differentiated monocytes, M, and DC; and the enhanced T effector cell activation in tumor-bearing mice with myeloid-specific PD-1 ablation that we identified in our studies. By such mechanism, PD-1 might centrally regulate antitumor immunity, independently of the expression of PD-1 and its ligands in the TME. Our studies showed that PD-1 expression on myeloid progenitors is an early event during tumor-mediated emergency myelopoiesis and indicate that PD-1 blockade at early stages of cancer might have a decisive effect on antitumor immunity by preventing MDSC generation from myeloid progenitors and inducing the systemic output of effector myeloid cells that drive antitumor T cell responses.

In addition to its expression in myeloid progenitors, in the bone marrow, we found that PD-1 is expressed in all myeloid subsets including M-MDSC, PMN-MDSC, CD11b+F4/80+ M, and CD11c+MHCII+ DC in the tumor and the spleen of tumor-bearing mice, albeit at different levels. This difference might be related to gradient of tumor-derived factors responsible for PD-1 induction such as G-CSF and GM-CSF that we found to induce PD-1 transcription in myeloid progenitors. This possibility would be consistent with the gradual up-regulation of PD-1 expression in splenic myeloid cells, determined by our kinetics studies, which correlates with tumor growth that might be responsible for the increase of systemic levels of tumor-derived soluble factors that induce PD-1. Other cues of the TME known to mediate the activation step of MDSC (14) might also be responsible for the induction of higher PD-1 expression level in the tumor versus the splenic myeloid cells. Our findings unravel a previously unidentified role of PD-1 in myeloid cell fate commitment during emergency myelopoiesis, a process that is involved not only in antitumor immunity but also in the control of pathogen-induced innate immune responses and sterile inflammation (62).

An additional important finding of our studies is that the nuclear receptors RORC and PPAR are up-regulated in myeloid cells by PD-1 ablation. RORs were initially considered retinoic acid receptors but were subsequently identified as sterol ligands. RORC not only is induced by sterols and isoprenoid intermediates (49) but also serves as the high-affinity receptor of the cholesterol precursor desmosterol (63, 64), a metabolic intermediate of cholesterol synthesis via the mevalonate pathway that regulates inflammatory responses of myeloid cells (52, 60). Desmosterol and as sterol sulfates function as endogenous RORC agonists and induce expression of RORC target genes (63, 64). Our studies showed that, in addition to cholesterol, the mevalonate metabolism product GGPP that has an active role in the up-regulation of RORC expression (49) was elevated in PD-1deficient myeloid cells, providing a mechanistic basis for our finding of the elevated RORC expression. Retinoid receptors and PPAR together regulate monocyte/macrophage terminal differentiation (26). Although initially thought to be involved in proinflammatory macrophage differentiation, it was subsequently understood that PPAR predominantly promotes macrophage-mediated resolution of inflammation by inducing expression of the nuclear receptor liver X receptor and the scavenger receptor CD36, thereby regulating tissue remodeling (65). PPAR also regulates macrophage-mediated tissue remodeling by efferocytosis and production of proresolving cytokines (66), which can suppress cancer growth (67). The combined actions of RORC and PPAR induced by myeloid-specific PD-1 ablation might be involved in the antitumor function by promoting both proinflammatory and tissue remodeling properties of myeloid cells. Future studies will dissect the specific role of each of these nuclear receptors on the antitumor immunity induced by myeloid cellspecific ablation of PD-1.

In conclusion, our results provide multiple levels of evidence that myeloid-specific PD-1 targeting mediates myeloid cellintrinsic effects, which have a decisive role on systemic antitumor responses. This might be a key mechanism by which PD-1 blockade induces antitumor function. Recapitulating this immunometabolic program of myeloid cells will improve the outcome of cancer immunotherapy.

immunology.sciencemag.org/cgi/content/full/5/43/eaay1863/DC1

Materials and Methods

Fig. S1. Gating strategy of hematopoietic and myeloid precursors in the bone marrow.

Fig. S2. Gating strategy of myeloid subsets in the spleen and tumor site.

