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Megakaryocyte–erythroid progenitor cell

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Megakaryocyte–erythroid progenitor cells (MEPs) are hematopoietic progenitor cells that give rise to erythrocytes (red blood cells) and megakaryocytes, which in turn produce platelets.[1] They represent a key branching point in hematopoiesis, the process in which hematopoietic stem cells (HSCs) differentiate into mature blood cell types.[2] MEPs and other progenitor cells are characterized based on their loss of self-renewal capacity.[2]

Hematopoietic Differentiation

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Classical model of hematopoiesis showing differentiation of hematopoietic stem cells (HSCs) into progenitor cells, including MPPs, CMPs, CLPs, MEPs, and GMPs, and their maturation into blood cells.

Hematopoiesis is the process by which the blood cells in the body are produced through the stepwise differentiation of HSCs into progressively more specialized progenitor cells, which ultimately give rise to fully mature blood cell types.[2]

In the classical model of hematopoiesis, HSCs first differentiate into multipotent progenitors (MPPs), which then give rise to the major progenitor populations, including the common lymphoid progenitor (CLP) and the common myeloid progenitor (CMP).[3] The CMP lineage further differentiates into another set of progenitor cells: MEPs and granulocyte-monocyte progenitors (GMPs).[3] GMPs give rise to immune cells, while MEPs differentiate into erythrocytes and megakaryocytes, which give rise to platelets.[3] MEPs differentiate into erythrocytes and megakaryocytes through erythropoiesis and megakaryopoiesis, respectively.[4][5] Erythrocytes are responsible for oxygen transport via hemoglobin in the blood, while megakaryocytes shed a part of their cytoplasm to give rise to platelets, which play a central role in blood clotting and tissue repair.[6][7]

Immunophenotype and Lineage Specification

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Immunophenotype is the pattern of surface markers on a cell that are important for characterization and identification of specific cell types. MEPs and other progenitor cells are distinguishable from each other by the different cell surface markers that are added or removed throughout hematopoiesis.[4] These changes in surface receptors reflect the progressive differentiation of progenitor cells during hematopoiesis. Cell surface markers can be easily identified with antibodies in flow cytometry, making them a useful identification tool.[8]

MEP Immunophenotype

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MEPs are identified by a characteristic combination of cell surface markers. Rather than one single marker, the presence, or absence, of multiple markers is essential for this immunophenotype.

MEPs express CD34 and CD38, indicating they are early but committed progenitor cells, while lacking the expression of CD123 and CD45RA.[9][10][11] These markers distinguish MEPs from the GMP lineage, as GMPs express CD123 and CD45RA and are committed to the immune cell lineage.[12]

Erythrocyte Cell Lineage

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Erythrocytes are one of the two main end products of MEPs. First, MEPs differentiate into erythroid progenitors, which undergo further differentiation into erythroblasts.[13] As MEPs begin erythropoiesis, CD34 is lost and the number of CD38 markers decreases.[11] Erythroblasts are identified by the addition of three main cell surface markers: CD71, CD235a, and CD36.[14][15] The first, CD71, is required for iron uptake and hemoglobin production.[15]

As erythropoiesis progresses, expression of CD71 and CD36 are lost.[16] However, there is continued expression of CD235a. Mature erythrocytes also have no nucleus.[17]

Megakaryocyte Cell Lineage

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The other blood cell type that arises from MEPs is megakaryocytes, which then give rise to platelets. The first step is megakaryopoiesis, the production of megakaryocytes. Similar to erythropoiesis, the first step is the loss in expression of CD34 and CD38.[11] Megakaryocytes have three major specific surface markers: CD41, CD61, and CD42.[18] The first two surface markers, CD41 and CD61, are platelet related integrins that play an important role in blood clotting and adhesion.[18] As megakaryopoiesis progresses, CD42 appears, indicating the presence of more mature megakaryocytes.[18]

Megakaryocytes are cells in the bone that will shed a piece of their cytoplasm to produce platelets.[7] Megakaryocytes are large cells that cannot circulate through blood vessels easily. Platelets, however, are small mobile cell fragments that can easily circulate through the blood and respond rapidly to injury.[19] The process of platelet production is known as thrombopoiesis. Platelets retain surface markers CD41, CD61, and CD42 (in the form of CD42b).

