Bone marrow

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Bone marrow
Section of bone marrow tissue (Prussian blue stain).jpg
A section of bone marrow tissue
(Prussian blue-stained)
Details
System Hematopoietic system, Immune system, [1] Lymphatic system
Identifiers
Latin medulla ossium
MeSH D001853
TA98 A13.1.01.001
TA2 388
FMA 9608
Anatomical terminology

Bone marrow is a semi-solid tissue found within the spongy (also known as cancellous) portions of bones. [2] In birds and mammals, bone marrow is the primary site of new blood cell production (or haematopoiesis). [3] 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. [4] Bone marrow comprises approximately 5% of total body mass in healthy adult humans, such that a man weighing 73 kg (161 lbs) will have around 3.7 kg (8 lbs) of bone marrow. [5]

Contents

Human marrow produces approximately 500 billion blood cells per day, which join the systemic circulation via permeable vasculature sinusoids within the medullary cavity. [6] All types of hematopoietic cells, including both myeloid and lymphoid lineages, are created in bone marrow; however, lymphoid cells must migrate to other lymphoid organs (e.g. thymus) in order to complete maturation.

Bone marrow transplants can be conducted to treat severe diseases of the bone marrow, including certain forms of cancer such as leukemia. Several types of stem cells are related to bone marrow. Hematopoietic stem cells in the bone marrow can give rise to hematopoietic lineage cells, and mesenchymal stem cells, which can be isolated from the primary culture of bone marrow stroma, can give rise to bone, adipose, and cartilage tissue. [7]

Structure

The composition of marrow is dynamic, as the mixture of cellular and non-cellular components (connective tissue) shifts with age and in response to systemic factors. In humans, marrow is colloquially characterized as "red" or "yellow" marrow (Latin : medulla ossium rubra, Latin : medulla ossium flava, respectively) depending on the prevalence of hematopoietic cells vs fat cells. While the precise mechanisms underlying marrow regulation are not understood, [6] compositional changes occur according to stereotypical patterns. [8] For example, a newborn baby's bones exclusively contain hematopoietically active "red" marrow, and there is a progressive conversion towards "yellow" marrow with age. In adults, red marrow is found mainly in the central skeleton, such as the pelvis, sternum, cranium, ribs, vertebrae and scapulae, and variably found in the proximal epiphyseal ends of long bones such as the femur and humerus. In circumstances of chronic hypoxia, the body can convert yellow marrow back to red marrow to increase blood cell production. [9]

Hematopoietic components

Bone marrow aspirate showing normal "trilineage hematopoiesis": myelomonocytic cells (an eosinophil myelocyte marked), erythroid cells (an orthochromatic erythroblast marked), and megakaryocytic cells Trilineage hematopoiesis, annotated.jpg
Bone marrow aspirate showing normal "trilineage hematopoiesis": myelomonocytic cells (an eosinophil myelocyte marked), erythroid cells (an orthochromatic erythroblast marked), and megakaryocytic cells
Hematopoietic precursor cells: promyelocyte in the center, two metamyelocytes next to it and band cells from a bone marrow aspirate Bone marrow WBC.JPG
Hematopoietic precursor cells: promyelocyte in the center, two metamyelocytes next to it and band cells from a bone marrow aspirate

At the cellular level, the main functional component of bone marrow includes the progenitor cells which are destined to mature into blood and lymphoid cells. Human marrow produces approximately 500 billion blood cells per day. [10] Marrow contains hematopoietic stem cells which give rise to the three classes of blood cells that are found in circulation: white blood cells (leukocytes), red blood cells (erythrocytes), and platelets (thrombocytes). [11]