Fig. S3. Cancer-induced emergency myelopoiesis in three different mouse tumor models.

Fig. S4. PD-1 expression is induced on myeloid progenitors by emergency cytokines.

Fig. S5. Gating strategy for identification of MDSC in human blood samples.

Fig. S6. PD-1 expression in human MDSC.

Fig. S7. PD-1 ablation alters tumor-driven emergency myelopoiesis.

Fig. S8. PD-1 ablation induces expression of RORC and IRF8 in myeloid cells expanding in response to tumor-driven emergency myelopoiesis.

Fig. S9. PD-1 ablation induces expression of RORC and IRF8 in myeloid cells expanding in mice-bearing MC38 or MC17-51 tumors.

Fig. S10. PD-1 ablation increases the output of RORChi effector-like myeloid cells at early stages of tumor growth.

Fig. S11. Therapeutic targeting of PD-1 increases effector features of myeloid cells and decreases tumor growth.

Fig. S12. Myeloid-specific and T cellspecific PD-1 deletion.

Fig. S13. Myeloid-specific PD-1 ablation promotes expansion of IRF8hi and RORChi monocytes and IFN-producing monocytes and macrophages in the tumor site.

Fig. S14. Tumor-induced emergency myelopoiesis and myeloid effector differentiation in Rag2-deficient mice treated with PD-1 antibody.

Fig. S15. PD-1 ablation reduces the threshold of growth factormediated signaling in GMP.

Fig. S16. Myeloid-specific PD-1 ablation induces a distinct metabolic profile characterized by elevated cholesterol.

Fig. S17. Metabolic pathways linking glycolysis to PPP, fatty acid, and cholesterol synthesis.

Fig. S18. Schematic presentation of the mevalonate pathway.

Fig. S19. Increase of glucose uptake and neutral lipid content in PD-1deficient myeloid progenitors early after tumor implantation.

Fig. S20. Myeloid-specific PD-1 deletion alters the immunological profile of CD8+ TEM cells.

Fig. S21. PD-1 ablation enhances antigen presentation ex vivo by tumor-matured DC.

Table S1. List of significantly different metabolites.

Table S2. List of antibodies used for surface staining.

Table S3. List of antibodies used for intracellular staining.

Table S4. List of antibodies used for phenotype of human MDSC.

Table S5. Raw data in Excel spreadsheet.

References (6871)

Acknowledgments: Funding: This work was supported by NIH grants CA183605, CA183605S1, and AI098129-01 and by the DoD grant PC140571. Author contribution: L.S. participated in the conceptualization of the project and experimental design, performed experiments and the analysis and validation of the data, prepared figures, and participated in the preparation of the manuscript. M.A.A.M. performed experiments and the analysis and validation of the data, prepared figures, and participated in the preparation of the manuscript. J.D.W., N.M.T.-O., A.C., R.P., Q.W., and M.Y. participated in various steps of the experimental studies. J.A. participated in the experimental design of metabolite studies and the formal analysis and the validation of the data and participated in the preparation of the manuscript. N.P. participated in the conceptualization of the project, designed and performed the bioenergetics studies, and participated in experiments, the analysis and validation of the data, and the preparation of the manuscript. V.A.B. had the overall responsibility of project conceptualization, experimental design, investigation, data analysis and validation, and preparation of the manuscript and figures. Competing interests: V.A.B. has patents on the PD-1 pathway licensed by Bristol-Myers Squibb, Roche, Merck, EMD-Serono, Boehringer Ingelheim, AstraZeneca, Novartis, and Dako. The authors declare no other competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper or the Supplementary Materials.

See the rest here:
Targeted deletion of PD-1 in myeloid cells induces antitumor immunity - Science

Bone Marrow Stem Cells Comments Off on Targeted deletion of PD-1 in myeloid cells induces antitumor immunity – Science | January 4th, 2020

Researchers at Baylor College of Medicine have discovered a new mechanism that helps maintain and repair bones in adults. Ultimately, this could help develop new therapeutic strategies to improve bone healing.