Clinical Significance of MEP Regulation

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Like many other processes, hematopoiesis is a very tightly regulated biological pathway. In the early 2000s, MEPs were defined as a distinct progenitor cell population in hematopoiesis.[20] The identification of MEPs provides important insight into the organization of hematopoiesis by defining a common progenitor for erythrocytes and platelets within the myeloid lineage. This discovery has improved the understanding of lineage commitment and improved the study of hematologic disorders.

Although erythrocytes and platelets both differentiate from MEPs, their production levels are separately regulated, and thus not completely dependent on each other.[21] Disruptions in the regulation of MEP differentiation can result in abnormal levels of erythrocytes and platelets in the blood, leading to many different hematologic disorders.

Increased production of erythrocytes results in polycythemia, which results in increased blood viscosity and a higher risk of thrombosis.[22] These effects cause increased strain on the heart and impairs normal blood flow.[22] Conversely, decreased production of erythrocytes leads to anemia, which results in reduced oxygen carrying capacity of the blood. With reduced oxygen delivery to the tissues, there is increased cardiac strain and organ dysfunction.[23]

Similarly, overproduction of platelets results in thrombocytosis, which leads to increased clot formation.[24] As a result, there is increased thrombosis risk and impaired blood flow, reducing oxygen delivery to tissues.[24] When MEPs do not produce enough platelets, thrombocytopenia occurs.[24] Low levels of platelets in the blood leads to the impaired ability to stop bleeding, resulting in easy bruising and, in some cases, severe hemorrhage.[24]

Emerging Perspectives

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While the classical model of hematopoiesis describes distinct progenitor cell stages, such as MEPs, the newer model postulates that differentiation is much more fluid rather than through strictly defined steps.[25] With this in mind, the role/definition of MEPs is being refined. MEPs and other progenitor cells may represent more functionally transitional stages rather than discrete, uniform cell types.[25]

