Extramedullary hematopoiesis

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Micrograph showing nucleated red blood cells (bottom left of image), one of the elements necessary to call extramedullary hematopoiesis, in an endometrial polyp. H&E stain. Nucleated red blood cells - endometrial polyp - high mag.jpg
Micrograph showing nucleated red blood cells (bottom left of image), one of the elements necessary to call extramedullary hematopoiesis, in an endometrial polyp. H&E stain.

Extramedullary hematopoiesis (EMH or sometimes EH [1] ) refers to hematopoiesis occurring outside of the medulla of the bone (bone marrow). [2] It can be physiologic or pathologic.

Contents

Physiologic EMH occurs during embryonic and fetal development; during this time the main site of fetal hematopoiesis are liver and the spleen.

Pathologic EMH can occur during adulthood when physiologic hematopoiesis can't work properly in the bone marrow and the hematopoietic stem cells (HSC) have to migrate to other tissues in order to continue with the formation of blood cellular components. Pathologic EMH can be caused by myelofibrosis, [3] thalassemias or disorders caused in the hematopoietic system.

Physiologic EMH

During fetal development, hematopoiesis occurs mainly in the fetal liver and in the spleen followed by localization to the bone marrow. [4] Hematopoiesis also takes place in many other tissues or organs such as the yolk sac, the aorta-gonad mesonephros (AGM) region, and lymph nodes. During development, vertebrates go through a primitive and a definitive phase of hematopoiesis. The lungs also play a role in platelet production in adults. [5]

Primitive hematopoiesis

Primitive hematopoiesis occurs in the yolk sac during early embryonic development. It is characterized by the production of primitive nucleated erythroid cells, which is thought to originate from endothelial cells or hemangioblasts, which are capable of forming both endothelium and primitive blood cells. The main objective of the production of these cells will be the facilitation of tissue oxygenation to support rapid embryonic growth. This primitive phase is transitory and the cells that are produced express embryonic hemoglobins (HBZ and HBE1 genes produce the alpha and beta chains, respectively) aren't pluripotent, and aren't capable of self-renewal. [6] [7]

Definitive hematopoiesis

Definitive hematopoiesis differs from the primitive phase through the production of hematopoietic stem cells. [8] The formation of these cells occurs in the AGM (aorta-gonad-mesonephros) later in development. This occurs by conversion of endothelial cells to hematopoietic stem and progenitor cells (HPSCs) - a process called endothelial-to-hematopoietic transition or EHT. These hematopoietic stem cells are further closely associated with endothelial cells throughout human life. Later, they migrate to the fetal liver where the majority of physiologic EMH (extra-medullary hematopoiesis) takes place. They can also migrate to the spleen and lymph nodes where hematopoiesis can occur, but to a lesser degree. Finally, once the bone marrow has developed, they migrate there. [9]

Pulmonary hematopoiesis

Pulmonary hematopoiesis also appears to play an important role in adults. [5] In comparison to the bone marrow, where trilineage hematopoiesis occurs, the lungs preferentially contribute to the production of platelets through a resident population of megakaryocytes. This is supported by studies showing that blood leaving the lungs has more platelets and fewer progenitor cells than blood entering the lungs. It has been seen that in cases of severe thrombocytopenia, pulmonary megakaryocytes migrate out of lungs into the bone marrow, where they help to replenish the depleted bone marrow population.[ citation needed ]

Pathologic EMH

In adults, the majority of hematopoiesis occurs in the bone marrow. Significant production in any other organ is usually the result of a pathological process. When red blood cell (RBC) numbers are low, the body induces a homeostatic mechanism aimed to increase the synthesis of RBCs, typically via the production of erythropoietin. If the loss of RBCs becomes severe, hematopoiesis will occur in the extramedullary spaces outside the bone. [10]

The cause of pathologic EMH can be one of many hematological diseases, such as myelofibrosis, or as a result of bone marrow irradiation. Thalassemia and its resultant hemolytic anemia is another important cause of pathologic EMH. EMH has been observed in numerous other benign hematological disorders such as sickle cell anemia, hereditary spherocytosis, congenital dyserythroblastic anemia and idiopathic thrombocytopenic purpura. [10] EMH can also be seen as part of the response to systemic inflammation or infection.

