Imagine finding out that your bone marrow or blood stem cells could save the life of someone who needed it even a complete stranger. Memorial Sloan Kettering Cancer Center (MSK) nurse Grace Yang, RN, received such a call in March 2024.

This is definitely something I was never expecting to happen to me, Yang says. But because I work in the Bone Marrow Transplant [BMT] Service, I knew the impact it could have on somebody elses life. It felt like a privilege to be able to help in a different way. Yang works as an office practice nurse for BMT and cellular therapy specialist Heather Landau, MD.

Stem cell and bone marrow donations can offer people with blood cancer and other blood diseases the best chance for a cure. There is an urgent need for more donors between the ages of 18 and 40, especially donors of non-European and mixed ancestry. Yang, who is of Asian ancestry, was 29 when she donated.

You may wonder how to donate, whether donating bone marrow or blood stem cells is painful, and whats involved in bone marrow and stem cell transplantation procedures. Heres what you need to know.

First, some background: Transplanting donor stem cells that form new blood cells in a patient is a lifesaving treatment for many people with blood cancers like leukemia and lymphoma,as well as some other blood diseases. Contrary to what many people might think, the cells used in the transplant are usually collected from the donors bloodstream. Only on rare occasions are the stem cells taken from the bone marrow.

These donor cells are needed because before receiving a transplant, patients are given chemotherapyand sometimes radiationto wipe out the cancer. These treatments also destroy the patients blood-making cells.So they need healthy blood stem cells to be infused into their body. This transplant procedure enables patients to grow new blood cells and recover from the treatment.

Every year, about 18,000 people in the United States are diagnosed with a life-threatening illness for which a stem cell transplant from a donor is the best treatment option. Unfortunately, only about 30% of those patients have a family member who is the best match. That means that about 12,000 people need to find an unrelated donor.

One way that donors are found is through NMDP, which maintains a registry for connecting unrelatedvolunteer donorswith patientsin need. Unfortunately, many people are reluctant to join this registrybecause they dont realize the process is easier than they think, nor do they fully appreciate the desperate need for donors.

Yang signed up for the NMDP registry through a community drive, before she even worked in the BMT field. More than a decade later, she learned she was a match with a patient. I encourage all the people around me to sign up, she says. They are shocked that its so easy.

Even if a patient has an adult sibling who is the right age to donate, there is only a 1 in 4 chance a sibling will be a perfect match.

Siblings and other family members are often a half match, and this can be a good option for many patients. But for some patients, the best way to maximize the chances of a successful transplant is to find a fully matched donor even one who is unrelated.

There are a lot of misconceptions about donating bone marrow and stem cells, especially that it is a burden or painful.

When Yang first told her parents that she had been matched to a patient in need, she found out that her father had also donated bone marrow to stranger more than 20 years ago. At that time, the process was more complicated. Because of his past experience, her father was a bit concerned about what she might go through, but she explained that thanks to advances in technology, the donation process is much easier than it used to be.

Here is a step-by-step guide:

Because studies have shown that patients receiving blood stem cells from younger donors have a better long-term survival rate, you must be between the ages of 18 and 40 to join the registry.

Joining the registry is simple. Go to http://www.bethematch.org to order a collection test kit that will be sent to your house. The website may also direct you to a local registration drive in your area. Once you get the kit, all you need to do is wipe a cotton swab on the inside of your cheek, seal it in a provided container, and mail it back.

You will be contacted if you are a full match or a partial match for a patient in need of a bone marrow or stem cell transplant. Congratulations! Your cells may be the best option to save that persons life.

Several additional steps will be needed to confirm that a transplant with your cells is likely to be successful. These include filling out a health questionnaire, having additional blood tests, and undergoing a physical examination.

If testing confirms that you are a suitable donor, your donation will be scheduled for a time that works for you and for the patients treatment schedule. Depending on where you live, you may need to travel to one of the specialized facilities that collects the stem cells from blood or bone marrow. If you need to travel, your expenses will be covered by NMDP.

Yang traveled to Chicago to make her donation, and the NMDP not only arranged her trip and paid for everything, but it also paid for her sister to travel with her so she didnt have to go alone.