References

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  1. ^ Xavier-Ferrucio, Juliana; Krause, Diane S. (2018-05-02). "Concise Review: Bipotent Megakaryocytic-Erythroid Progenitors: Concepts and Controversies". Stem Cells (Dayton, Ohio). 36 (8): 1138–1145. doi:10.1002/stem.2834. ISSN 1549-4918. PMC 6105498. PMID 29658164.
  2. ^ a b c Jagannathan-Bogdan, Madhumita; Zon, Leonard I. (2013-06-15). "Hematopoiesis". Development (Cambridge, England). 140 (12): 2463–2467. doi:10.1242/dev.083147. ISSN 1477-9129. PMC 3666375. PMID 23715539.
  3. ^ a b c Cheng, Hui; Zheng, Zhaofeng; Cheng, Tao (2019-06-14). "New paradigms on hematopoietic stem cell differentiation". Protein & Cell. 11 (1): 34–44. doi:10.1007/s13238-019-0633-0. ISSN 1674-8018. PMC 6949320. PMID 31201709.
  4. ^ a b Lu, Yi-Chien; Sanada, Chad; Xavier-Ferrucio, Juliana; Wang, Lin; Zhang, Ping-Xia; Grimes, H. Leighton; Venkatasubramanian, Meenakshi; Chetal, Kashish; Aronow, Bruce; Salomonis, Nathan; Krause, Diane S. (2018-11-20). "The Molecular Signature of Megakaryocyte-Erythroid Progenitors Reveals a Role for the Cell Cycle in Fate Specification". Cell Reports. 25 (8): 2083–2093.e4. doi:10.1016/j.celrep.2018.10.084. ISSN 2211-1247. PMC 6336197. PMID 30463007.
  5. ^ Hall, Mark A.; Curtis, David J.; Metcalf, Donald; Elefanty, Andrew G.; Sourris, K.; Robb, Lorraine; Göthert, Joachim R.; Jane, Stephen M.; Begley, C. Glenn (2003-02-04). "The critical regulator of embryonic hematopoiesis, SCL, is vital in the adult for megakaryopoiesis, erythropoiesis, and lineage choice in CFU-S12". Proceedings of the National Academy of Sciences. 100 (3): 992–997. doi:10.1073/pnas.0237324100. PMC 298714. PMID 12552125.
  6. ^ Xu, Ying; Yu, Zhangjie; Liu, Hanxuan; Bian, Xiaohan; Tang, Weiliang (2025). "Erythrocytes enhance oxygen-carrying capacity through self-regulation". Frontiers in Physiology. 16 1592176. doi:10.3389/fphys.2025.1592176. ISSN 1664-042X. PMC 12122758. PMID 40453108.
  7. ^ a b Machlus, Kellie R.; Italiano, Joseph E. (2013-06-10). "The incredible journey: From megakaryocyte development to platelet formation". The Journal of Cell Biology. 201 (6): 785–796. doi:10.1083/jcb.201304054. ISSN 1540-8140. PMC 3678154. PMID 23751492.
  8. ^ Robinson, J. Paul; Ostafe, Raluca; Iyengar, Sharath Narayana; Rajwa, Bartek; Fischer, Rainer (2023-07-17). "Flow Cytometry: The Next Revolution". Cells. 12 (14): 1875. doi:10.3390/cells12141875. ISSN 2073-4409. PMC 10378642. PMID 37508539.
  9. ^ Sidney, Laura E.; Branch, Matthew J.; Dunphy, Siobhán E.; Dua, Harminder S.; Hopkinson, Andrew (2014-06-01). "Concise Review: Evidence for CD34 as a Common Marker for Diverse Progenitors". Stem Cells. 32 (6): 1380–1389. doi:10.1002/stem.1661. ISSN 1066-5099. PMC 4260088. PMID 24497003.
  10. ^ Wong, W. M.; Dolinska, M.; Sigvardsson, M.; Ekblom, M.; Qian, H. (2019-06-11). "A novel Lin−CD34+CD38− integrin α2− bipotential megakaryocyte–erythrocyte progenitor population in the human bone marrow". Leukemia. 30 (6): 1399–1402. doi:10.1038/leu.2015.300. ISSN 1476-5551. PMC 4895173. PMID 26500141.
  11. ^ a b c Sanada, Chad; Xavier-Ferrucio, Juliana; Lu, Yi-Chien; Min, Elizabeth; Zhang, Ping-Xia; Zou, Siying; Kang, Elaine; Zhang, Meng; Zerafati, Gazelle; Gallagher, Patrick G.; Krause, Diane S. (2016-08-18). "Adult human megakaryocyte-erythroid progenitors are in the CD34+CD38mid fraction". Blood. 128 (7): 923–933. doi:10.1182/blood-2016-01-693705. ISSN 1528-0020. PMC 4990855. PMID 27268089.
  12. ^ Testa, Ugo; Pelosi, Elvira; Frankel, Arthur (2014-02-10). "CD 123 is a membrane biomarker and a therapeutic target in hematologic malignancies". Biomarker Research. 2 (1): 4. doi:10.1186/2050-7771-2-4. ISSN 2050-7771. PMC 3928610. PMID 24513123.