Knee Bones

Osteoporosis is a skeletal disease characterized by reduced bone density and changes in the microarchitecture of bones. These changes weaken the bone and increase the risk of fracture. This disease develops particularly in older people. Today, a new study could eventually lead to the development of therapeutic strategies to improve bone healing in these patients. According to the results published in the journal Cell Stem Cell on the 5th December, 2019 researchers have discovered a new mechanism that contributes to the maintenance and repair of bones in adults.

Read Also: HGH Is Now A Solid Treatment For Osteoporosis According To Studies

Adult bone repair relies on the activation of bone stem cells, which still remain poorly characterized. Bone stem cells have been found both in the bone marrow inside the bone and also in the periosteum the outer layer of tissue that envelopes the bone. Previous studies have shown that these two populations of stem cells, although they share many characteristics, also have unique functions and specific regulatory mechanisms. said Dr. Dongsu Park, assistant professor of molecular and human genetics, pathology and immunology at Baylor College of Medicine, where the study was conducted.

Of these two populations, periosteal stem cells are the least known. Although the scientists know that this is a heterogeneous population of cells that can contribute to the thickness, formation and repair of bone fractures, no one has yet been able to distinguish between the different subtypes of bone stem cells in order to study the regulation of their different functions.

Here, however, Dongsu Park and colleagues were able to develop a technique in mice to identify different subpopulations of periosteal stem cells, define their contribution to the repair of bone fractures and identify the specific factors that regulate their migration and proliferation under physiological conditions.

In rats, they discovered specific markers for this class of cells. They identified a specific subset of stem cells that contribute to lifelong bone regeneration in adults. They also observed that periosteal stem cells react to inflammatory molecules, chemokines, which are normally produced in bone injuries.

Read Also: The Exciting Future of Joint and Cartilage Repair

In detail, periosteal stem cells have receptors that bind to the CCL5 chemokine. The CCL5 chemokine sends a signal to the cells to migrate to the injured bone and repair it. By suppressing the CCL5 gene in rats, the researchers found defects in bone repair that delayed healing. However, when they gave CCL5 to rats that had lost CCL5, the bones recovered faster.

Our findings contribute to a better understanding of the healing of adult bones. We believe this is one of the first studies to show that bone stem cells are heterogeneous and that different subtypes have unique properties that are regulated by specific mechanisms, said Dongsu Park. We have identified markers that allow us to distinguish between the subtypes of bone stem cells and have investigated what each subtype contributes to bone health. The understanding of how the functions of bone stem cells are regulated offers the possibility of developing new therapeutic strategies for the treatment of bone damage in adults.

Read Also: Implants from Own Stem Cells May Offer Solution to Back Pain, Researchers Say

In the long term, these findings may therefore have potential therapeutic applications, particularly in people with osteoporosis or diabetes.Indeed, people with diabetes may be prone to falls and fractures due to possible neurological, visual or renal complications. In addition, bone fragility in diabetics is likely to be due to changes in bone remodeling and, in particular, an increase in bone resorption.

https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(19)30458-8?

Mitochondrial Damage Can Cause Osteoporosis According to Study

Man Destroys Kidneys With Too Much Vitamin D

Could Stem Cell Injections Get Rid of Low Back Pain Completely?

Natural Remedies You May Want to Try For Arthritis

To Grow Taller With Limb Lengthening Surgery Is Not For The Fainthearted

HGH Deficiency in Children: The Latest Facts

Hormones Replacement Therapy for Graceful Aging A Major Trend

Continued here:
Researchers at Baylor College of Medicine Discover How to Improve Bone Repair - Gilmore Health News

Bone Marrow Stem Cells Comments Off on Researchers at Baylor College of Medicine Discover How to Improve Bone Repair – Gilmore Health News | January 4th, 2020

This weeks Cardio Round-up features a look back at what you may have missed during the holidays, as well as some of the big 2019 cardiology stories.

