Bone Marrow Anatomy

Bone marrow is the soft, spongy, gelatinous tissue found in the hollow spaces in the interior of bones. ^[1]  The average weight of this tissue is about 4% of the total body weight or 2.6 kg in an adult weighing 65 kg. ^[2]  Progenitor cell (stem cell) lines in the bone marrow produce new blood cells and stromal cells. Bone marrow is also an important part of the lymphatic system.

Bone marrow consists of stem cells, which are large, "primitive," undifferentiated cells supported by the fibrous tissue called stroma.

Bone marrow comprises two primary types of stem cells:

• Hematopoietic stem cells (HSCs): These cells are responsible for generating all types of blood cells, including red blood cells, white blood cells, and platelets. ^{[3, 4, 5]}
• Mesenchymal stem cells (MSCs) (also referred to as stromal stem cells): These cells differentiate into stromal components such as fibroblasts, adipocytes, and osteoblasts. They provide structural support and a specialized microenvironment for HSCs. ^{[3, 4, 5]}

In addition to these stem cells, the bone marrow also houses macrophages and other immune cells that interact with HSCs to regulate their behavior and maintain homeostasis. ^{[3, 4, 5]}  The bone marrow is organized into distinct microenvironments or niches that facilitate the self-renewal and differentiation of HSCs and their progenitors. ^{[3, 4, 5]}

Niche microenvironments: Research indicates that these niches are spatially organized to regulate various aspects of hematopoiesis. Specific regions within the bone marrow, such as the endosteal niche (near the bone surface), play critical roles in supporting HSC maintenance and expansion after injuries such as chemotherapy. ^{[3, 4, 5]}

Endothelial interactions: Studies show that conditions such as hypertension and atherosclerosis can lead to notable changes in the endothelial function of the bone marrow, which in turn affects hematopoiesis. For example, hypertensive conditions have been associated with increased arteriolar wall thickness and altered endothelial cell proliferation rates, which may contribute to systemic inflammation and leukocytosis. ^{[3, 4, 5]}

Bone marrow can be one of two types, red or yellow, depending on its composition. Red bone marrow primarily consists of hematopoietic tissue, giving it a reddish color, while yellow bone marrow is predominantly made up of adipose (fatty) tissue, imparting a yellow appearance. Both bone marrow types are highly vascular,enriched with numerous blood vessels and capillaries.

Bone marrow first appears in the clavicle near the end of fetal life and becomes active about three weeks later. Around 32-36 weeks of gestation, bone marrow supersedes the liver as the major hematopoietic organ. At birth, all the bone marrow is red. As a person ages, a significant portion transitions to yellow marrow, but in adults, about half the bone marrow remains red. ^[6]

Red Bone Marrow:

Red marrow is found mainly in flat bones, such as the hip bone, sternum (breast) bone, skull, ribs, vertebrae, and shoulder blades, as well as in the metaphyseal and epiphyseal ends of long bones, such as the femur, tibia, and humerus, where the bone is cancellous or spongy.Red bone marrow is the hematopoietically active component of the bone marrow, primarily responsible for the production of blood cells. It consists of: ^{[4, 7, 8]}

• Hematopoietic Stem Cells (HSCs) - These stem cells give rise to all types of blood cells, including red blood cells (erythrocytes), white blood cells (leukocytes), and platelets (thrombocytes).
• Reticular connective tissue - This forms the structural framework that supports hematopoietic cells.
• Sinusoidal capillaries - These specialized blood vessels facilitate nutrient and waste exchange between the blood and marrow. ^{[4, 7, 8]}

Yellow Bone Marrow:

Yellow marrow is found in the hollow interior of the diaphysis (shaft) of long bones. By the time a person reaches old age, nearly all the red marrow is replaced by the yellow marrow. However, the yellow marrow can revert to red if there is increased demand for red blood cells such as in instances of blood loss. ^[9]