Sites of EMH

Sites of EMH can be widespread however, most common localizations are in the spleen, liver, and lymph nodes. Other manifestations occur in the thymus, heart, breast, prostate, broad ligaments, kidneys, adrenal glands, pleura, retroperitoneal tissue, skin, peripheral and cranial nerves, and the spinal canal. [10] [11]

Spleen

During the postnatal period, the spleen becomes a frequent site of EMH whereas, during the embryonic stages of hematopoiesis, it is only a minor factor. Despite the hypoxic/acidic conditions of the splenic microenvironment, supplied with a legion of macrophages making it inhospitable for HSCs, EMH usually occurs within the red pulp. Among the various organs associated with EMH, the spleen offers a unique site for evaluation of hematopoietic stem cell (HSC)/niche interactions. [12] [11]

Liver

It is normal for infants have hepatic EMH as they are developing up until roughly 5 weeks of age. [13] On the other hand, hepatic EMH in adults can indicate a pathological state. This includes transplantation, hepatic tumors, hepatic disorders, or sepsis. Hepatoblastoma, adenomas and hepatocellular carcinomas can also lead to EMH in adults. [14] [15] Additionally, EMH is often observed within the hepatic sinusoids.

Lymph nodes

EMH in the lymph nodes is usually associated with underlying hematopoietic neoplasms. Myeloproliferative neoplasms (MPNs) tend to result in EMH. [16] If EMH is identified in the lymph nodes of an adult or infant, a hematologic evaluation, including blood cell counts, peripheral blood smear and potentially a bone marrow biopsy should be performed. [11]

Other sites

The following tissues may also be associated with EMH: thymus, heart, breast, prostate, fatty tissue, adrenal glands, kidney, periosteum, pleural cavity, para-vertebral regions, intra-spinal tissue, retroperitoneal tissue, skin, peripheral and cranial nerves, the spinal canal, pre-sacral region, nasopharyngeal region, para-nasal sinuses and numerous types of benign/malignant neoplasms. The most common sites of EMH associated with neoplastic disorder are the spleen, lymph nodes, skin, bone, small intestine, orbit, breast, cervix, nasal sinus, mediastinum and brain. [11] [17] [18] [19]

Microenvironment of EMH

Of the various organs associated with EMH, the spleen offers a unique site for evaluating HSC/niche interactions as it is one of the most common sites of EMH, however it does not play a major role in embryonic/developmental hematopoiesis. [11] High expression levels of CXCL12 were found in the human spleens of EMH-positive patients compared to those who were EMH-negative. The high expression of CXCL12, a candidate marker of bone marrow niche-constituting in cells, indicates HSC/niche interactions in the spleen. [20] Studies have shown that CXCL12 localizes in the sinus endothelial cells of the red pulp in EMH-positive spleens; whereas, CXCL12 was expressed throughout the vascular endothelial cells of the white pulp in spleens of EMH-negative and -positive cases. [20] The fact that EMH frequently occurs in the red pulp, is supported by current data that suggests that splenic sinus endothelial cells expressing CXCL12 may contribute to the attachment and recruitment of circulating hematopoietic precursor cells, forming bone marrow niche-like regions of EMH in the human spleen. [20]

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">Stem cell</span> Undifferentiated biological cells that can differentiate into specialized cells

In multicellular organisms, stem cells are undifferentiated or partially differentiated cells that can change into various types of cells and proliferate indefinitely to produce more of the same stem cell. They are the earliest type of cell in a cell lineage. They are found in both embryonic and adult organisms, but they have slightly different properties in each. They are usually distinguished from progenitor cells, which cannot divide indefinitely, and precursor or blast cells, which are usually committed to differentiating into one cell type.

<span class="mw-page-title-main">Bone marrow</span> Semi-solid tissue in the spongy portions of bones

Bone marrow is a semi-solid tissue found within the spongy portions of bones. In birds and mammals, bone marrow is the primary site of new blood cell production. 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 man weighing 73 kg (161 lbs) will have around 3.7 kg (8 lbs) of bone marrow.

<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 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.

Primary myelofibrosis (PMF) is a rare bone marrow blood cancer. It is classified by the World Health Organization (WHO) as a type of myeloproliferative neoplasm, a group of cancers in which there is activation and growth of mutated cells in the bone marrow. This is most often associated with a somatic mutation in the JAK2, CALR, or MPL genes. In PMF, the bony aspects of bone marrow are remodeled in a process called osteosclerosis; in addition, fibroblast secrete collagen and reticulin proteins that are collectively referred to as (fibrosis). These two pathological processes compromise the normal function of bone marrow resulting in decreased production of blood cells such as erythrocytes, granulocytes and megakaryocytes, the latter cells responsible for the production of platelets.

<span class="mw-page-title-main">CD34</span> Protein found in humans

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

<span class="mw-page-title-main">Adult stem cell</span> Multipotent stem cell in the adult body

Adult stem cells are undifferentiated cells, found throughout the body after development, that multiply by cell division to replenish dying cells and regenerate damaged tissues. Also known as somatic stem cells, they can be found in juvenile, adult animals, and humans, unlike embryonic stem cells.