Thanks to procedures developed over the past few decades, 90% of the time the stem cells needed for the transplant are taken from the blood, not the bone marrow. This process is much easier for donors because it does not require surgery.

With stemcell donation from the blood, there is little pain. It is very similar to donating blood platelets. The main difference is that for a few days ahead of time, donors need to receive an injection of a drug called filgrastim (Neupogen), which stimulates the bone marrow to produce extra blood-forming stem cells. Donors may experience some bone pain or a low-grade fever while taking filgrastim, but the side effects usually are not severe and go away after the donation process is complete.

Most people are able to give themselves injections of filgrastim at home, so they dont need to go to the doctor every day.

On the day of the donation, the donor is hooked up to what is called an apheresis machine. The blood is collected from one arm, sent through a machine that removes the stem cells, and then returned to the other arm. Other than the initial needle prick, it is not a painful experience.

The process takes several hours, during which donors often read or watch movies. It may be necessary for donors to return for a second day, depending on how many cells are retrieved.

For Yang, the donation took about 3 hours. We started in the morning, and I was done before lunch, she says. The nurses did a great job of making me feel comfortable and checked on me often throughout the process.

In only about 10% of cases, doctors may recommend the patient receive a bone marrow donation requiring a surgical procedure. Donors are placed under general anesthesia, while bone marrow is removed from small holes drilled into their pelvic bones.

This procedure takes an hour or two, and usually donors can go home that same day.

If you have donated stem cells from your blood, you may feel tired for a few days, but many donors feel no effects at all the next day.

If you have donated bone marrow, you will probably have some pelvic and hip pain, as well as some bruising, for a few days after the procedure. These aches and pains can be controlled with over-the-counter pain medications like Advil and Tylenol. Most people can go back to regular activities right away, but your medical team can provide more details for specific activities.

The process by which the donor and recipient are matched is called HLA (human leukocyte antigen) typing. Its not the same as blood type.Instead, it has to do with the immune proteins that we all inherit at birth from both of our parents. The immune system uses these proteins to understand which cells belong to your body and which do not. A perfect match means that 8 out of 8 markers are the same.

Matching is not related to gender, so your donation can go to someone of any gender as long as the HLA markers align.

Yang has not yet learned anything about the patient who received her cells, but hopes to in the coming months. I just feel so lucky that I was able to do something amazing for somebody else, she says.

Not everyone who needs a donor is able to find one who is fully matched. A patients best chance of finding a donor is someone within their own ethnic group. Members of certain ethnic groups, including those of Latin American, Asian, African, and Middle Eastern ancestry, have a harder time finding a match. These groups tend to be underrepresented in public registries.

For example, for people of Latin American descent, the odds of finding a matched donor in a public registry are less than 50%. For Black patients, the odds are only about 30%. It may be even harder for people of mixed ethnic backgrounds to find donors because their HLA makeup can be more complex.

This makes it especially important for people from these underrepresented ethnic groups, as well as those who have mixed ancestry, to join a public registry like NMDP.

For patients who are unable to find a fully matched donor, there are other options. These include:

These treatments can offer patients very good outcomes, but in some cases its better to have a donor who is a perfect match.

Yang says even though she works as a BMT nurse, she still had questions throughout the donation process. Everyone at NMDP is great about addressing any concerns you may have about the process, and they have many great resources, she says. Any time I have the opportunity to talk to someone about this, I encourage them to get involved.

Read the original post:
Donating Bone Marrow and Stem Cells: The Process and What To Expect

Diseases like leukemia, lymphoma, multiple myeloma or bone marrow failure syndromes can affect bone marrow. Bone marrow is a spongy tissue inside bones that is rich in stem cells and helps to produce blood and immune cells. Healthy stem cells are often needed to treat these marrow-impacting diseases. This is why stem cell transplant and bone marrow transplant are often used interchangeably, the main difference being the method of collection of the stem cells.

In some cases especially for some blood cancers a person can use stem cells from their own body to facilitate giving higher doses of chemotherapy in an attempt to cure the disease. This is called an autologous stem cell transplant. The other option, especially when a recipients bone marrow is already compromised, requires a donor to provide healthy stem cells, which is called an allogeneic stem cell transplant.

