Bone Marrow: A Comprehensive Overview PDF

Bone marrow and Hematopoiesis Assoc. Prof. Dr. Seda Karabulut  Bone marrow Bone marrow is a jelly-like substance that fills the cavity left by the trabecular network of bone. Bone marrow accounts for about 4 – 5% of the total body weight of an individual. it is respon...

Bone marrow and Hematopoiesis Assoc. Prof. Dr. Seda Karabulut  Bone marrow Bone marrow is a jelly-like substance that fills the cavity left by the trabecular network of bone. Bone marrow accounts for about 4 – 5% of the total body weight of an individual. it is responsible for producing blood cells and to store fat. There are two types of marrow found in the body: – Red marrow: the highly vascular marrow which is haematopoietically active – yellow marrow: fat rich that has significantly less haematopoietic centres and more adipocytes red bone marrow ile ilgili görsel sonucu trabeculae of the bone ile ilgili görsel sonucu  Red bone marrow Clusters of haematopoietic cells known as haematopoietic islands are widely distributed throughout the loose connective tissue network observed in red marrow. These islands are found next to relatively large, yet thin walled, sinusoids that also communicate with nutrient vessels of the bone.  Where is red marrow? Red marrow is most abundant in all skeletal structures from intrauterine life up until around the 5th year of life. As time progresses, red marrow is restricted to the central flat bones (i.e. cranial bones, clavicle, sternum, ribs, scapula, vertebrae, and pelvis) and the proximal ends of the proximal long bones of the upper and lower limbs. axial skeleton labeled ile ilgili görsel sonucu epiphysis ile ilgili görsel sonucu Hematopoietic stem cells of adults are located in the red bone marrow of short and flat bones of the axial skeleton and of the epiphyses of long bones. red bone marrow location ile ilgili görsel sonucu red bone marrow ile ilgili görsel sonucu  The reticular connective tissue supports the haematopoietic and adipocyte cells in the marrow is reticular connective tissue labeled ile ilgili görsel sonucu made up of reticulin. This is a fine type III collagen that is produced by mesenchyme derived reticular cells (fibroblast- like cells). Other housekeeping cells like macrophages exist in the stroma and facilitate haematopoiesis by phagocytosing cellular debris generated from the process.  red bone marrow histology ile ilgili görsel sonucu Red bone marrow contains: a reticular connective tissue called stroma, islands of hematopoietic cells called hemopoietic cords (marrow cords; C), vascular sinusoids (S).  reticular cells bone marrow ile ilgili görsel sonucu Sinusoids are lined by endothelial cells. Adventitial reticular cells, (specialized fibroblastic cells with long, branched cytoplasmic processes) reside in stroma and produce reticulin fibres (type III collagen). They may also accumulate fat instead of adipocytes (A).  Yellow bone marrow Depending on the age and haematological demand of an individual, the reticular cells become swollen as a result of increased lipid uptake. Subsequently, yellow marrow is formed. It contains mainly supportive connective tissue that provides scaffolding for the neurovascular structures that traverse the cavitation. There are also numerous adipocytes in addition to very few dormant haematopoietic clusters. These latent haematopoietic centres can be reactivated in the event of an increase demand for red blood cells.  The marrow of long bones is red in young individuals, but when it becomes infiltrated by fat in the adult, it takes on a yellow appearance and is known as yellow marrow. The yellow marrow has the potential to become hematopoietic if necessary. red bone marrow location ile ilgili görsel sonucu Hematopoiesis Hematopoiesis (hemopoiesis) is the process of production of blood cells from precursors. This production is derived from the hematopoietic stem cells.  mesodermal wall of the yolk sac wall of the chorion ile ilgili görsel sonucu The formation of blood and blood vessels begins in the mesodermal wall of the yolk sac and in the wall of the chorion outside the embryo proper.  mesodermal wall of the yolk sac ile ilgili görsel sonucu Visceral endoderm Endoderm of the yolk sac Stimulated by an inductive interaction with the endoderm of the yolk sac and possibly also with the visceral endoderm, Many hemangioblastic aggregates (blood islands), consisting of stem cells called hemangioblasts, appear in the extraembryonic splanchnic mesoderm of the yolk sac.  The yolk sac is the first supplier of blood cells to the embryonic circulation. hemangioblast aggregates (blood islands ile ilgili görsel sonucu  Two cell lineages arise from the hemangioblasts within the hemangioblastic aggregates: primitive hematopoietic stem cells (HSCs) and endothelial precursor cells (EPCs). Primitive HSCs of the yolk sac form almost exclusively erythropoietic cells (and some pluripotent progenitor cells for megakaryocytes and primitive macrophages). These cells are predominantly primitive erythrocytes: large nucleated cells containing embryonic hemoglobin. 