Bone marrow is a semisolid tissue located within the cancellous (spongy) regions of bones. In avian and mammalian species, it serves as the principal site for hematopoiesis, the production of new blood cells. Its composition includes hematopoietic cells, marrow adipose tissue, and supportive stromal cells. In adult humans, bone marrow is predominantly situated within the ribs, vertebrae, sternum, and pelvic bones. Bone marrow constitutes approximately 5% of the total body mass in healthy adult humans; for instance, an individual weighing 73 kg (161 lbs) would possess approximately 3.7 kg (8 lbs) of bone marrow.
Bone marrow is a semi-solid tissue found within the spongy (also known as cancellous) portions of bones. In birds and mammals, bone marrow is the primary site of new blood cell production (or haematopoiesis). It is composed of hematopoietic cells, marrow adipose tissue, and supportive stromal cells. In adult humans, bone marrow is primarily located in the ribs, vertebrae, sternum, and bones of the pelvis. Bone marrow comprises approximately 5% of total body mass in healthy adult humans, such that a person weighing 73 kg (161 lbs) will have around 3.7 kg (8 lbs) of bone marrow.
Human marrow generates an estimated 500 billion blood cells daily, which enter the systemic circulation through permeable vascular sinusoids located within the medullary cavity. Both myeloid and lymphoid lineages of hematopoietic cells originate within the bone marrow; nevertheless, lymphoid cells necessitate migration to other lymphoid organs, such as the thymus, for their complete maturation.
Bone marrow transplantation serves as a therapeutic intervention for severe marrow-related pathologies, including specific malignancies like leukemia. The bone marrow is associated with various types of stem cells. Hematopoietic stem cells (HSCs) residing in the bone marrow are capable of differentiating into all hematopoietic lineage cells. Furthermore, mesenchymal stem cells (MSCs), isolatable from primary cultures of bone marrow stroma, possess the capacity to differentiate into bone, adipose, and cartilage tissues.
Structure
Marrow composition exhibits dynamism, with its cellular and non-cellular (connective tissue) constituents undergoing alterations influenced by age and systemic factors. In humans, marrow is commonly categorized as either red bone marrow or yellow bone marrow (Latin: medulla ossium rubra and medulla ossium flava, respectively), a distinction based on the relative abundance of hematopoietic cells versus adipocytes. Although the exact regulatory mechanisms governing marrow remain incompletely elucidated, its compositional transformations follow predictable patterns. For instance, the skeletal system of neonates contains exclusively hematopoietically active red marrow, which progressively converts to yellow marrow with advancing age. In adults, red marrow is predominantly situated within the axial skeleton, including the pelvis, sternum, cranium, ribs, vertebrae, and scapulae, and is variably present in the proximal epiphyseal regions of long bones like the femur and humerus. Under conditions of chronic hypoxia, the organism is capable of reconverting yellow marrow to red marrow, thereby augmenting erythropoiesis.
Hematopoietic components
Cellularly, the primary functional constituents of bone marrow are progenitor cells, which are programmed to differentiate into mature blood and lymphoid cells. Human marrow generates an estimated 500 billion blood cells daily. The marrow houses hematopoietic stem cells (HSCs) that are responsible for producing the three principal classes of circulating blood cells: leukocytes (white blood cells), erythrocytes (red blood cells), and thrombocytes (platelets).
Stroma
The bone marrow stroma encompasses all tissues not directly engaged in the primary hematopoietic function. Stromal cells indirectly facilitate hematopoiesis by furnishing a specialized microenvironment that modulates the function and differentiation of hematopoietic cells. For instance, these cells synthesize colony-stimulating factors, which are crucial regulators of blood cell genesis.
The cellular components comprising the bone marrow stroma include:
- Fibroblasts, which form reticular connective tissue.
- Macrophages, notably contributing to erythropoiesis through the provision of iron essential for hemoglobin synthesis.
- Adipocytes (fat cells).
- Osteoblasts, responsible for bone synthesis.
- Osteoclasts, which facilitate bone resorption.
- Endothelial cells, forming the sinusoids, originate from endothelial stem cells also found within the bone marrow.