William Hogan, M.B., B.Ch., is a consultant hematologist and director of the Mayo Clinic Blood and Bone Marrow Transplant Program. Dr. Hogan says that about one-quarter of transplant recipients at Mayo Clinic receive an allogeneic transplant, which means a donors immune system is used in a life-sustaining and curative therapy to help eradicate disease.

If you are selected (as a bone marrow donor), you might be a critically important part of a persons treatment, he says.

To help someone with an allogenic stem cell transplant, you can donate stem cells from your:

Health care providers determine which type of donation is best for a person on a case-by-case basis. Factors that influence this decision can include the type of disease, the degree of donor matching, and other patient characteristics like age and remission status.

Dr. Hogan says that in the past, family members especially fully matched siblings were considered the best option to donate bone marrow. But the fact is that a majority of people who need a bone marrow transplant dont have a family member who is a full match.

Additionally, cancers that require bone marrow transplants frequently affect older adults. Older adult sibling donors are more likely to have co-morbidities that can put the donor at risk and can increase the risk of complications with the recipient.

For these reasons, the National Marrow Donor Program manages a registry of bone marrow donors that can be matched with unrelated recipients.

To help increase the long-term survival rate of a bone marrow recipient, the National Marrow Donor Program prefers healthy donors who are 18 to 35 years old, although Dr. Hogan says that older donors can be an option in select circumstances. He says that determining a good match for a bone marrow transplant includes looking at a donors proteins in cells called human leukocyte antigens (HLA) and blood type. Optimal donors will match HLA and blood type and be free of genetic and infectious diseases.

Being a donor does require a time commitment, often 20 to 30 hours over 4 to 6 weeks from screening to donation. In terms of financial requirements to be a bone marrow donor through the National Marrow Donor Program, there arent any. All your medical and travel expenses are covered.

The U.S. Health Resources & Services Administration states that even though there are more than 40 million potential bone marrow donors in the world, its harder for people with racially and ethnically diverse backgrounds to find a match.

Getting greater diversity in the bone marrow registry is important, since ethnicity impacts HLA matching to some degree, says Dr. Hogan. We need to ensure that underrepresented minorities have adequate representation. We want to provide better donors for better outcomes.

According to the National Marrow Donor Program, people who need bone marrow are most likely to match with someone of their own ethnic background. The odds of finding a match through the bone marrow donation registry vary based on ethnic background. For example, if a recipient is white, they have a 79% chance of finding a match. If they are Hispanic or Latino, the odds of a match drop to 48%. And for recipients who are Black or African American, the chance of finding a match is just 29%.

If you donate bone marrow, you will undergo surgery. During the surgery, you are under general anesthesia and a needle is inserted into your hip bones to collect the bone marrow. The effects of general anesthesia can include more minor complaints such as a sore throat and nausea, as well as some serious but rare complications.

Aside from the use of anesthesia, other risks of bone marrow donation surgery include:

After the surgery to collect bone marrow, you might experience pain where the needle was inserted when you bend or walk. The pain tends to lessen after the first several days and is usually gone within 6 to 12 weeks.

Dr. Hogan says that there are misconceptions about the pain associated with bone marrow donation. Many donors report that the value of their donation and the contribution to saving somebodys life often outweighs the discomfort of the procedure, he says.

He explains that donation surgery is more involved than a blood draw, but the pain should be well managed, and most donors have a positive experience.

Many people take several days off following bone marrow collection surgery so that they can take rest periods throughout the day and slowly resume normal activities. After the collection, it takes a few weeks for your bone marrow to replenish, and after that, most symptoms like soreness and fatigue should be gone. The total recovery process can typically take 2 to 6 weeks, according to Dr. Hogan.

If you are highly motivated to help others, Dr. Hogan suggests that you start at the National Marrow Donor Programs Be the Match site, where you can learn more about the process to join and what happens if you are selected as a match.

Joining the voluntary registry is a simple process. First, youll answer questions about your medical history in an initial screening. If you qualify, the next step is to swab the inside of your cheek to determine your HLA type. Those two steps are what it takes to join.

Once youve joined the registry, you might not be identified as a match until you opt out or age out when you turn 61. Once youve joined the registry, you can change your mind about being a donor at any time.