3 rd week development blood islands ile ilgili görsel sonucu aorta/genital ridge/mesonephros (AGM) region. ile ilgili görsel sonucu Definitive intraembryonic hematopoiesis begins at 28 days (4 th week) of embryonic development in the AGM (aorta/genital ridge/mesonephros) region  HSCs formed in the AGM (aorta/genital ridge/mesonephros) region, the yolk sac, and the placenta become transported to the liver via the circulation to the liver.  H H By 5 to 6 weeks of gestation, sites of hematopoiesis in the vascular spaces between the hepatocytes (H) become prominent in the liver. By 6 to 8 weeks of gestation in humans, the liver replaces the yolk sac as the main source of blood cells. This organ remains the main hematopoietic organ of the embryo and fetus until initiation of bone marrow hematopoiesis near parturition.  The liver is where long-term definitive HSCs arise that have the potential to generate all the hematopoietic cell lineages of the adult. Both primitive and definitive HSC production overlaps for a time. Definite HSCs start to colonize the bone marrow and contribute blood cells as early as 10.5 weeks. primitive and definitive HSC production ile ilgili görsel sonucu 1. Stem cells (pluripotential) are capable of self-renewal and can undergo enormous proliferation. a. These cells can differentiate into multiple cell lineages. b. They are present in circulation (as null cells) and bone marrow. 2. Progenitor cells (multipotential) have reduced potentiality and are committed to a single cell lineage. a. They proliferate and differentiate into precursor cells in the presence of appropriate growth factors. b. They are morphologically indistinguishable from stem cells and both appear similar to small lymphocytes. 3. Precursor cells (blasts) are all the cells in each lineage that display distinct morphologic characteristics.  All blood cells develop from a single BFU-E pluripotential precursor cell known as the pluripotential hematopoietic stem cell (PHSC/ CFU-ML)). These cells undergo mitotic activity, whereby they give rise to two types of multipotential hemopoietic stem cells: Colony-forming unit-spleen (CFU- S) are the Myeloid stem cells. Colony-forming unit-lymphocyte (CFU-Ly) are the Lymphoid stem cells. Burst forming units (BFU) are a subset progenitor cells within a lineage of blood cells. erythropoiesis granulopoiesis ile ilgili görsel sonucu  Erythropoiesis Red blood cell (erythrocyte) production Steady state erythropoiesis occurs primarily in the bone marrow and maintains erythroid homeostasis, resulting in erythrocyte generation at a rate of 1011 cells/day.  Erythrocyte development proceeds from CFU-S, which, in response to elevated levels of erythropoietin, gives rise to cells known as BFU-E, which, in response to lower erythropoietin levels, then give rise to CFU-E. CFU-E gives rise to the first histologically recognizable erythrocyte precursor, the proerythroblast (P); large cell with loose, lacy chromatin, nucleoli, and basophilic cytoplasm. erythrocyte development bfu ile ilgili görsel sonucu  The next stage is represented by the basophilic erythroblast (B), with more strongly basophilic cytoplasm and a condensed nucleus with no visible nucleolus. The basophilia of these two cell types is caused by the large number of polysomes synthesizing hemoglobin. During the next stage cell volume is reduced, polysomes decrease, and some cytoplasmic areas begin to be filled with hemoglobin, producing regions of both basophilia and acidophilia in the cell, now called a polychromatophilic erythroblasts (Pe and late Pe: LPe). erythrocyte development bfu ile ilgili görsel sonucu  Polychromatophilic erythroblasts divide mitotically to form orthochromatophilic erythroblasts (Oe; normoblasts). Orthochromatophilic erythroblasts have more condensed cell and nuclear volumes and no basophilia is evident, resulting in a uniformly acidophilic cytoplasm. Cells of this stage no longer divide. erythrocyte development bfu ile ilgili görsel sonucu  Late in this stage, this cell ejects its nucleus which is then phagocytosed by macrophages and differentiate into reticulocytes (arrows). The reticulocytes still have a small number of polyribosomes that, when treated with the dye brilliant cresyl blue, form a faintly stained network. Reticulocytes pass to the circulation (where they may constitute 1% of the red blood cells), quickly lose the polyribosomes, and mature as erythrocytes. erythrocyte development bfu ile ilgili görsel sonucu  The color change in the cytoplasm shows the continuous decrease in basophilia and the increase in hemoglobin concentration. There is also a gradual decrease in nuclear volume and an increase in chromatin condensation, followed by extrusion of a pyknotic nucleus (nuclear shrinkage).  Granulocyte formation ile ilgili görsel sonucu Granulocyte (neutrophils, eosinophils, and basophils) formation begins with production of three unipotential or bipotential cells, all of which are descendants of CFU-S. Granulocyte progenitor cells give rise to histologically identical myeloblasts and promyelocytes in all three cell lineages. 1. CFU-Eo is the progenitor of the eosinophil lineage. 2. CFU-Ba is the progenitor of the basophil lineage. 