Adipocytes are the predominant cell types in the yellow marrow, responsible for fat storage. Besides adipocytes, the yellow marrow also contains mesenchymal stem cells (MSCs),which can differentiate into various cell types, including the cartilage, bone, and fat cells, when needed. ^{[4, 7, 8]}

The bone marrow's microenvironment, or niche, plays a critical role in regulating stem cell behavior, including self-renewal and differentiation. The production of blood cells in the red marrow is substantial, with approximately 500 billion blood cells being produced daily in adults. The hematopoietic process is essential for maintaining normal blood cell levels and adapting to physiological stresses. ^{[4, 7, 8]}

All types of blood cells are derived from a single type of stem cell, the hematopoietic stem cell (HSC), which persists throughout an individual’s life. HSCs differentiate into two main stem cell lineages: the myeloid stem cell and the lymphoid stem cell. These stem cells further divide and differentiate to produce red blood cells, platelets, and most white blood cells in the red marrow. As a result, bone marrow contains blood cells at varying stages of development.

Illustration of the pelvis to show the site of bone marrow and blood cells derived from bone marrow.

View Media Gallery

Erythrocytes, granulocytes, monocytes, thrombocytes, and lymphocytes are all formed in the bone marrow. T lymphocytes originate from lymphoid stem cells that migrate to the thymus and differentiate under the influence of the thymic hormones thymopoietin and thymosin.

The rate of blood cell production is regulated by the body's physiological needs. Blood cells have a finite lifespan. White blood cells last anywhere from a few hours to a few days, platelets for about 10 days, and red blood cells for about 120 days. These cells are constantly replaced to maintain balance. Certain conditions such as hemorrhage, infection, and stress may trigger additional production of blood cells. ^[4]

When oxygen levels in body tissues drop due to blood loss, anemia, or reduced red blood counts, the kidneys release erythoropoietin, a hormone that stimulates the bone marrow to produce more red blood cells. Similarly:

• The bone marrow increases white blood cell production in response to infections.
• It releases more platelets during bleeding episodes. If a person experiences serious blood loss, the yellow bone marrow can convert to red bone marrow to enhance blood cell production.

As individuals age, more red marrow is converted into yellow marrow, which can make it more challenging to maintain robust blood cell production.

Under normal conditions, blood cell formation occurs predominantly in the bone marrow. However, in response to hematopoietic stress such as significant blood loss or tissue damage, blood-forming stem cells can migrate to the spleen. This organ acts as an auxillary site for hematopoiesis, particularly during critical situations such as excessive bleeding or pregnancy. The spleen’s microenvironment supports the survival and differentiation of these migrating stem cells in a manner similar to the bone marrow.

Hematopoiesis is a dynamic process governed by intrinsic factors within the bone marrow and extrinsic signals from other organs such as the spleen. This process plays a central role in normal physiology and offers therapeutic avenues for conditions like anemia or post-chemotherapy recovery. Insights into hematopoiesis form the foundation for clinical practices such as bone marrow transplantation, where healthy stem cells can restore blood cell production in patients with conditions such as leukemia. ^{[4, 10]}

The bone marrow stroma contains MSCs, which are multipotent stem cells that can differentiate into a variety of cell types, including osteoblasts, osteoclasts, chondrocytes, myocytes, fibroblasts, macrophages, adipocytes, and endothelial cells. This remarkable differentiation potential is critical for maintaining and regenerating the bone marrow niche and has significant implications for influencing bone tissue engineering and regeneration. ^{[11, 12, 13]}

MSCs have been identified in nearly all tissues of the human body and are characterized by their immunomodulatory properties and ability to migrate to inflammatory and tumor sites. ^{[11, 12, 13]}  Althoguh the stroma is not directly responsible for the primary function of hematopoiesis, it provides the essential microenvironment and colony-stimulating factors that enable hematopoiesis to occur effectively within the parenchymal cells of the bone marrow.