Cellular constitution of the red bone marrow parenchyma [12]
GroupCell typeAverage
fraction		 Reference
range
Myelopoietic
cells		 Myeloblasts 0.90.2–1.5
Promyelocytes 3.3%2.1–4.1
Neutrophilic myelocytes 12.7%8.2–15.7
Eosinophilic myelocytes 0.8%0.2–1.3
Neutrophilic metamyelocytes 15.9%9.6–24.6
Eosinophilic metamyelocytes 1.2%0.4–2.2
Neutrophilic band cells 12.4%9.5–15.3
Eosinophilic band cells 0.9%0.2–2.4
Segmented neutrophils 7.4%6.0–12.0
Segmented eosinophils 0.5%0.0–1.3
Segmented basophils and mast cells 0.1%0.0–0.2
Erythropoietic
cells		 Pronormoblasts 0.6%0.2–1.3
Basophilic normoblasts 1.4%0.5–2.4
Polychromatic normoblasts 21.6%17.9–29.2
Orthochromatic normoblast 2.0%0.4–4.6
Other cell
types		 Megakaryocytes < 0.1%0.0-0.4
Plasma cells 1.3%0.4-3.9
Reticular cells 0.3%0.0-0.9
Lymphocytes 16.2%11.1-23.2
Monocytes 0.3%0.0-0.8

Stroma

The stroma of the bone marrow includes all tissue not directly involved in the marrow's primary function of hematopoiesis. [6] Stromal cells may be indirectly involved in hematopoiesis, providing a microenvironment that influences the function and differentiation of hematopoietic cells. For instance, they generate colony stimulating factors, which have a significant effect on hematopoiesis. Cell types that constitute the bone marrow stroma include:

Function

Central hematopoietic and antigen-responsive organ

That bone marrow is a priming site for T-cell responses to blood-borne antigens was first described in 2003. [13] Mature circulating naïve T cells home to bone marrow sinuses after they have passed through arteries and arterioles. [14] They transmigrate sinus endothelium and enter the parenchyma which contains dendritic cells (DCs). These have a capacity of antigen uptake, processing, and presentation. [13] Cognate interactions between antigen-specific T cells and antigen-presenting DCs (APCs) in parenchyma lead to rapid T-APC cluster formation followed by T cell activation, T cell proliferation and T cell re-circulation to blood. [13] These findings were corroborated and extended in 2013 by in situ two-photon dynamic imaging of mice skulls. [15]

Importance for storage and long-term survival of memory B and memory T cells

Bone marrow is a nest for migratory memory T cells [16] and a sanctuary for plasma cells. [17] This has implications for adaptive immunity and vaccinology. [17] Memory B and T cells persist in the parenchyma in dedicated survival niches organized by stromal cells. [18] This memory can be maintained over long time periods in the form of quiescent cells [18] or by repeated antigenic restimulation. [19] Bone marrow protects and optimizes immunological memory during dietary restriction. [20] In cancer patients, cancer-reactive memory T cells can arise in bone marrow spontaneously or after specific vaccination. [21] Bone marrow is a center of a variety of immune activities: i) hematopoiesis, ii) osteogenesis, iii) immune responses, iv) distinction between self and non-self antigens, v) central immune regulatory function, vi) storage of memory cells, vii) immune surveillance of the central nervous system, viii) adaptation to energy crisis, ix) provision of mesenchymal stem cells for tissue repair. [22]

Mesenchymal stem cells

The bone marrow stroma contains mesenchymal stem cells (MSCs), [11] which are also known as marrow stromal cells. These are multipotent stem cells that can differentiate into a variety of cell types. MSCs have been shown to differentiate, in vitro or in vivo, into osteoblasts, chondrocytes, myocytes, marrow adipocytes and beta-pancreatic islets cells.[ citation needed ]

Bone marrow barrier

The blood vessels of the bone marrow constitute a barrier, inhibiting immature blood cells from leaving the marrow. Only mature blood cells contain the membrane proteins, such as aquaporin and glycophorin, that are required to attach to and pass the blood vessel endothelium. [23] Hematopoietic stem cells may also cross the bone marrow barrier, and may thus be harvested from blood.[ citation needed ]

Lymphatic role

The red bone marrow is a key element of the lymphatic system, being one of the primary lymphoid organs that generate lymphocytes from immature hematopoietic progenitor cells. [24] The bone marrow and thymus constitute the primary lymphoid tissues involved in the production and early selection of lymphocytes. Furthermore, bone marrow performs a valve-like function to prevent the backflow of lymphatic fluid in the lymphatic system.[ citation needed ]

Compartmentalization

Biological compartmentalization is evident within the bone marrow, in that certain cell types tend to aggregate in specific areas. For instance, erythrocytes, macrophages, and their precursors tend to gather around blood vessels, while granulocytes gather at the borders of the bone marrow. [11]

