Deciphering the Differential Impact of Thrombopoietin/MPL Signaling on Hematopoietic Stem/progenitor Cell Function in Bone Marrow and Spleen

Overview

Journal Stem Cell Reports

Publisher Cell Press

Specialty Cell Biology

Date 2024 Jan 12

PMID 38215758

Authors

Sandy Lee

Huichun Zhan

Affiliations

Soon will be listed here.

Abstract

Thrombopoietin (TPO) and its receptor MPL play crucial roles in hematopoietic stem cell (HSC) function and platelet production. However, the precise effects of TPO/MPL signaling on HSC regulation in different hematopoietic niches remain unclear. Here, we investigated the effects of TPO/MPL ablation on marrow and splenic hematopoiesis in TPO and MPL mice during aging. Despite severe thrombocytopenia, TPO and MPL mice did not develop marrow failure during a 2-year follow-up. Marrow and splenic HSCs exhibited different responses to TPO/MPL ablation and exogenous TPO treatment. Splenic niche cells compensated for marrow HSC loss in TPO and MPL mice by upregulating CXCL12 levels. These findings provide new insights into the complex regulation of HSCs by TPO/MPL and reveal a previously unknown link between TPO and CXCL12, two key growth factors for HSC maintenance. Understanding the distinct regulatory mechanisms between marrow and spleen hematopoiesis will help to develop novel therapeutic approaches for hematopoietic disorders.

Citing Articles

Cellular crosstalk in the bone marrow niche.

Huang Z, Iqbal Z, Zhao Z, Liu J, Alabsi A, Shabbir M J Transl Med. 2024; 22(1):1096.

PMID: 39627858 PMC: 11613879. DOI: 10.1186/s12967-024-05900-6.

References

Kimura S, Roberts A, Metcalf D, Alexander W . Hematopoietic stem cell deficiencies in mice lacking c-Mpl, the receptor for thrombopoietin. Proc Natl Acad Sci U S A. 1998; 95(3):1195-200. PMC: 18717. DOI: 10.1073/pnas.95.3.1195. View

Lee S, Wong H, Castiglione M, Murphy M, Kaushansky K, Zhan H . JAK2V617F Mutant Megakaryocytes Contribute to Hematopoietic Aging in a Murine Model of Myeloproliferative Neoplasm. Stem Cells. 2022; 40(4):359-370. PMC: 9199841. DOI: 10.1093/stmcls/sxac005. View

Harrison D, Jordan C, Zhong R, Astle C . Primitive hemopoietic stem cells: direct assay of most productive populations by competitive repopulation with simple binomial, correlation and covariance calculations. Exp Hematol. 1993; 21(2):206-19. View

Avecilla S, Hattori K, Heissig B, Tejada R, Liao F, Shido K . Chemokine-mediated interaction of hematopoietic progenitors with the bone marrow vascular niche is required for thrombopoiesis. Nat Med. 2004; 10(1):64-71. DOI: 10.1038/nm973. View

Pecci A, Ragab I, Bozzi V, De Rocco D, Barozzi S, Giangregorio T . Thrombopoietin mutation in congenital amegakaryocytic thrombocytopenia treatable with romiplostim. EMBO Mol Med. 2017; 10(1):63-75. PMC: 5760853. DOI: 10.15252/emmm.201708168. View

Crane G, Jeffery E, Morrison S . Adult haematopoietic stem cell niches. Nat Rev Immunol. 2017; 17(9):573-590. DOI: 10.1038/nri.2017.53. View

Yoshihara H, Arai F, Hosokawa K, Hagiwara T, Takubo K, Nakamura Y . Thrombopoietin/MPL signaling regulates hematopoietic stem cell quiescence and interaction with the osteoblastic niche. Cell Stem Cell. 2008; 1(6):685-97. DOI: 10.1016/j.stem.2007.10.020. View

Alexander W, Roberts A, Nicola N, Li R, Metcalf D . Deficiencies in progenitor cells of multiple hematopoietic lineages and defective megakaryocytopoiesis in mice lacking the thrombopoietic receptor c-Mpl. Blood. 1996; 87(6):2162-70. View

Mende N, Bastos H, Santoro A, Mahbubani K, Ciaurro V, Calderbank E . Unique molecular and functional features of extramedullary hematopoietic stem and progenitor cell reservoirs in humans. Blood. 2022; 139(23):3387-3401. PMC: 7612845. DOI: 10.1182/blood.2021013450. View

10.