Even if you join the registry with the intent of helping a friend or family member, it might turn out that youre a better match for someone you dont know. If you do match, you might be asked to donate either bone marrow or blood, depending on what the recipient needs.

If you are selected as a match, your donation has the power to transform someones life.

Relevant reading

Mayo Clinic The Integrative Guide to Good Health

As Americans seek greater control of their health, explosive growth is taking place in the field of integrative medicine. More and more, people are looking for more natural or holistic ways to maintain good health; they want not only to manage and prevent illness but also to improve their quality

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What to expect as a stem cell or bone marrow donor

Curr Opin Hematol. Author manuscript; available in PMC 2022 Jan 1.

Published in final edited form as:

PMCID: PMC7769132

NIHMSID: NIHMS1651634

1.Division of Experimental Hematology and Cancer Biology, Cincinnati Childrens Medical center, Cincinnati, Ohio, 25228, USA

2.Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, 45229, USA

1.Division of Experimental Hematology and Cancer Biology, Cincinnati Childrens Medical center, Cincinnati, Ohio, 25228, USA

2.Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, 45229, USA

The bone marrow is the main site for hematopoiesis. It contains a unique microenvironment that provides niches that support self-renewal and differentiation of hematopoietic stem cells (HSC), multipotent progenitors (MPP), and lineage committed progenitors to produce the large number of blood cells required to sustain life. The bone marrow is notoriously difficult to image; because of this the anatomy of blood cell production- and how local signals spatially organize hematopoiesis-are not well defined. Here we review our current understanding of the spatial organization of the mouse bone marrow with a special focus in recent advances that are transforming our understanding of this tissue.

Imaging studies of HSC and their interaction with candidate niches have relied on ex vivo imaging of fixed tissue. Two recent manuscripts demonstrating live imaging of subsets of HSC in unperturbed bone marrow have revealed unexpected HSC behavior and open the door to examine HSC regulation, in situ, over time. We also discuss recent findings showing that the bone marrow contains distinct microenvironments, spatially organized, that regulate unique aspects of hematopoiesis.

Defining the spatial architecture of hematopoiesis in the bone marrow is indispensable to understand how this tissue ensures stepwise, balanced, differentiation to meet organism demand; for deciphering alterations to hematopoiesis during disease; and for designing organ systems for blood cell production ex vivo.

Keywords: Hematopoiesis, bone marrow organization and architecture, hematopoietic stem cell niches, hematopoietic progenitor niches, bone marrow microenvironment

Hematopoiesis takes place in the bone marrow (BM) where hematopoietic stem cells and multipotent progenitors (HSPC) self-renew and progressively differentiate into lineage-specific, unipotent, progenitors responsible for production of each major blood lineage. The bone marrow has been studied in detail using multiple approaches including scRNAseq, and in vivo lineage tracing studies [19]. These and other studies have dramatically changed our understanding of how the different stem and progenitor populations differentiate, and how they are regulated by the BM microenvironment- the collection of hematopoietic and stromal cells and structures that supports differentiation- during normal and stress hematopoiesis. Our understanding of the spatial organization of hematopoiesis in the bone marrow is less comprehensive. Spatial analyses of differentiating progenitors, their offspring, and the supporting microenvironment are challenging due to several factors (reviewed in [10]); a) the bone marrow is fully enclosed by opaque bone which makes direct observation difficult and requires extensive preparation steps in order to generate high quality samples for imaging analyses; b) the hematology field has used increasingly complex combinations of cell surface markers -requiring simultaneous detection upwards of 15 antibodies- to define each hematopoietic progenitor and mature cell in the bone marrow. In contrast fluorescent analyses are generally limited to much fewer (4-7) parameters preventing simultaneous identification of multiple cell types. Further, many antibodies used to define cells by flow cytometry fail to detect the same cells in imaging analyses, either because the signals are too dim or because sample preparation destroyed the epitopes recognized by that antibody; c) scRNAseq analyses of stromal cells in the bone marrow have revealed extraordinary complexity [79**]. However, there are no validated antibodies to detect many of these stromal populations and the field relies in Cre/fluorescent reporter mice that identify some stromal components but fail to completely resolve the different populations [11]; d) the bone marrow contains large numbers of mature cells but stem cells and progenitors are exceedingly rare. This makes identification of sufficient numbers of HSPC for adequately powered statistical analyses very challenging and time consuming; e) different groups have used different statistical approaches and methods to define proximity of cells to structures and a global consensus on which approaches to use has yet to emerge. Despite numerous challenges the field has made tremendous progress in defining the architecture of the BM and deciphering how local cues from the microenvironment regulate stem and progenitor cells. Here we summarize our current understanding of the spatial organization of the bone marrow, its impact on hematopoiesis, and discuss recent discoveries that are transforming the field.