Function
Central hematopoietic and antigen-responsive organ
The bone marrow was first identified in 2003 as a primary site for priming T-cell responses to blood-borne antigens. Mature, circulating naive T cells migrate to bone marrow sinuses subsequent to their passage through arteries and arterioles. These cells then transmigrate the sinus endothelium, entering the parenchyma, which is rich in dendritic cells (DCs). Dendritic cells possess the capability for antigen uptake, processing, and presentation. Specific interactions between antigen-specific T cells and antigen-presenting DCs (APCs) within the parenchyma initiate the rapid formation of T-APC clusters, culminating in T cell activation, proliferation, and subsequent recirculation into the bloodstream. Further corroboration and expansion of these observations occurred in 2013 through in situ two-photon dynamic imaging conducted on mouse skulls.
Role in Memory B and T Cell Storage and Long-Term Survival
The bone marrow serves as a crucial site for migratory memory T cells and a protective sanctuary for plasma cells. This function holds significant implications for adaptive immunity and vaccinology. Within the parenchyma, memory B and T cells are sustained in specialized survival niches orchestrated by stromal cells. Immunological memory can be preserved for extended durations, either through the presence of quiescent cells or via recurrent antigenic restimulation. The bone marrow also safeguards and enhances immunological memory during periods of dietary restriction. In individuals with cancer, cancer-reactive memory T cells may emerge within the bone marrow, either spontaneously or following targeted vaccination. The bone marrow functions as a central hub for diverse immune activities, including: i) hematopoiesis, ii) osteogenesis, iii) immune responses, iv) discrimination between self and non-self antigens, v) central immune regulation, vi) memory cell storage, vii) immune surveillance of the central nervous system, viii) adaptation to energy crises, and ix) the provision of mesenchymal stem cells for tissue repair.
Mesenchymal Stem Cells
The bone marrow stroma comprises mesenchymal stem cells (MSCs), alternatively termed marrow stromal cells. These multipotent stem cells possess the capacity to differentiate into numerous cell types. Studies have demonstrated that MSCs can differentiate, both in vitro and in vivo, into osteoblasts, chondrocytes, myocytes, marrow adipocytes, and beta-pancreatic islet cells.
Bone Marrow Barrier
The vascular network within the bone marrow forms a barrier that prevents immature blood cells from exiting the marrow. Only mature blood cells possess the requisite membrane proteins, such as aquaporin and glycophorin, necessary for attachment to and transmigration across the blood vessel endothelium. Hematopoietic stem cells are also capable of traversing the bone marrow barrier, enabling their collection from peripheral blood.
Lymphatic Function
Red bone marrow represents a fundamental component of the lymphatic system, serving as one of the primary lymphoid organs responsible for generating lymphocytes from immature hematopoietic progenitor cells. Together, the bone marrow and thymus comprise the primary lymphoid tissues implicated in the genesis and initial selection of lymphocytes. Additionally, the bone marrow exhibits a valve-like mechanism that impedes the retrograde flow of lymphatic fluid within the lymphatic system.
Compartmentalization
Biological compartmentalization is distinctly observed within the bone marrow, characterized by the aggregation of specific cell types in designated regions. For example, erythrocytes, macrophages, and their precursors typically congregate around blood vessels, whereas granulocytes accumulate at the periphery of the bone marrow.
Culinary Use
Animal bone marrow has been utilized in culinary traditions globally for millennia, exemplified by dishes such as the renowned Milanese Ossobuco.
Clinical Significance
Diseases
The typical architecture of bone marrow can be compromised or displaced by conditions such as aplastic anemia, malignancies like multiple myeloma, or infections including tuberculosis, resulting in diminished production of blood cells and platelets. Furthermore, the bone marrow is susceptible to various forms of leukemia, which target its hematopoietic progenitor cells. Moreover, exposure to radiation or chemotherapy eradicates many of the rapidly proliferating cells within the bone marrow, consequently leading to an immunocompromised state. A significant number of symptoms associated with radiation poisoning are attributable to damage inflicted upon bone marrow cells.
For the diagnosis of bone marrow-related diseases, a bone marrow aspiration procedure is occasionally conducted. This procedure typically entails the use of a hollow needle to obtain a sample of red bone marrow from the iliac crest, performed under either general or local anesthesia.