Dasouki M, Rafi S, Olm-Shipman A, Wilson N, Abhyankar S, Ganter B . Exome sequencing reveals a thrombopoietin ligand mutation in a Micronesian family with autosomal recessive aplastic anemia. Blood. 2013; 122(20):3440-9. PMC: 3829117. DOI: 10.1182/blood-2012-12-473538. View

11.

Ballmaier M, Germeshausen M, Schulze H, Cherkaoui K, Lang S, Gaudig A . c-mpl mutations are the cause of congenital amegakaryocytic thrombocytopenia. Blood. 2001; 97(1):139-46. DOI: 10.1182/blood.v97.1.139. View

12.

Seo A, Ben-Harosh M, Sirin M, Stein J, Dgany O, Kaplelushnik J . Bone marrow failure unresponsive to bone marrow transplant is caused by mutations in . Blood. 2017; 130(7):875-880. PMC: 5561901. DOI: 10.1182/blood-2017-02-768036. View

13.

Omatsu Y, Seike M, Sugiyama T, Kume T, Nagasawa T . Foxc1 is a critical regulator of haematopoietic stem/progenitor cell niche formation. Nature. 2014; 508(7497):536-40. DOI: 10.1038/nature13071. View

14.

Levin J, Cocault L, Demerens C, Challier C, Pauchard M, Caen J . Thrombocytopenic c-mpl(-/-) mice can produce a normal level of platelets after administration of 5-fluorouracil: the effect of age on the response. Blood. 2001; 98(4):1019-27. DOI: 10.1182/blood.v98.4.1019. View

15.

Zhang Y, Lin C, Kaushansky K, Zhan H . JAK2V617F Megakaryocytes Promote Hematopoietic Stem/Progenitor Cell Expansion in Mice Through Thrombopoietin/MPL Signaling. Stem Cells. 2018; 36(11):1676-1684. PMC: 6819142. DOI: 10.1002/stem.2888. View

16.

Kaushansky K, Lok S, Holly R, Broudy V, Lin N, BAILEY M . Promotion of megakaryocyte progenitor expansion and differentiation by the c-Mpl ligand thrombopoietin. Nature. 1994; 369(6481):568-71. DOI: 10.1038/369568a0. View

17.

Zhan H, Lin C, Segal Y, Kaushansky K . The JAK2V617F-bearing vascular niche promotes clonal expansion in myeloproliferative neoplasms. Leukemia. 2017; 32(2):462-469. PMC: 5783797. DOI: 10.1038/leu.2017.233. View

18.

Tzeng Y, Li H, Kang Y, Chen W, Cheng W, Lai D . Loss of Cxcl12/Sdf-1 in adult mice decreases the quiescent state of hematopoietic stem/progenitor cells and alters the pattern of hematopoietic regeneration after myelosuppression. Blood. 2010; 117(2):429-39. DOI: 10.1182/blood-2010-01-266833. View

19.

de Sauvage F, Luoh S, Ryan A, Dowd M, Eaton D, Moore M . Physiological regulation of early and late stages of megakaryocytopoiesis by thrombopoietin. J Exp Med. 1996; 183(2):651-6. PMC: 2192470. DOI: 10.1084/jem.183.2.651. View

20.

Ihara K, Ishii E, Eguchi M, Takada H, Suminoe A, GOOD R . Identification of mutations in the c-mpl gene in congenital amegakaryocytic thrombocytopenia. Proc Natl Acad Sci U S A. 1999; 96(6):3132-6. PMC: 15907. DOI: 10.1073/pnas.96.6.3132. View