In the stroma, MSCs play a pivotal role in creating a supportive environment for hematopoietic stem cells. These stromal cells secrete key cytokines and growth factors necessary for HSC maintenance and function. For instance, leptin receptor-expressing MSCs have been identified as a primary source of bone-forming cells in the adult bone marrow. Furthermore, MSCs release paracrine factors that recruit endothelial lineage cells, further promoting the hematopoietic process. ^{[11, 12, 13]}

Emerging studies underscore the ability of stromal cells to adapt to stress and infection, modulating immune responses and maintaining HSC function under adverse conditions, such as sepsis or systemic inflammation. These findings highlight the dynamic role of MSCs in both maintaining homeostasis and responding to physiological challenges, further emphasizing their importance in bone marrow function and therapeutic applications. ^{[11, 12, 13, 14]}

The blood vessels in the bone marrow create a selective barrier, preventing immature blood cells from leaving the marrow prematurely. Only mature blood cells contain the membrane proteins required to attach to and pass the blood vessel endothelium. HSCs may also cross the bone marrow barrier, enabling their collection from peripheral blood for therapeutic purposes.

Research has identified vascular endothelial-cadherin as a key regulator of the blood vessel barrier in the bone marrow. This protein controls the endothelial permeability, which is essential for maintaining homeostasis and facilitating the migration of hematopoietic stem and progenitor cells (HSPCs) into the bone marrow. Interestingly, HSPCs predominantly migrate through the bone marrow endothelium via a transcellular route, utilizing podosome-like structures rather than significantly disrupting the endothelial junctions. ^{[15, 16, 17]}

The bone marrow exhibits biologic compartmentalization, with specific cell types aggregating in distinct regions. Erythrocytes, macrophages, and their precursors cluster around blood vessels, while granulocytes are typically found near the borders of the bone marrow. This compartmentalization is not merely structural butplays a functional role in hematopoiesis. The unique microenvironments within these niches have varying oxygen levels and signaling molecules that regulate the activity, self-renewal, and differentiation of HSPCs. ^{[15, 16, 17]}

Endothelial cells within these niches are critical for regulating cellular exchanges and maintaining homeostasis. These cells also play a role in tumor metastasis and hematologic malignancies by producing angiocrine factors that support cancer cell survival and proliferation. These insights into the bone marrow microenvironment are critical for advancing therapies involving stem cell mobilization and transplantation and for understanding disorders such as leukemia, where these regulatory systems are disrupted. ^{[15, 16, 17]}

Bone marrow can be affected by pathologic states such as malignancies, aplastic anemia (AA), or infections such as tuberculosis, leading to a reduced production of blood cells and blood platelets. Furthermore, the hematologic progenitor cells can turn malignant in the bone marrow, causing leukemias.

Exposure to radiation or chemotherapy will kill many of the rapidly dividing cells of the bone marrow and will therefore result in a depressed immune system, making patients more vulnerable to infections. Many of the symptoms of radiation sickness, including fatigue, anemia, and susceptibility to infections, are directly linked to damage to the bone marrow cells.

Leukemia, a cancer of the bone marrow and blood, results from the malignant transformation of hematopoietic progenitor cells, causing the overproduction of abnormal white blood cells that crowd out healthy cells. This can lead to symptoms such as anemia, bleeding, and an increased risk for infections due to immunosuppression. ^{[18, 19, 20]}  Advances in understanding the molecular mechanisms of leukemogenesis have opened new avenues for targeted treatments. ^{[21, 22]}

Aplastic anemia (AA) is characterized by bone marrow hypocellularity, resulting in a deficiency of hematopoietic stem and progenitor cells. Recent studies indicate that AA can arise from autoimmune mechanisms where dysregulated T-cell activity damages HSCs. ^{[23, 24]}  Somatic mutations associated with myeloid malignancies are prevalent among patients with AA. These mutations may contribute to the progression of the disease into more severe forms such as myelodysplastic syndromes or acute myeloid leukemia. The condition of approximately 10-20% of patients with AA may become malignant, particularly in those who do not achieve a complete response to initial treatments. ^{[18, 19, 20]}