Imaging
Medical imaging techniques offer restricted insights into bone marrow composition. Plain film x-rays traverse soft tissues, including marrow, precluding direct visualization, though structural alterations in the adjacent bone may be discernible. Computed tomography (CT) imaging demonstrates an improved capability for assessing the marrow cavity of bones, albeit with suboptimal sensitivity and specificity. For instance, the normal fatty "yellow" marrow found in adult long bones exhibits low density, typically ranging from -30 to -100 Hounsfield units, positioning it between subcutaneous fat and other soft tissues. Conversely, tissues characterized by elevated cellularity, such as normal "red" marrow or neoplastic cells within the medullary cavity, will demonstrate proportionally higher density measurements.
Magnetic Resonance Imaging (MRI) demonstrates superior sensitivity and specificity for evaluating bone marrow composition. MRI facilitates the evaluation of soft tissue's average molecular composition, thereby yielding data on marrow's relative lipid content. In adult humans, "yellow" fatty marrow is the predominant tissue within bones, especially within the peripheral appendicular skeleton. Given the high T1-relaxivity of fat molecules, T1-weighted imaging sequences depict "yellow" fatty marrow as bright, or hyperintense. Additionally, normal fatty marrow exhibits signal loss on fat-saturation sequences, mirroring the behavior of subcutaneous fat.
The replacement of "yellow" fatty marrow by tissue of increased cellularity manifests as reduced signal intensity on T1-weighted sequences. Both physiological "red" marrow and pathological marrow lesions, such as neoplastic infiltrations, appear hypointense relative to "yellow" marrow on T1-weighted sequences. However, differentiation is often achievable through comparative analysis with the MR signal intensity of contiguous soft tissues. Typically, normal "red" marrow demonstrates signal intensity equivalent to or greater than that of skeletal muscle or intervertebral discs on T1-weighted sequences.
Adipose marrow conversion, which represents the inverse of red marrow hyperplasia, may manifest during physiological aging or as a consequence of specific therapeutic interventions, such as radiation therapy. Diffuse T1 hypointensity within the marrow, in the absence of contrast enhancement or cortical disruption, is indicative of either red marrow conversion or myelofibrosis. A misleadingly normal T1 signal in the marrow can be observed in cases of diffuse multiple myeloma or leukemic infiltration, particularly when the water-to-fat ratio remains insufficiently perturbed, a scenario common in lower-grade tumors or during the early stages of disease progression.
Histological Analysis
Bone marrow examination encompasses the pathological analysis of samples acquired through bone marrow biopsy and aspiration. This diagnostic procedure is instrumental in identifying various conditions, such as leukemia, multiple myeloma, anemia, and pancytopenia. The bone marrow is responsible for generating the cellular components of blood, including platelets, erythrocytes, and leukocytes. Although substantial diagnostic data can be derived from peripheral blood analysis (obtained via phlebotomy), a direct examination of the bone marrow, the progenitor site of blood cells, is occasionally requisite to gain comprehensive insights into hematopoiesis; this constitutes the primary function of bone marrow aspiration and biopsy.
The myeloid-to-erythroid cell ratio holds significant diagnostic relevance for assessing bone marrow function and identifying pathologies affecting both the marrow and peripheral blood, including leukemias and anemias. Typically, this ratio approximates 3:1. Deviations from this norm include an elevation in myelogenous leukemias, a reduction in polycythemias, and a reversal in thalassemic conditions.
Donation and Transplantation Procedures
During a bone marrow transplant, hematopoietic stem cells are extracted from an individual and subsequently infused into either another person (allogeneic transplantation) or the same individual at a later juncture (autologous transplantation). Provided donor-recipient compatibility, these engrafted cells migrate to the bone marrow and commence hematopoiesis. Allogeneic transplantation is performed to address severe bone marrow disorders, including congenital anomalies, autoimmune conditions, or malignancies. Initially, the recipient's endogenous marrow is ablated using pharmacological agents or radiation, followed by the introduction of the new stem cells. In oncology, prior to administering radiation therapy or chemotherapy, a portion of the patient's hematopoietic stem cells may be harvested for subsequent reinfusion post-treatment, aiming to reconstitute the immune system.