The main structures that spatially organize the bone marrow are the bone, the vasculature, and a network of reticular stromal cells. The bone completely encloses the bone marrow, defines its boundaries, and projects trabeculae that penetrate into the BM parenchyma (). The bone marrow vasculature is composed of rare arterioles that enter through the bone and transform into transitional vessels that give rise to an extremely dense network of fenestrated sinusoids that occupy most of the BM space (). The vasculature is tightly associated with a network of perivascular reticular cells that spreads through the BM. Hematopoiesis takes place in the spaces between vessels, bone, and reticular cells (). Many other types of stromal (non-hematopoietic) cells are present in the bone marrow including sympathetic nerves, Schwann cells, adipocytes, osteoblasts, osteocytes, osteoblastic precursors, and diverse types of fibroblasts. These are reviewed elsewhere [1214]. These cells and structures in association with different types of hematopoietic cells-cooperate to provide distinct microenvironments that regulate and regionally organize-hematopoiesis in the bone marrow.

Schematic representation of the spatial organization of the mouse bone marrow under homeostasis. The endosteum, the vasculature and a network of reticular stromal cells define the volumes available for hematopoiesis. vWF+ HSC reside in a sinusoidal/megakaryocytic/reticular niche far from arterioles and the endosteum while vWF- reside in an arteriolar niche enriched in Ng2+ cells [38]. Note that this arteriolar niche also contains sinusoids and reticular cells. HSC in the central BM constantly traffic between reticular cells [27**]. Subsets of HSC -reserve HSC [33*] and MFG-HSC [26] localize to endosteal regions where they proliferate in response to stress, likely in areas undergoing simultaneous bone deposition by osteoblasts and bone resorption by osteoclasts [26]. GMP are distributed through the BM but form clusters in respond to stress [50]. Lymphoid progenitors have been mapped to the endosteum [18] but also to different types of reticular cells [42,60]. Erythropoiesis takes place in erythroblastic islands presumably adjacent to the same sinusoids that support erythroid progenitors [61,62,64*].

The best studied microenvironments in the bone marrow are the hematopoietic stem cell niches, which are responsible for ensuring that HSC are maintained through the life of the organism. The discovery of a two color strategy (LinCD48CD41CD150+) to detect HSC using confocal microscopy [15] led to an explosion of studies that used imaging to identify candidate HSC niche components that were later validated using complementary approaches [1522]. These analyses have been further refined by the development of mouse fluorescent reporter lines that identify populations highly enriched in HSC [2327**]. These studies showed that in the steady-state- HSC are always found as single cells and adjacent to perivascular cells and sinusoids. Most HSC exclusively localize to sinusoids but smaller fractions localize to areas that also contain arterioles and endosteal surfaces. Cells associated with each of these structures produce cytokines and growth factors that regulate HSC self-renewal and function (). The precise components of HSC niches and how they regulate HSC have been reviewed in detail elsewhere [13,28,29]. Here we will highlight recent insights from live imaging analyses of HSC.