Tuberculosis - Mycobacterium tuberculosis can infect the bone marrow, leading to reduced production of blood cell lines. ^[25]  While bone marrow involvement in TB may sometimes present without hematologic abnormalities, it often manifests as miliary lesions in other organs, such as the lungs or spine. The bacteria may persist within the bone marrow stem and progenitor cells, potentially acting as a reservoir during latent infections. This persistence can lead to a compromised immune response and may facilitate the propagation of tuberculosis, particularly when these infected cells are transferred to naive hosts, such as during bone marrow transplantation. ^{[19, 20]}  Monitoring and managing latent TB in immunocompromised patients or transplant recipients are therefore critical.

Bone marrow can be obtained for examination by bone marrow biopsy and bone marrow aspiration to identify and diagnose pathologic processes such as leukemia, multiple myeloma, anemia, and pancytopenia.

Bone marrow aspiration (seen in the image below) can be performed under local or general anesthesia. The site of aspiration is usually the iliac crest, as shown below, or the sternum. In children, the upper tibia can be used to obtain a good sample because it still contains a substantial amount of red bone marrow. The average number of cells in a leg bone is about 440 billion.

Illustration showing bone marrow aspiration from the iliac crest, a common site for this investigation.

View Media Gallery

Another option for evaluating bone marrow function involves administering certain drugs that stimulate the release of stem cells from the bone marrow into the bloodstream. A blood sample is then obtained, and stem cells are isolated for microscopic examination. In newborns, stem cells may be retrieved from the umbilical cord.

The use of umbilical cord stem cells has expanded significantly in clinical applications, particularly in cord blood transplantation for treating various hematologic and immunologic diseases. Because cord blood is rich in primitive stem cells, it often shows advantages in engraftment and has a lower risk for graft-versus-host disease (GVHD) than traditional sources of stem cells like bone marrow or peripheral blood. ^{[26, 27, 28, 29, 30]}

Bone marrow aspiration and biopsy procedures are frequently performed under ultrasound guidance to minimize complications and ensure precise sampling. ^{[26, 27, 28, 29, 30]}  This approach is particularly important for patients with challenging anatomical considerations, such as obesity, osteoporosis, or prior surgical alterations, ensuring safer and more accurate sampling.

The use of peripheral blood stem cell mobilization is an increasingly preferred, less invasive option to assess bone marrow function. This process involves administering granulocyte-colony stimulating factors (G-CSFs) or agents like plerixafor (a selective CXCR4 antagonist), which stimulate the release of HSCs into the bloodstream. Hematopoietic stem cell transplantation procedures use this process, thereby reducing the need for invasive bone marrow harvests in both allogeneic and autologous transplants. For patients unable to undergo traditional bone marrow aspiration, these cytokine-based techniques provide a more efficient and patient-friendly option. ^{[26, 27, 28, 29, 30]}

Flow cytometry and next-generation sequencing (NGS) - These technologies are increasingly being employed in analyzing bone marrow aspirates, particularly for detect the minimal residual disease in hematologic malignancies such as leukemia. The high sensitivity of NGS allows for the earlier detection of relapse by identifying minute genetic or molecular changes, allowing for timely interventions and improved patient outcomes. Flow cytometry complements this by providing rapid, quantitative analysis of cell populations, aiding in disease monitoring and therapeutic decision-making. ^{[26, 27, 28, 29, 30]}

Immunohistochemistry and cytogenetics - These techniques continue to play a critical role in diagnosing and prognosticating hematologic malignancies. Immunohistochemistry provides insights into protein expression patterns, aiding the identification of specific cell markers associated with various diseases. Cytogenetics, including advancements in fluorescence in situ hybridization (FISH) and karyotyping, has significantly improved the detection of chromosomal abnormalities in bone marrow samples. ^{[31, 32, 33]}  These methods are essential for risk stratification, treatment planning, and monitoring disease progression in conditions such as acute leukemia and myelodysplastic syndromes. ^{[26, 27, 28, 29, 30]}

Stem cells from blood and bone marrow donation are used to treat some cancers such as leukemia, multiple myeloma, and lymphoma, as well as other diseases. HSCs from a donor who is histocompatible can be infused into another person or into the same person at a later time. These infused cells will then travel to the bone marrow and initiate blood cell production.