As food

People have used animal bone-marrow in cuisine worldwide for millennia, as in the famed Milanese Ossobuco. [25]

Clinical significance

Disease

The normal bone marrow architecture can be damaged or displaced by aplastic anemia, malignancies such as multiple myeloma, or infections such as tuberculosis, leading to a decrease in the production of blood cells and blood platelets. The bone marrow can also be affected by various forms of leukemia, which attacks its hematologic progenitor cells. [26] Furthermore, 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. Many of the symptoms of radiation poisoning are due to damage sustained by the bone marrow cells.[ citation needed ]

To diagnose diseases involving the bone marrow, a bone marrow aspiration is sometimes performed. This typically involves using a hollow needle to acquire a sample of red bone marrow from the crest of the ilium under general or local anesthesia. [27]

Application of stem cells in therapeutics

Bone marrow derived stem cells have a wide array of application in regenerative medicine. [28]

Imaging

Medical imaging may provide a limited amount of information regarding bone marrow. Plain film x-rays pass through soft tissues such as marrow and do not provide visualization, although any changes in the structure of the associated bone may be detected. [29] CT imaging has somewhat better capacity for assessing the marrow cavity of bones, although with low sensitivity and specificity. For example, normal fatty "yellow" marrow in adult long bones is of low density (-30 to -100 Hounsfield units), between subcutaneous fat and soft tissue. Tissue with increased cellular composition, such as normal "red" marrow or cancer cells within the medullary cavity will measure variably higher in density. [30]

MRI is more sensitive and specific for assessing bone composition. MRI enables assessment of the average molecular composition of soft tissues and thus provides information regarding the relative fat content of marrow. In adult humans, "yellow" fatty marrow is the dominant tissue in bones, particularly in the (peripheral) appendicular skeleton. Because fat molecules have a high T1-relaxivity, T1-weighted imaging sequences show "yellow" fatty marrow as bright (hyperintense). Furthermore, normal fatty marrow loses signal on fat-saturation sequences, in a similar pattern to subcutaneous fat.[ citation needed ]

When "yellow" fatty marrow becomes replaced by tissue with more cellular composition, this change is apparent as decreased brightness on T1-weighted sequences. Both normal "red" marrow and pathologic marrow lesions (such as cancer) are darker than "yellow" marrow on T1-weight sequences, although can often be distinguished by comparison with the MR signal intensity of adjacent soft tissues. Normal "red" marrow is typically equivalent or brighter than skeletal muscle or intervertebral disc on T1-weighted sequences. [8] [31]

Fatty marrow change, the inverse of red marrow hyperplasia, can occur with normal aging, [32] though it can also be seen with certain treatments such as radiation therapy. Diffuse marrow T1 hypointensity without contrast enhancement or cortical discontinuity suggests red marrow conversion or myelofibrosis. Falsely normal marrow on T1 can be seen with diffuse multiple myeloma or leukemic infiltration when the water to fat ratio is not sufficiently altered, as may be seen with lower grade tumors or earlier in the disease process. [33]

Histology

A Wright's-stained bone marrow aspirate smear from a patient with leukemia Acute leukemia-ALL.jpg
A Wright's-stained bone marrow aspirate smear from a patient with leukemia

Bone marrow examination is the pathologic analysis of samples of bone marrow obtained via biopsy and bone marrow aspiration. Bone marrow examination is used in the diagnosis of a number of conditions, including leukemia, multiple myeloma, anemia, and pancytopenia. The bone marrow produces the cellular elements of the blood, including platelets, red blood cells and white blood cells. While much information can be gleaned by testing the blood itself (drawn from a vein by phlebotomy), it is sometimes necessary to examine the source of the blood cells in the bone marrow to obtain more information on hematopoiesis; this is the role of bone marrow aspiration and biopsy.[ citation needed ]

The ratio between myeloid series and erythroid cells is relevant to bone marrow function, and also to diseases of the bone marrow and peripheral blood, such as leukemia and anemia. The normal myeloid-to-erythroid ratio is around 3:1; this ratio may increase in myelogenous leukemias, decrease in polycythemias, and reverse in cases of thalassemia. [34]

Donation and transplantation

A bone marrow harvest in progress Bone marrow biopsy.jpg
A bone marrow harvest in progress
The preferred sites for the procedure Site for procedure of Bone Marrow.jpg
The preferred sites for the procedure