Until recently live imaging of HSC in the bone marrow was restricted to experiments were HSC were prospectively isolated, transferred into recipient mice, and then imaged [30]. This has changed with the development of live imaging approaches of unperturbed HSC. Christodoulou et al., [26**] used Mds1GFP+, and Mds1GFP/+Flt3-Cre mice. In Mds1GFP+ mice the Mds1 promoter drives GFP expression in HSC and multipotent progenitors. However, in the Mds1GFP/+Flt3-Cre mice, Cre expression results in excision of the GFP cassette in all cells except a small (12%) subset of quiescent LT-HSC (MFG-HSC). Using live imaging of the calvarium they found that both the Mds1GFP+ HSPC and MFG-HSC were adjacent (less than 10m) to blood vessels. However, HSPC preferentially associated with transition zone vessels when compared to the MFG-HSC. In contrast the MFG-HSC were closer to the endosteum and sinusoids suggesting the existence of different microenvironments for HSC and downstream progenitors. Live imaging demonstrated that in the steady-state- the MFG-HSC were largely non-motile (moving less than 10m over a period of two hours) whereas the Mds1GFP+ HSPC migrated more and further. Treatment with chemotherapy and G-CSF -which dramatically induces HSC proliferation and mobilization into the circulation- led to the formation of clonal MFG-HSC clusters in endosteal regions undergoing both bone deposition and remodeling. This study demonstrates live imaging of a subset of minimally motile LT-HSC and suggests that a unique endosteal microenvironment supports MFG-HSC expansion after chemotherapy injury. Note that multiple studies have shown that less than 10% of LT-HSC localize near the endosteum and that most are associated with sinusoids in the central BM [12,17,21,23]. These suggest that the MFG-HSC represents a subset of HSC that specifically associates with the endosteum (). A subset of macrophages also localizes near the endosteal surface (osteomacs). These macrophages promote HSC retention in the bone marrow, and are suppressed after mobilizing doses of G-CSF [31,32]. It would be of great interest to the field to examine whether these osteomacs localize near the MFG-HSC as this will further support the existence of a discrete niche for amplifying and mobilizing HSC in response to stress.

Upadhaya et al., [27**] used Pdzk1ip1-CreER:tdTomato mice for live imaging of HSC. In these mice low dose tamoxifen expression results in TdTomato expression in 23% of LT-HSC. Live imaging of mouse calvarium or tibia showed that the labeled HSC are highly motile with ~90% of the labeled HSC moving more than 20m whereas ~10% of the labeled HSC showed minimal movement. Combining Pdzk1ip1-CreER:tdTomato with Fgd5ZsGreen or KitLGFP/+ reporter mice allowed visualization of endothelial cells or stem cell factor (SCF)-producing perivascular cells. These confirmed the perivascular location of HSC but also revealed that over short periods of time- HSC form multiple, close, transient contacts with various SCF-producing cells. Thus HSC might travel between different niches/microenvironments to receive different signals that regulate their behavior (). Surprisingly a drug treatment that inhibits the CXCR4 receptor and 41/91 integrins -and mobilizes HSC to the circulation- also blocked HSC movement in the BM. This indicates that HSC movement requires CXCL12-CXCR4 and/or integrin signaling.

Although additional analyses are needed to resolve the observed discrepancies in motility between the HSC examined, the Christodoulou et al., and Upadhaya et al., studies open the door to deciphering HSC regulation by different signals, in situ, with single cell resolution.

It is becoming increasingly clear that hematopoiesis in the bone marrow is spatially and regionally organized and that local cues produced by distinct microenvironments are responsible for regulating different HSPC. The best characterized example of this spatial heterogeneity is the data supporting the existence of distinct sinusoidal and arteriolar niches for HSC. As discussed in the previous sections most HSC localize reside exclusively in sinusoidal locations whereas smaller fractions also associate with arterioles and/or the endosteum [12,17,21,23,24,33*,34,35]. Note that the precise fractions of HSC associated which each structure and whether these associations are specific-remains a source of controversy. Each group has used different methods to identify HSC and different criteria to define proximity to each type of structure. These further highlight a need for a common criteria in the field for defining cell proximity to niche components. Also note that due to the abundance of sinusoids- almost all hematopoietic cells locate within 30m of a sinusoid [36]. Therefore an arteriolar niche or endosteal niche is going to also contain sinusoids [12,26**,36]. Kunisaki et al., showed that 30% of LinCD48CD150+ HSC localized near arterioles ensheathed by Ng2+ periarteriolar cells and that Ng2+ cell ablation caused loss of HSC quiescence and function [17]; another 30% of HSC specifically map within 5m of megakaryocytes and loss of megakaryocytes or megakaryocyte-derived CXCL4 or TGF resulted in HSC proliferation in sinusoidal locations without affecting HSC in arteriolar locations [21,22]. Pinho et al., found that von Willebrand factor (vWF) positive HSC, which are biased towards megakaryocyte fates [37] selectively localized near megakaryocytes (60% of vWF+ HSC are within 5m of a megakaryocyte) whereas vWF- HSC localized near arterioles. Megakaryocyte ablation specifically expanded vWF+ HSC [38]. Itkin et al., discovered that HSC could be fractionated based on intracellular ROS (reactive oxygen species) levels and that HSC with lower levels of ROS where enriched near arterioles whereas HSC with higher levels of ROS located near sinusoids [39]. Further data supporting a distinct arteriolar HSC niche was provided by Kusumbe et al., which showed that constitutive Notch signaling in the vasculature increased the number of arterioles in the BM followed by accumulation of HSC suggesting that arteriole number controls HSC abundance. Together these studies support the existence of a megakaryocyte/sinusoidal niche that maintains HSC biased towards megakaryocyte fates and an arteriolar niche that maintains more quiescent HSC ().