In severe cases of disease of the bone marrow, existing bone marrow cells are destroyed using high-dose chemotherapy or irradiation before new stem cells are introduced. This preparative regimen ensures that the transplanted cells can engraft successfully without competition from diseased or dysfunctional cells.

In cancer patients undergoing radiation or chemotherapy, autologous stem cell transplantation is often performed. This involves harvesting the patient’s own HSCs before therapy and reinfusing them afterward to restore the immune system and blood cell production. In some cases, in a patient with cancer, prior to the administration of radiation therapy or chemotherapy, some of the patient's HSCs are harvested and later infused back into the patient when the therapy is finished to restore the immune system. Advances in transplantation  enable  the use of less-than-perfectly matched donors, such as half-matched family members, expanding the donor pool for patients who previously lacked a suitable match. Furthermore, the discovery of biomarkers that predict a patient’s risk for severe graft-versus-host disease has paved the way for personalized approaches to mitigate this condition. ^{[34, 35, 36]}

Chimeric antigen receptor (CAR)-T cell therapy - This involves using a patient's T cells that are genetically modified to target and destroy cancer cells. Initially approved for certain blood cancers such as leukemia and lymphoma, CAR-T therapy is also being explored for noncancerous conditions, including AA and inflammatory diseases such as multiple sclerosis. This innovative therapy holds promise for a wide range of conditions by leveraging the immune system’s ability to fight disease. ^{[34, 35]}

Reduced-intensity conditioning - For older or frail patients who were once ineligible for transplants, reduced-intensity conditioning using lower doses of chemotherapy and radiation has made transplants safer and more accessible. These regimens reduce toxicity while still allowing effective engraftment of donor cells, improving outcomes for a broader patient population. ^{[34, 35, 36]}

A growing body of evidence supports the potential of bone marrow-derived MSCs to enhance fracture healing. Bone marrow aspirate injections hold significant potential for accelerating fracture repair, but further studies are needed to standardize protocols and optimize outcomes, particularly for more complex fracture types. However, challenges persist, such as inconsistent results in femoral neck fractures and the need for improved delivery methods such as precise seeding of the injected cells to maximize efficacy. ^{[37, 38, 39]}

It is not yet known whether these cells improve fracture healing directly by differentiating into osteoblasts or indirectly by secreting paracrine factors that recruit blood vessels and the accompanying perivascular stem cells.

Bone marrow aspirated from the iliac crest contains these progenitor cells. These cells can be used for bone healing in conditions associated with delayed or nonunion of a fracture in the bone.

Recent studies have continued to explore the efficacy of percutaneous autologous bone marrow injections in treating delayed unions and nonunions of long bone fractures. For instance, a 2017 study involving 93 patients noted that all fractures were united within 12 weeks. ^[40]  This study concluded that percutaneous autologous bone marrow injections were a safe and effective treatment for non-union and delayed union.

Additionally, the use of Wharton’s jelly-derived mesenchymal stem cells (WJ-MSCs) is gaining attention for their osteogenic and regenerative properties. A phase I/IIa clinical trial in 2020 studied combined treatment of WJ-MSCs and teriparatide in 20 patients with osteoporotic vertebral compression fractures, and found that mean bone density significantly improved in the treatment group. Shim et al. concluded that this combined treatment has a clinical benefit for fracture healing by promoting bone architecture. ^[37]