  13. ^ Johnson, CS; Keckler, DJ; Topper, MI; Braunschweiger, PG; Furmanski, P (1989-02-15). "In vivo hematopoietic effects of recombinant interleukin-1 alpha in mice: stimulation of granulocytic, monocytic, megakaryocytic, and early erythroid progenitors, suppression of late-stage erythropoiesis, and reversal of erythroid suppression with erythropoietin". Blood. 73 (3): 678–683. doi:10.1182/blood.v73.3.678.678. ISSN 0006-4971. PMID 2783864.
  14. ^ Mao, Bin; Huang, Shu; Lu, Xulin; Sun, Wencui; Zhou, Ya; Pan, Xu; Yu, Jinfeng; Lai, Mowen; Chen, Bo; Zhou, Qiongxiu; Mao, Song; Bian, Guohui; Zhou, Jiaxi; Nakahata, Tatsutoshi; Ma, Feng (2016-11-08). "Early Development of Definitive Erythroblasts from Human Pluripotent Stem Cells Defined by Expression of Glycophorin A/CD235a, CD34, and CD36". Stem Cell Reports. 7 (5): 869–883. doi:10.1016/j.stemcr.2016.09.002. ISSN 2213-6711. PMC 5106477. PMID 27720903.
  15. ^ a b Koulnis, Miroslav; Pop, Ramona; Porpiglia, Ermelinda; Shearstone, Jeffrey R.; Hidalgo, Daniel; Socolovsky, Merav (2011-08-05). "Identification and analysis of mouse erythroid progenitors using the CD71/TER119 flow-cytometric assay". Journal of Visualized Experiments: JoVE (54): 2809. doi:10.3791/2809. ISSN 1940-087X. PMC 3211121. PMID 21847081.
  16. ^ Katiyar, Shobhita; Shah, Arunim; Rahman, Khaliqur; Tripathy, Naresh Kumar; Kashyap, Rajesh; Nityanand, Soniya; Chaturvedi, Chandra Prakash (2023-05-02). "Analysis of Immunophenotypic Changes during Ex Vivo Human Erythropoiesis and Its Application in the Study of Normal and Defective Erythropoiesis". Cells. 12 (9): 1303. doi:10.3390/cells12091303. ISSN 2073-4409. PMC 10177526. PMID 37174702.
  17. ^ Huang, Peng; Zhao, Yongzhong; Zhong, Jianmei; Zhang, Xinhua; Liu, Qifa; Qiu, Xiaoxia; Chen, Shaoke; Yan, Hongxia; Hillyer, Christopher; Mohandas, Narla; Pan, Xinghua; Xu, Xiangmin (2020). "Putative regulators for the continuum of erythroid differentiation revealed by single-cell transcriptome of human BM and UCB cells". Proceedings of the National Academy of Sciences. 117 (23): 12868–12876. Bibcode:2020PNAS..11712868H. doi:10.1073/pnas.1915085117. PMC 7293633. PMID 32457162.
  18. ^ a b c Singh, Shiv Vardan; Lucerne, Audrey; Ravid, Katya (2025-07-10). "Immune and Inflammatory Properties of Megakaryocytes". Cells. 14 (14): 1053. doi:10.3390/cells14141053. ISSN 2073-4409. PMC 12294114. PMID 40710306.
  19. ^ Koupenova, Milka; Livada, Alison C.; Morrell, Craig N. (2022-01-21). "Platelet and Megakaryocyte Roles in Innate and Adaptive Immunity". Circulation Research. 130 (2): 288–308. doi:10.1161/CIRCRESAHA.121.319821. ISSN 1524-4571. PMC 8852355. PMID 35050690.
  20. ^ Akashi, Koichi; Traver, David; Miyamoto, Toshihiro; Weissman, Irving L. (2000-03-09). "A clonogenic common myeloid progenitor that gives rise to all myeloid lineages". Nature. 404 (6774): 193–197. Bibcode:2000Natur.404..193A. doi:10.1038/35004599. ISSN 1476-4687. PMID 10724173.
  21. ^ Geddis, Amy E. (July 2010). "Megakaryopoiesis". Seminars in Hematology. 47 (3): 212–219. doi:10.1053/j.seminhematol.2010.03.001. ISSN 1532-8686. PMC 2904992. PMID 20620431.
  22. ^ a b Pillai, Ashwin A.; Kaur, Anahat; Mukkamalla, Shiva Kumar R. (2026), "Polycythemia", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID 30252337, retrieved 2026-04-24
  23. ^ Obeagu, Emmanuel Ifeanyi; Obeagu, Getrude Uzoma (2025-06-21). "Anemia and cerebrovascular disease: pathophysiological insights and clinical implications". Annals of Medicine and Surgery (2012). 87 (6): 3254–3267. doi:10.1097/MS9.0000000000002907. ISSN 2049-0801. PMC 12140788. PMID 40486649.
  24. ^ a b c d "Platelet Disorders - Thrombocythemia and Thrombocytosis | NHLBI, NIH". www.nhlbi.nih.gov. 2022-03-24. Retrieved 2026-04-24.
  25. ^ a b Cheng, Hui; Zheng, Zhaofeng; Cheng, Tao (2020-06-14). "New paradigms on hematopoietic stem cell differentiation". Protein & Cell. 11 (1): 34–44. doi:10.1007/s13238-019-0633-0. ISSN 1674-8018. PMC 6949320. PMID 31201709.
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