3. CFU-NM (CFU-GM), the common progenitor of neutrophils and monocytes, gives rise to CFU-N (neutrophil) and CFU-M (monocyte). CFU-Eo CFU-Ba  Indentation of the nucleus begins The myeloblast is the most immature recognizable cell in the myeloid series with finely dispersed chromatin and faint nucleoli. The promyelocyte is characterized by basophilic cytoplasm and azurophilic granules. Different promyelocytes activate different sets of genes, resulting in lineages for the three types of granulocytes.  Indentation of the nucleus begins The first visible sign of this differentiation appears in the myelocyte stage, in which specific granules gradually increase in number and eventually occupy most of the cytoplasm at the metamyelocyte stage. These neutrophilic, basophilic, and eosinophilic metamyelocytes mature with further condensations of the nuclei. Granulocyte formation ile ilgili görsel sonucu Granulopoiesis stab (band) stage. ile ilgili görsel sonucu The distinctive nuclear shape develops during the stab (band) stage.  Monocyte formation begins with the common progenitor CFU-NM (CFU-GM). Monocytes leave the bone marrow to enter the circulation. From the bloodstream, they enter connective tissue where they differentiate into macrophages.  Monocyte formation ile ilgili görsel sonucu The monoblast is the first precursor cell of the monocyte lineage. Further differentiation leads to the promonocyte, a large cell (up to 18 μm in diameter) with basophilic cytoplasm and a large, slightly indented nucleus. The chromatin is lacy and nucleoli are evident. Promonocytes divide twice as they develop into monocytes. Differentiating monocytes contain extensive RER and large Golgi complexes forming lysosomes, which are observed as fine azurophilic granules at maturity. MONOBLAST PROMONOCYTE MONOCYTE  The platelets originate in the red bone marrow by dissociating from mature megakaryocytes (M), which in turn differentiate from megakaryoblasts (Mb) in a process driven by thrombopoietin. The megakaryoblast is 25 to 50 μm in diameter and has a large ovoid or kidney-shaped nucleus, often with several small nucleoli.  Before differentiating, these cells undergo endomitosis, with repeated rounds of DNA replication not separated by cell divisions, resulting in a nucleus that is highly polyploid. The cytoplasm of this cell is homogeneous and highly basophilic. Megakaryocytes are giant cells, up to 150 μm in diameter, with large, irregularly lobulated polyploid nuclei, coarse chromatin, and no visible nucleoli. İlgili resim  Megakaryocytes (Mk) sit next to the sinusoids (S) so their cytoplasmic processes, proplatelets, penetrate the sinusoidal endothelium and are exposed in the blood.  megakaryocyte produces a few thousand platelets ile ilgili görsel sonucu platelet formation ile ilgili görsel sonucu  Cytoplasm of megakaryocytes contains numerous mitochondria, a well-developed RER, and an extensive Golgi apparatus from which arise the conspicuous specific granules of platelets. Mature megakaryocytes have numerous invaginations of plasma membrane called demarcation membranes (D), which represent a membrane reservoir that facilitates the continuous rapid proplatelet elongation. Each megakaryocyte produces a few thousand platelets, after which the remainder of the cell shows apoptotic changes and is removed by macrophages. N: the lobulated nucleus  The first identifiable progenitor of lymphoid cells is the lymphoblast (Lb), a large cell capable of dividing two or three times. As lymphocytes (Lc) develop, their nuclei become smaller, nucleoli become less visible, and the cells decrease in size overall. In the bone marrow and in the thymus, these cells synthesize the specific cell surface proteins that characterize B or T lymphocytes, respectively. lymphocyte formation ile ilgili görsel sonucu  Megakaryocytes (Mk) sit next to the sinusoids (S) so their cytoplasmic processes, proplatelets, can be released into the circulation. Macrophages are located in extravascular areas near sinusoids and extend processes between endothelial cells into sinusoidal lumina.  Erythroblastic islands also sit next to sinusoids, with red cell precursors adhering to long macrophage processes that direct red cells to pass into the sinusoids. Granulocyte precursors tend to sit away from the sinusoids, but these are motile cells which can migrate into sinusoids. Red marrow is also a site where older, defective erythrocytes undergo phagocytosis by macrophages, which then reprocess heme-bound iron for delivery to the differentiating erythrocytes.  Polycythemia vera (primary polycythemia) is a rare disorder of the blood that manifests itself by an excess production of red blood cells and, frequently, platelets, resulting in greater blood volume and an increase in the viscosity of blood. It mainly involves individuals who are in their early sixties, although occasionally it occurs in patients who are in their early twenties. Symptoms may be absent for a number of years after the onset of the condition, but patients suffering from this disorder may exhibit headaches, vertigo, fatigue, shortness of breath, enlarged liver and spleen, burning sensation in the extremities, visual disorders, as well as gingival bleeding, and generalized itching. If left untreated, the patient may die within 2 years, but with proper treatment, the lifespan can be extended by 10 to 20 years.