Bone marrow stem cells possess the capacity to differentiate into neural cells, offering potential therapeutic avenues for neurological disorders. Furthermore, their application extends to the treatment of other conditions, including inflammatory bowel disease. A 2013 clinical trial suggested that bone marrow transplantation, when combined with antiretroviral drugs, might serve as a treatment for HIV; however, subsequent findings indicated the persistence of HIV within the study participants.
Procurement Methods
Stem cells are commonly procured directly from the red marrow located within the iliac crest, frequently necessitating general anesthesia. This procedure is characterized by minimal invasiveness and does not typically require post-operative suturing. The duration of recovery, ranging from an outpatient procedure to 1–2 days of hospitalization, is contingent upon the donor's health status and their physiological response to the intervention.
Alternatively, pharmacological agents can be administered to stimulate the mobilization of stem cells from the bone marrow into the peripheral circulation. Subsequently, an intravenous catheter is inserted into the donor's arm, enabling the filtration of stem cells from the blood, a process analogous to blood or platelet donation. In adult individuals, bone marrow can also be extracted from the sternum, whereas the tibia is frequently utilized for infant samples. For neonates, stem cells are retrievable from the umbilical cord.
Fertility Enhancement
The uterus frequently sustains significant damage as a consequence of chemotherapy. Post-treatment uterine damage, particularly to follicles, impedes conception even when viable ova are present. Bone marrow stem cell transplantation has demonstrated the capacity to enhance fertility in chemotherapy patients by facilitating the repair of follicular damage. Given the critical role of follicles in ovum attachment to the endometrium, their restoration is essential for improving reproductive outcomes. For individuals experiencing damage to both oocytes and follicles, in vitro fertilization (IVF) has shown increased efficacy subsequent to bone marrow stem cell transplantation.
A documented human clinical case illustrates improvements in uterine lining thickness and overall endometrial repair subsequent to bone marrow stem cell transplantation. This restorative process enabled the patient to achieve a successful pregnancy and carry it to term.
Further endometrial improvements observed after bone marrow stem cell transplantation encompass enhanced vascularity and elevated iron levels. Notably, ovum implantation tends to cluster in regions characterized by robust blood flow.
Persistent Viruses
Through the application of quantitative polymerase chain reaction (qPCR) and next-generation sequencing (NGS), up to five distinct DNA viruses have been identified per individual. These include various herpesviruses, hepatitis B virus, Merkel cell polyomavirus, and human papillomavirus 31. Considering the potential for reactivation and/or oncogenesis associated with these viruses, their implications for hematopoietic and malignant disorders warrant comprehensive further investigation.
Fossil Record
The earliest fossilized evidence of bone marrow was identified in 2014 within Eusthenopteron, a lobe-finned fish inhabiting the Devonian period approximately 370 million years ago. Researchers from Uppsala University and the European Synchrotron Radiation Facility employed X-ray synchrotron microtomography to analyze the fossilized internal structure of the skeleton's humerus, revealing organized tubular formations analogous to contemporary vertebrate bone marrow. Eusthenopteron shares a close phylogenetic relationship with early tetrapods, which subsequently diversified into extant terrestrial mammals and reptiles.
- LOC100272216 protein
- National Marrow Donor Program
- List of distinct cell types in the adult human body
References
- Nature Bone Marrow Transplantation (Nature Publishing Group) – specialist scientific journal with articles on bone marrow biology and clinical uses.
- Cooper, B (2011). "The origins of bone marrow as the seedbed of our blood: from antiquity to the time of Osler." Baylor University Medical Center Proceedings. 24 (2): 115–8. doi:10.1080/08998280.2011.11928697. PMC 3069519. PMID 21566758.Wang J, Liu X, Lu H, Jiang C, Cui X, Yu L, Fu X, Li Q, Wang J (2015). "CXCR4(+)CD45(-) BMMNC subpopulation is superior to unfractionated BMMNCs for protection after ischemic stroke in mice". Brain Behav. Immun. 45: 98–108. doi:10.1016/j.bbi.2014.12.015. PMC 4342301. PMID 25526817.
- Bone marrow histology photomicrographs