There is also evidence supporting the existence of a distinct endosteal HSC niche. After adoptive transfer into recipient mice the donor HSC are selectively enriched near endosteal cells [30,40,41]. In agreement Zhao et al., discovered that CD48CD49b HSC are resistant to chemotherapy and proposed that they represent a reserve HSC (rHSC) population. Sixteen percent of these rHSC localize -and amplify after chemotherapy near the endosteum, adjacent to N-cadherin+ stromal cells that support them [33*]. Live imaging analyses also demonstrated that after chemotherapy- a subset of HSC selectively proliferate in endosteal regions undergoing bone remodeling and deposition [26**]. Together these studies support the concept that the endosteum might provide a niche for regenerating HSC ().

The localization of progenitors downstream of HSC is less characterized. Multipotent progenitors are immediately below HSC in the hematopoietic hierarchy and are major contributors to blood cell production in the steady-state [13]. Live animal imaging of transplanted HSC -or a population enriched in MPP- into non-irradiated recipients showed that the MPP located further away from the endosteum [30]. In agreement live animal imaging of Mds1GFP+ HSPC also enriched in MPP- and MFG-HSC [26**] showed different spatial distributions for these two populations and increased HSPC localization near transitional vessels. These studies suggest that HSC and MPP might occupy different niches. In contrast, Cordeiro-Gomes et al., found similar spatial organization for HSC and MPP and in rare occasions- observed colocalization of HSC and MPP suggesting that they occupy the same niche [42]. Note that each of these studies used different markers/reporter mice to define HSC/HSPC/MPP as well as different imaging approaches (live imaging of transplanted cells/live imaging of subsets of HSC and HSPC in the calvarium/fixed femur whole mounts) and additional studies are needed to resolve the question on whether HSC and MPP (of which there are multiple subsets [43]) occupy the same or distinct niches.

Several components of the bone marrow microenvironment including endothelial cells [44,45], perivascular cells [4648], osteocytes [49], megakaryocytes [50], and even neutrophils [51] produce signals that support and regulate myeloid cell production in the steady-state and after stress (reviewed in [52]). However, the specific sites for myelopoiesis in the bone marrow, or whether myeloid progenitors and HSC share the same niche, remain unknown. This is mainly due to lack of approaches to image myeloid progenitors. Herault et al., were able to image a population of classically defined granulocyte monocyte progenitors (GMP) as Lin-Sca1-CD150-c-kit+FcR+ cells [50]. Note that subsequent studies have shown that these phenotypically defined GMP are heterogeneous and contain bipotent and unipotent monocyte and granulocyte progenitors [4,53]. Herault et al., showed that these heterogeneous GMP were almost always found as single cells, distributed through the bone marrow. Insults that trigger emergency myeloid cell production induced formation of tightly packed GMP clusters. This cluster formation required signals provided from the microenvironment [50] suggesting that specific regions of the bone marrow support emergency myeloid progenitor expansion in response to stress.