In a bone marrow transplant, hematopoietic stem cells are removed from a person and infused into another person (allogenic) or into the same person at a later time (autologous). If the donor and recipient are compatible, these infused cells will then travel to the bone marrow and initiate blood cell production. Transplantation from one person to another is conducted for the treatment of severe bone marrow diseases, such as congenital defects, autoimmune diseases or malignancies. The patient's own marrow is first killed off with drugs or radiation, and then the new stem cells are introduced. Before radiation therapy or chemotherapy in cases of cancer, some of the patient's hematopoietic stem cells are sometimes harvested and later infused back when the therapy is finished to restore the immune system. [35]

Bone marrow stem cells can be induced to become neural cells to treat neurological illnesses, [36] and can also potentially be used for the treatment of other illnesses, such as inflammatory bowel disease. [37] In 2013, following a clinical trial, scientists proposed that bone marrow transplantation could be used to treat HIV in conjunction with antiretroviral drugs; [38] [39] however, it was later found that HIV remained in the bodies of the test subjects. [40]

Harvesting

The stem cells are typically harvested directly from the red marrow in the iliac crest, often under general anesthesia. The procedure is minimally invasive and does not require stitches afterwards. Depending on the donor's health and reaction to the procedure, the actual harvesting can be an outpatient procedure, or can require 1–2 days of recovery in the hospital. [41]

Another option is to administer certain drugs that stimulate the release of stem cells from the bone marrow into circulating blood. [42] An intravenous catheter is inserted into the donor's arm, and the stem cells are then filtered out of the blood. This procedure is similar to that used in blood or platelet donation. In adults, bone marrow may also be taken from the sternum, while the tibia is often used when taking samples from infants. [27] In newborns, stem cells may be retrieved from the umbilical cord. [43]

Persistent viruses

Using quantitative Polymerase Chain Reaction (qPCR) and Next-generation Sequencing (NGS) a maximum of five DNA viruses per individual have been identified. Included were several herpesviruses, hepatitis B virus, Merkel cell polyomavirus, and human papillomavirus 31. Given the reactivation and/or oncogenic potential of these viruses, their repercussion on hematopoietic and malignant disorders calls for further studies. [44]

Fossil record

Bone marrow may have first evolved in Eusthenopteron, a species of prehistoric fish with close links to early tetrapods. Eusthenopteron BW.jpg
Bone marrow may have first evolved in Eusthenopteron , a species of prehistoric fish with close links to early tetrapods.

The earliest fossilised evidence of bone marrow was discovered in 2014 in Eusthenopteron , a lobe-finned fish which lived during the Devonian period approximately 370 million years ago. [45] Scientists from Uppsala University and the European Synchrotron Radiation Facility used X-ray synchrotron microtomography to study the fossilised interior of the skeleton's humerus, finding organised tubular structures akin to modern vertebrate bone marrow. [45] Eusthenopteron is closely related to the early tetrapods, which ultimately evolved into the land-dwelling mammals and lizards of the present day. [45]

See also

Related Research Articles

<span class="mw-page-title-main">Haematopoiesis</span> Formation of blood cellular components

Haematopoiesis is the formation of blood cellular components. All cellular blood components are derived from haematopoietic stem cells. In a healthy adult human, roughly ten billion to a hundred billion new blood cells are produced per day, in order to maintain steady state levels in the peripheral circulation.

<span class="mw-page-title-main">Lymphatic system</span> Organ system in vertebrates complementary to the circulatory system

The lymphatic system, or lymphoid system, is an organ system in vertebrates that is part of the immune system, and complementary to the circulatory system. It consists of a large network of lymphatic vessels, lymph nodes, lymphoid organs, lymphoid tissues and lymph. Lymph is a clear fluid carried by the lymphatic vessels back to the heart for re-circulation. The Latin word for lymph, lympha, refers to the deity of fresh water, "Lympha".

<span class="mw-page-title-main">Dendritic cell</span> Accessory cell of the mammalian immune system

A dendritic cell (DC) is an antigen-presenting cell of the mammalian immune system. A DC's main function is to process antigen material and present it on the cell surface to the T cells of the immune system. They act as messengers between the innate and adaptive immune systems.