<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.

The aorta-gonad-mesonephros (AGM) is a region of embryonic mesoderm that develops during embryonic development from the para-aortic splanchnopleura in chick, mouse and human embryos. The very first adult definitive haematopoietic stem cells, capable of long-term multilineage repopulation of adult irradiated recipients, originate from the ventral endothelial wall of the embryonic dorsal aorta, through an endothelial transdifferentiation process referred to as an 'endothelial-to-haematopoietic transition' (EHT). In the mouse embryo, these very first HSCs are characterised by their expression of Ly6A-GFP (Sca1), CD31, CD34, cKit, CD27, CD41, Gata2, Runx1, Notch1, and BMP amongst others.

Hemangioblasts are the multipotent precursor cells that can differentiate into both hematopoietic and endothelial cells. In the mouse embryo, the emergence of blood islands in the yolk sac at embryonic day 7 marks the onset of hematopoiesis. From these blood islands, the hematopoietic cells and vasculature are formed shortly after. Hemangioblasts are the progenitors that form the blood islands. To date, the hemangioblast has been identified in human, mouse and zebrafish embryos.

Myelophthisic anemia is a severe type of anemia found in some people with diseases that affect the bone marrow. Myelophthisis refers to the displacement of hemopoietic bone-marrow tissue by fibrosis, tumors, or granulomas. The word comes from the roots myelo-, which refers to bone marrow, and phthisis, shrinkage or atrophy.

<span class="mw-page-title-main">Sialoadhesin</span> Protein-coding gene in the species Homo sapiens

Sialoadhesin (SIGLEC-1) is a cell adhesion molecule found on the surface of macrophages. It is found in especially high amounts on macrophages of the spleen, liver, lymph node, bone marrow, colon, and lungs.

<span class="mw-page-title-main">Stem cell factor</span> Mammalian protein found in Homo sapiens

Stem cell factor is a cytokine that binds to the c-KIT receptor (CD117). SCF can exist both as a transmembrane protein and a soluble protein. This cytokine plays an important role in hematopoiesis, spermatogenesis, and melanogenesis.

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

T-cell-prolymphocytic leukemia (T-PLL) is a mature T-cell leukemia with aggressive behavior and predilection for blood, bone marrow, lymph nodes, liver, spleen, and skin involvement. T-PLL is a very rare leukemia, primarily affecting adults over the age of 30. It represents 2% of all small lymphocytic leukemias in adults. Other names include T-cell chronic lymphocytic leukemia, "knobby" type of T-cell leukemia, and T-prolymphocytic leukemia/T-cell lymphocytic leukemia.

<span class="mw-page-title-main">Sean J. Morrison</span> Canadian-American cancer researcher

Sean J. Morrison is a Canadian-American stem cell biologist and cancer researcher. Morrison is the director of Children's Medical Center Research Institute at UT Southwestern (CRI), a nonprofit research institute established in 2011 as a joint venture between Children’s Health System of Texas and UT Southwestern Medical Center. With Morrison as founding director, CRI was established to perform transformative biomedical research at the interface of stem cell biology, cancer and metabolism to better understand the biological basis of disease. He is a Howard Hughes Medical Institute Investigator, has served as president of the International Society for Stem Cell Research, and is a member of the U.S. National Academy of Medicine, U.S. National Academy of Sciences and European Molecular Biology Organization.

<span class="mw-page-title-main">Megakaryocyte–erythroid progenitor cell</span>

Megakaryocyte–erythroid progenitor cells (MEPs), among other blood cells, are generated as a result of hematopoiesis, which occurs in the bone marrow. Hematopoietic stem cells (HSC) can differentiate into one of two progenitor cells: the common lymphoid progenitor and the common myeloid progenitor. MEPs derive from the common myeloid progenitor lineage. Megakaryocyte–erythroid progenitor cells must commit to becoming either platelet-producing megakaryocytes via megakaryopoiesis or erythrocyte-producing erythroblasts via erythropoiesis. Most of the blood cells produced in the bone marrow during hematopoiesis come from megakaryocyte–erythroid progenitor cells.

<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 stem-cell 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.

<span class="mw-page-title-main">Nucleated red blood cell</span> Red blood cell with a cell nucleus

A nucleated red blood cell (NRBC), also known by several other names, is a red blood cell that contains a cell nucleus. Almost all vertebrate organisms have hemoglobin-containing cells in their blood, and with the exception of mammals, all of these red blood cells are nucleated. In mammals, NRBCs occur in normal development as precursors to mature red blood cells in erythropoiesis, the process by which the body produces red blood cells.