Similarly, lymphopoiesis is dependent on signals produced by perivascular stromal cells [42], endothelial cells [42], and osteoblastic lineage cells, which include osteoblastic progenitors, osteoblasts, and osteocytes [18,20,41,5459]. While these studies support the concept of an endosteal niche for lymphopoiesis the spatial localization of lymphoid progenitors is not clear. Ding et al., found that 30% of LinIL7Ra+ cells which are enriched in lymphoid progenitor- were in contact with the endosteum [18]. In contrast, Tokoyoda et al., found that B220+flk2+ pre-pro-B cells and B220+c-kit+ pro-B cells were scattered through the central bone marrow. Additionally, 65% of Pre-pro-B cells and 0% pro-B cells were in contact with CXCL12 producing reticular cells whereas 11% of Pre-pro-B cells and 89% of pro-B cells contacted IL7-producing reticular cells. These suggest a perivascular location for lymphopoiesis and that CXCL12 and IL7 producing stromal cells provide niches for different stages of lymphocyte maturation [60]. Surprisingly, Cordeiro-Gomes et al., found that IL7-producing cells are a subset of CXCL12-producing reticular cells and that Ly6D+ common lymphoid progenitors localize to this subset. Since HSC also associate with IL7+CXCL12+ reticular stromal cells [42] this also suggested that common lymphoid progenitors and HSC occupy the same niche. Additional studies are necessary to reconcile these findings.

Erythropoiesis is also regionally organized; classical studies demonstrated that a subset of macrophages that localize near sinusoids provides a niche that supports islands of erythroblasts maturation [61,62] (for a recent review see [63]). Recently, Comazzetto et al., were able to image Lin-Sca1-c-kit+CD105+ erythroid progenitors. These selectively localize to reticular stromal cells in perisinusoidal locations. These stromal cells maintained these adjacent progenitors via SCF secretion [64**]. These indicate that sinusoids are the site of erythropoiesis.

The bone marrow is highly organized and contains specialized regions that provide distinct microenvironments that selectively regulate unique types of hematopoietic cells (). The field has made tremendous progress in defining the spatial architecture of hematopoiesis. The development of approaches to image hematopoiesis in vivo will further transform the field by allowing visualization of cell decisions in real time. However, several challenges remain including: a) the lack of approaches to simultaneously image many types of hematopoietic progenitors and precursors. These prevent examination of stepwise differentiation in situ to determine how local signals impact progenitor function; b) scRNAseq analyses have identified several new types of stromal cells with unknown functions in hematopoiesis and shown that known populations e.g endothelial cells and perivascular cells- are highly heterogeneous with different subsets producing unique combinations of cytokines and growth factors [79**]. Visualization of these novel populations and subsets will likely lead to the identification of unique niches for hematopoietic progenitors and precursors. The development of novel techniques allowing imaging of cytokines in the BM [65*] will be invaluable for these approaches; c) the bone marrow extracellular matrix is increasingly being recognized as a key regulator of hematopoiesis [66] that is spatially organized [67]. How differentiating hematopoietic cells interact with the extracellular matrix remains poorly understood; d) most studies in the field have focused in dissecting how each type of cell in the microenvironment interacts with- and regulates- one type of HSPC. However, multiple stromal cell types cooperate to regulate each type of HSPC and different stromal cells regulate different stages of HSPC maturation [58,60,68]; how the bone marrow ensures that each HSPC localizes to the right microenvironment as they mature remains unknown. Answers to these questions will define how the spatial architecture of the bone marrow regulates hematopoiesis during homeostasis and disease and allow the development of culture systems containing all the niche structures to necessary to produce large amounts of blood ex vivo.

Key points:

The spatial organization of the bone marrow ensures that distinct microenvironments regulate different types of stem cells and progenitors.

The best studies microenvironments are HSC niches and mounting evidence supports the existence of distinct sinusoidal and arteriolar HSC niches.

It is becoming increasingly clear that the bone marrow contains distinct niches for progenitors downstream of HSC.

Despite tremendous progress the spatial organization of hematopoiesis remains poorly understood and new approaches are needed.

New live imaging studies of native HSC open the door to examine HSC regulation, in situ.

The author apologizes to colleagues whose work was not cited because of space constraints.

Financial support and sponsorship

This work was partially supported by the National Heart Lung and Blood Institute (R01HL136529 to D.L.).

Conflicts of interest

The author has no conflicts of interest

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