Aplastic anemia (AA) is a severe hematologic condition in which the body fails to make blood cells in sufficient numbers. Aplastic anemia is associated with cancer and various cancer syndromes. Blood cells are produced in the bone marrow by stem cells that reside there. Aplastic anemia causes a deficiency of all blood cell types: red blood cells, white blood cells, and platelets.

<span class="mw-page-title-main">B cell</span> Type of white blood cell

B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or inserted into the plasma membrane where they serve as a part of B-cell receptors. When a naïve or memory B cell is activated by an antigen, it proliferates and differentiates into an antibody-secreting effector cell, known as a plasmablast or plasma cell. In addition, B cells present antigens and secrete cytokines. In mammals, B cells mature in the bone marrow, which is at the core of most bones. In birds, B cells mature in the bursa of Fabricius, a lymphoid organ where they were first discovered by Chang and Glick, which is why the B stands for bursa and not bone marrow, as commonly believed.

<span class="mw-page-title-main">Lymphocyte</span> Subtype of white blood cell

A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include T cells, B cells, and Innate lymphoid cells (ILCs), of which natural killer cells are an important subtype. They are the main type of cell found in lymph, which prompted the name "lymphocyte". Lymphocytes make up between 18% and 42% of circulating white blood cells.

<span class="mw-page-title-main">Hematopoietic stem cell transplantation</span> Medical procedure to replace blood or immune stem cells

Hematopoietic stem-cell transplantation (HSCT) is the transplantation of multipotent hematopoietic stem cells, usually derived from bone marrow, peripheral blood, or umbilical cord blood in order to replicate inside of a patient and to produce additional normal blood cells. It may be autologous, allogeneic or syngeneic.

<span class="mw-page-title-main">Graft-versus-host disease</span> Medical condition

Graft-versus-host disease (GvHD) is a syndrome, characterized by inflammation in different organs. GvHD is commonly associated with bone marrow transplants and stem cell transplants.

<span class="mw-page-title-main">Hematopoietic stem cell</span> Stem cells that give rise to other blood cells

Hematopoietic stem cells (HSCs) are the stem cells that give rise to other blood cells. This process is called haematopoiesis. In vertebrates, the very first definitive HSCs arise from the ventral endothelial wall of the embryonic aorta within the (midgestational) aorta-gonad-mesonephros region, through a process known as endothelial-to-hematopoietic transition. In adults, haematopoiesis occurs in the red bone marrow, in the core of most bones. The red bone marrow is derived from the layer of the embryo called the mesoderm.

<span class="mw-page-title-main">CD34</span> Cluster of differentiation protocol that identifies cell surface antigens.

CD34 is a transmembrane phosphoglycoprotein protein encoded by the CD34 gene in humans, mice, rats and other species.

<span class="mw-page-title-main">Myeloid tissue</span> Tissue of bone marrow

Myeloid tissue, in the bone marrow sense of the word myeloid, is tissue of bone marrow, of bone marrow cell lineage, or resembling bone marrow, and myelogenous tissue is any tissue of, or arising from, bone marrow; in these senses the terms are usually used synonymously, as for example with chronic myeloid/myelogenous leukemia.

<span class="mw-page-title-main">Extramedullary hematopoiesis</span> Medical condition

Extramedullary hematopoiesis refers to hematopoiesis occurring outside of the medulla of the bone. It can be physiologic or pathologic.

<span class="mw-page-title-main">Monoblast</span>

Monoblasts are the committed progenitor cells that differentiated from a committed macrophage or dendritic cell precursor (MDP) in the process of hematopoiesis. They are the first developmental stage in the monocyte series leading to a macrophage. Their myeloid cell fate is induced by the concentration of cytokines they are surrounded by during development. These cytokines induce the activation of transcription factors which push completion of the monoblast's myeloid cell fate. Monoblasts are normally found in bone marrow and do not appear in the normal peripheral blood. They mature into monocytes which, in turn, develop into macrophages. They then are seen as macrophages in the normal peripheral blood and many different tissues of the body. Macrophages can produce a variety of effector molecules that initiate local, systemic inflammatory responses. These monoblast differentiated cells are equipped to fight off foreign invaders using pattern recognition receptors to detect antigen as part of the innate immune response.