The past year saw some big stories like the Apple Heart study, presented at ACC.19, which essentially validated the ability of a wearable device (an Apple iWatch) equipped with a tachogram-tracking algorithm was able to detect pulse irregularities associated with atrial fibrillation. Icosapent ethyl also featured prominently, gaining an FDA approval for the reduction of cardiovascular disease risk as an add-on to statin therapy in high-risk patients with hypertriglyceridemia. Dapagliflozin (highlighted in the DAPA-HF study) also was shown to be an effective treatment for heart failure in both diabetic and non-diabetic patients.

2019 In Cardiology: Apple Heart Study Lands; Icosapent Ethyl Gets FDA Nod for New Indication; Dapagliflozin For Nondiabetics; and More

A new observational study published inEuropacesuggests it is possible to monitor and predict individual progression ofatrial fibrillation (AFib) using pacemakers or defibrillators.We aimed to study the progression of AER in individual patients with implantable devices and AFib episodes, the paper authors wrote. The study results indicated that the slope of AAR changes during the progression of AFib showed patient-specific patterns correlating with the time-to-completion of AER (R2 = 0.85). This technology opens up enormous possibilities in personalized medicine for AFib patients because it allows us to determine the progression rate of the arrhythmia in each individual and to optimize the timing of medical intervention with current treatment options, one of the researchers said in a press release.

Personalized Medicine for AFib: How Electric Activity in the Heart Can Predict Individual Progression of Atrial Fibrillation

A research team, publishing the study in the Journal of Molecular and Cellular Cardiology, worked on converting adipogenic mesenchymal stem cells, which reside within fat cells, into cardiac progenitor cells. The ensuing cardiac progenitor cells can be programmed to aid heartbeats as a sinoatrial node (SAN), which is part of the electrical cardiac conduction system.We are reprogramming the cardiac progenitor cell and guiding it to become a conducting cell of the heart to conduct electrical current, said study co-author Bradley McConnell, associate professor of pharmacology, in a press release. Results of this study show that the SHT5 combination of transcription factors can reprogram CPCs into Pacemaker-like cells.

The Next Generation of Biologic Pacemakers? New Discovery in Stem Cells from Fat Creates Another Alternative Treatment

Diabetes mellitus is an independent predictor for heart failure, according to the findings of a study published inMayo Clinic Proceedings. In this study, using the Rochester Epidemiology Project, researchers assessed the long-term impact ofdiabeteson the development of heart failure by including 116 study subjects with diabetes, who were matched 1:2 based on age, hypertension, sex, coronary artery disease and diastolic with 232 participants without diabetes. The results showed that that diabetes is an independent risk factor for the development of heart failure. Over the duration of 10 years, 21% of participants with diabetes developed heart failure, independent of other causes. The researchers observed that by comparison, only 12% of patients without diabetes developed heart failure. The key takeaway is that diabetes mellitus alone is an independent risk factor for the development of heart failure, wrote one of the authors.

Diabetes is an Independent Predictor for Heart Failure

A new study suggests that regularly getting a good nights sleep isnt just a helpful overall health recommendation but is also an essential way to keep risk for heart disease and stroke down. The paper, published in theEuropean Journal of Cardiology, included more than 300,000 participants initially free of cardiovascular disease (CVD) from UK Biobank. According to the results, there were 7,280 documented cases of incident CVD (4,667 coronary heart disease and 2,650 stroke) cases. Participants with a sleep score of 5 had a 35% reduced risk for CVD, a 34% reduced risk for coronary heart disease, and a 34% reduced risk for stroke when compared to participants with a score of 0-1.As with other findings from observational studies, our results indicate an association, not a causal relation, one of the authors said in a press release. However, these findings may motivate other investigations and, at least, suggest that it is essential to consider overall sleep behaviors when considering a persons risk of heart disease or stroke.

Getting Quality Sleep, and the Right Amount, Can Offset Genetic Susceptibility for Heart Disease and Stroke Risk

Read more:
Cardio Round-up: Look Back at 2019, The Importance of Sleep, and More - DocWire News

Cardiac Stem Cells Comments Off on Cardio Round-up: Look Back at 2019, The Importance of Sleep, and More – DocWire News | January 4th, 2020