<span class="mw-page-title-main">Malignant infantile osteopetrosis</span> Human disease

Malignant infantile osteopetrosis is a rare osteosclerosing type of skeletal dysplasia that typically presents in infancy and is characterized by a unique radiographic appearance of generalized hyperostosis.

References

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  2. ↑ Birbrair A, Frenette PS (April 2016). "Niche heterogeneity in the bone marrow". Annals of the New York Academy of Sciences. 1370 (1): 82–96. Bibcode:2016NYASA1370...82B. doi:10.1111/nyas.13016. PMC   4938003 . PMID   27015419.
  3. ↑ Chunduri S, Gaitonde S, Ciurea SO, Hoffman R, Rondelli D (October 2008). "Pulmonary extramedullary hematopoiesis in patients with myelofibrosis undergoing allogeneic stem cell transplantation". Haematologica. 93 (10): 1593–5. doi: 10.3324/haematol.13203 . PMID   18641018.
  4. ↑ Jagannathan-Bogdan M, Zon LI (June 2013). "Hematopoiesis". Development. 140 (12): 2463–7. doi:10.1242/dev.083147. PMC   3666375 . PMID   23715539.
  5. 1 2 Lefrançais E, Ortiz-Muñoz G, Caudrillier A, Mallavia B, Liu F, Sayah DM, et al. (April 2017). "The lung is a site of platelet biogenesis and a reservoir for haematopoietic progenitors". Nature. 544 (7648): 105–109. Bibcode:2017Natur.544..105L. doi:10.1038/nature21706. PMC   5663284 . PMID   28329764.
  6. ↑ Ottersbach, Katrin (2019). "Endothelial-to-haematopoietic transition: an update on the process of making blood". Biochemical Society Transactions. 47 (2): 591–601. doi:10.1042/BST20180320. PMC   6490701 . PMID   30902922 – via PubMed Central.
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  9. ↑ Ottersbach, Katrin (2019). "Endothelial-to-haematopoietic transition: an update on the process of making blood". Biochemical Society Transactions. 47 (2): 591–601. doi:10.1042/BST20180320. PMC   6490701 . PMID   30902922 – via PubMed Central.
  10. 1 2 3 Sohawon D, Lau KK, Lau T, Bowden DK (October 2012). "Extra-medullary haematopoiesis: a pictorial review of its typical and atypical locations". Journal of Medical Imaging and Radiation Oncology. 56 (5): 538–44. doi: 10.1111/j.1754-9485.2012.02397.x . PMID   23043573.
  11. 1 2 3 4 5 Yamamoto K, Miwa Y, Abe-Suzuki S, Abe S, Kirimura S, Onishi I, et al. (January 2016). "Extramedullary hematopoiesis: Elucidating the function of the hematopoietic stem cell niche (Review)". Molecular Medicine Reports. 13 (1): 587–91. doi: 10.3892/mmr.2015.4621 . PMID   26648325.
  12. ↑ Wolf BC, Neiman RS (1987). "Hypothesis: splenic filtration and the pathogenesis of extramedullary hematopoiesis in agnogenic myeloid metaplasia". Hematologic Pathology. 1 (1): 77–80. PMID   3332874.
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  14. ↑ Tsamandas AC, Jain AB, Raikow RB, Demetris AJ, Nalesnik MA, Randhawa PS (August 1995). "Extramedullary hematopoiesis in the allograft liver". Modern Pathology. 8 (6): 671–4. PMID   8532704.
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  18. ↑ Sohawon D, Lau KK, Lau T, Bowden DK (October 2012). "Extra-medullary haematopoiesis: a pictorial review of its typical and atypical locations". Journal of Medical Imaging and Radiation Oncology. 56 (5): 538–44. doi: 10.1111/j.1754-9485.2012.02397.x . PMID   23043573.
  19. ↑ Palatnik A, Narayan R, Walters M (November 2012). "Extramedullary hematopoiesis involving uterus, fallopian tubes, and ovaries, mimicking bilateral tuboovarian abscesses". International Journal of Gynecological Pathology. 31 (6): 584–7. doi:10.1097/PGP.0b013e31825183ad. PMID   23018220.
  20. 1 2 3 Miwa Y, Hayashi T, Suzuki S, Abe S, Onishi I, Kirimura S, et al. (June 2013). "Up-regulated expression of CXCL12 in human spleens with extramedullary haematopoiesis". Pathology. 45 (4): 408–16. doi:10.1097/pat.0b013e3283613dbf. PMID   23619587. S2CID   24821351.
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