The National Marrow Donor Program (NMDP) is a nonprofit organization founded in 1986 and based in Minneapolis, Minnesota, that operates the Be The Match Registry of volunteer hematopoietic cell donors and umbilical cord blood units in the United States.

<span class="mw-page-title-main">B-cell prolymphocytic leukemia</span> Medical condition

B-cell prolymphocytic leukemia, referred to as B-PLL, is a rare blood cancer. It is a more aggressive, but still treatable, form of leukemia.

<span class="mw-page-title-main">White blood cell</span> Type of cells of the immunological system

White blood cells, also called immune cells, or immunocytes, are cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. White blood cells include three main subtypes; granulocytes, lymphocytes and monocytes.

<span class="mw-page-title-main">Haematopoietic system</span>

The haematopoietic system is the system in the body involved in the creation of the cells of blood.

Many human blood cells, such as red blood cells (RBCs), immune cells, and even platelets all originate from the same progenitor cell, the hematopoietic stem cell (HSC). As these cells are short-lived, there needs to be a steady turnover of new blood cells and the maintenance of an HSC pool. This is broadly termed hematopoiesis. This event requires a special environment, termed the hematopoietic stem cell niche, which provides the protection and signals necessary to carry out the differentiation of cells from HSC progenitors. This niche relocates from the yolk sac to eventually rest in the bone marrow of mammals. Many pathological states can arise from disturbances in this niche environment, highlighting its importance in maintaining hematopoiesis.

Clonal hypereosinophilia, also termed primary hypereosinophilia or clonal eosinophilia, is a grouping of hematological disorders all of which are characterized by the development and growth of a pre-malignant or malignant population of eosinophils, a type of white blood cell that occupies the bone marrow, blood, and other tissues. This population consists of a clone of eosinophils, i.e. a group of genetically identical eosinophils derived from a sufficiently mutated ancestor cell.

GATA2 deficiency is a grouping of several disorders caused by common defect, namely, familial or sporadic inactivating mutations in one of the two parental GATA2 genes. Being the gene haploinsufficient, mutations that cause a reduction in the cellular levels of the gene's product, GATA2, are autosomal dominant. The GATA2 protein is a transcription factor critical for the embryonic development, maintenance, and functionality of blood-forming, lymphatic-forming, and other tissue-forming stem cells. In consequence of these mutations, cellular levels of GATA2 are deficient and individuals develop over time hematological, immunological, lymphatic, or other presentations that may begin as apparently benign abnormalities but commonly progress to severe organ failure, opportunistic infections, virus infection-induced cancers, the myelodysplastic syndrome, and/or leukemia. GATA2 deficiency is a life-threatening and precancerous condition.

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  33. ↑ Vande Berg, BC; Lecouvet, FE; Galant, C; Maldague, BE; Malghem, J (July 2005). "Normal variants and frequent marrow alterations that simulate bone marrow lesions at MR imaging". Radiologic Clinics of North America. 43 (4): 761–70, ix. doi:10.1016/j.rcl.2005.01.007. PMID   15893536.
  34. ↑ "Definition: 'M:E Ratio'". Stedman's Medical Dictionary via MediLexicon.com. 2006. Archived from the original on 10 May 2013. Retrieved 20 December 2012.
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  36. ↑ "Antibody Transforms Stem Cells Directly into Brain Cells". Science Daily. 22 April 2013. Retrieved 24 April 2013.
  37. ↑ "Research Supports Promise of Cell Therapy for Bowel Disease". Wake Forest Baptist Medical Center. 28 February 2013. Archived from the original on 8 August 2017. Retrieved 5 March 2013.
  38. ↑ "Bone marrow 'frees men of HIV drugs'". BBC. 3 July 2013. Retrieved 3 July 2013.
  39. ↑ "Stem-Cell Transplants Erase HIV in Two Men". PopSci. 3 July 2013. Retrieved 3 July 2013.
  40. ↑ "HIV Returns in Two Men Thought 'Cured' by Bone Marrow Transplants". RH Reality Check. 10 December 2013. Retrieved 10 December 2013.
  41. ↑ National Marrow Donor Program Donor Guide Archived 8 September 2008 at the Wayback Machine . Marrow.org. Retrieved 5 November 2012.
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