Megakaryocyte Ontogeny: Clinical and Molecular Significance

Overview

Journal Exp Hematol

Specialty Hematology

Date 2018 Mar 5

PMID 29501467

Citations 11

Authors

Kamaleldin E Elagib

Ashton T Brock

Adam N Goldfarb

Affiliations

Soon will be listed here.

Abstract

Fetal megakaryocytes (Mks) differ from adult Mks in key parameters that affect their capacity for platelet production. However, despite being smaller, more proliferative, and less polyploid, fetal Mks generally mature in the same manner as adult Mks. The phenotypic features unique to fetal Mks predispose patients to several disease conditions, including infantile thrombocytopenia, infantile megakaryoblastic leukemias, and poor platelet recovery after umbilical cord blood stem cell transplantations. Ontogenic Mk differences also affect new strategies being developed to address global shortages of platelet transfusion units. These donor-independent, ex vivo production platforms are hampered by the limited proliferative capacity of adult-type Mks and the inferior platelet production by fetal-type Mks. Understanding the molecular programs that distinguish fetal versus adult megakaryopoiesis will help in improving approaches to these clinical problems. This review summarizes the phenotypic differences between fetal and adult Mks, the disease states associated with fetal megakaryopoiesis, and recent advances in the understanding of mechanisms that determine ontogenic Mk transitions.

Citing Articles

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Relieving DYRK1A repression of MKL1 confers an adult-like phenotype to human infantile megakaryocytes.

Elagib K, Brock A, Clementelli C, Mosoyan G, Delehanty L, Sahu R J Clin Invest. 2022; 132(19).

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References

Ruggeri Z, De Marco L, Gatti L, Bader R, Montgomery R . Platelets have more than one binding site for von Willebrand factor. J Clin Invest. 1983; 72(1):1-12. PMC: 1129155. DOI: 10.1172/jci110946. View

Notta F, Zandi S, Takayama N, Dobson S, Gan O, Wilson G . Distinct routes of lineage development reshape the human blood hierarchy across ontogeny. Science. 2015; 351(6269):aab2116. PMC: 4816201. DOI: 10.1126/science.aab2116. View

Allen Graeve J, de Alarcon P . Megakaryocytopoiesis in the human fetus. Arch Dis Child. 1989; 64(4 Spec No):481-4. PMC: 1592041. DOI: 10.1136/adc.64.4_spec_no.481. View

Emmrich S, Henke K, Hegermann J, Ochs M, Reinhardt D, Klusmann J . miRNAs can increase the efficiency of ex vivo platelet generation. Ann Hematol. 2012; 91(11):1673-84. DOI: 10.1007/s00277-012-1517-z. View

Ree I, Fustolo-Gunnink S, Bekker V, Fijnvandraat K, Steggerda S, Lopriore E . Thrombocytopenia in neonatal sepsis: Incidence, severity and risk factors. PLoS One. 2017; 12(10):e0185581. PMC: 5627935. DOI: 10.1371/journal.pone.0185581. View

Mazharian A, Watson S, Severin S . Critical role for ERK1/2 in bone marrow and fetal liver-derived primary megakaryocyte differentiation, motility, and proplatelet formation. Exp Hematol. 2009; 37(10):1238-1249.e5. PMC: 2755112. DOI: 10.1016/j.exphem.2009.07.006. View

Dutta A, Hutchison R, Mohi G . Hmga2 promotes the development of myelofibrosis in Jak2 knockin mice by enhancing TGF-β1 and Cxcl12 pathways. Blood. 2017; 130(7):920-932. PMC: 5561898. DOI: 10.1182/blood-2016-12-757344. View

Solh M, Brunstein C, Morgan S, Weisdorf D . Platelet and red blood cell utilization and transfusion independence in umbilical cord blood and allogeneic peripheral blood hematopoietic cell transplants. Biol Blood Marrow Transplant. 2010; 17(5):710-6. PMC: 3010271. DOI: 10.1016/j.bbmt.2010.08.017. View

Macaulay I, Thon J, Tijssen M, Steele B, MacDonald B, Meade G . Canonical Wnt signaling in megakaryocytes regulates proplatelet formation. Blood. 2012; 121(1):188-96. PMC: 3538329. DOI: 10.1182/blood-2012-03-416875. View

10.

Smith E, Thon J, Devine M, Lin S, Schulz V, Guo Y . MKL1 and MKL2 play redundant and crucial roles in megakaryocyte maturation and platelet formation. Blood. 2012; 120(11):2317-29. PMC: 3447785. DOI: 10.1182/blood-2012-04-420828. View

11.

Liu X, Zhang Y, Ni M, Cao H, Signer R, Li D . Regulation of mitochondrial biogenesis in erythropoiesis by mTORC1-mediated protein translation. Nat Cell Biol. 2017; 19(6):626-638. PMC: 5771482. DOI: 10.1038/ncb3527. View

12.

Kandi R, Gutti U, Undi R, Sahu I, Gutti R . Understanding thrombocytopenia: physiological role of microRNA in survival of neonatal megakaryocytes. J Thromb Thrombolysis. 2015; 40(3):310-6. DOI: 10.1007/s11239-015-1238-y. View

13.

Nurden P, Debili N, Coupry I, Bryckaert M, Youlyouz-Marfak I, Sole G . Thrombocytopenia resulting from mutations in filamin A can be expressed as an isolated syndrome. Blood. 2011; 118(22):5928-37. DOI: 10.1182/blood-2011-07-365601. View

14.

Li X, Zhang J, Gao L, McClellan S, Finan M, Butler T . MiR-181 mediates cell differentiation by interrupting the Lin28 and let-7 feedback circuit. Cell Death Differ. 2011; 19(3):378-86. PMC: 3278736. DOI: 10.1038/cdd.2011.127. View

15.

Badalucco S, Di Buduo C, Campanelli R, Pallotta I, Catarsi P, Rosti V . Involvement of TGFβ1 in autocrine regulation of proplatelet formation in healthy subjects and patients with primary myelofibrosis. Haematologica. 2013; 98(4):514-7. PMC: 3659980. DOI: 10.3324/haematol.2012.076752. View

16.

Huang N, Lou M, Liu H, Avila C, Ma Y . Identification of a potent small molecule capable of regulating polyploidization, megakaryocyte maturation, and platelet production. J Hematol Oncol. 2016; 9(1):136. PMC: 5143458. DOI: 10.1186/s13045-016-0358-y. View

17.

Gluckman E . History of cord blood transplantation. Bone Marrow Transplant. 2009; 44(10):621-6. DOI: 10.1038/bmt.2009.280. View

18.

Sparger K, Assmann S, Granger S, Winston A, Christensen R, Widness J . Platelet Transfusion Practices Among Very-Low-Birth-Weight Infants. JAMA Pediatr. 2016; 170(7):687-94. PMC: 6377279. DOI: 10.1001/jamapediatrics.2016.0507. View

19.

Ma D, Sun Y, Chang K, Zuo W . Developmental change of megakaryocyte maturation and DNA ploidy in human fetus. Eur J Haematol. 1996; 57(2):121-7. DOI: 10.1111/j.1600-0609.1996.tb01349.x. View

20.

Elagib K, Lu C, Mosoyan G, Khalil S, Zasadzinska E, Foltz D . Neonatal expression of RNA-binding protein IGF2BP3 regulates the human fetal-adult megakaryocyte transition. J Clin Invest. 2017; 127(6):2365-2377. PMC: 5451240. DOI: 10.1172/JCI88936. View