Ptpn21 Controls Hematopoietic Stem Cell Homeostasis and Biomechanics

Overview

Journal Cell Stem Cell

Publisher Cell Press

Specialty Cell Biology

Date 2019 Mar 19

PMID 30880025

Citations 27

Authors

Fang Ni

Wen-Mei Yu

Xinyi Wang

Meredith E Fay

Katherine M Young

Yongzhi Qiu

Wilbur A Lam

Todd A Sulchek

Tao Cheng

David T Scadden

Cheng-Kui Qu

Affiliations

Soon will be listed here.

Abstract

Hematopoietic stem cell (HSC) quiescence is a tightly regulated process crucial for hematopoietic regeneration, which requires a healthy and supportive microenvironmental niche within the bone marrow (BM). Here, we show that deletion of Ptpn21, a protein tyrosine phosphatase highly expressed in HSCs, induces stem cell egress from the niche due to impaired retention within the BM. Ptpn21 HSCs exhibit enhanced mobility, decreased quiescence, increased apoptosis, and defective reconstitution capacity. Ptpn21 deletion also decreased HSC stiffness and increased physical deformability, in part by dephosphorylating Spetin1 (Tyr), a poorly described component of the cytoskeleton. Elevated phosphorylation of Spetin1 in Ptpn21 cells impaired cytoskeletal remodeling, contributed to cortical instability, and decreased cell rigidity. Collectively, these findings show that Ptpn21 maintains cellular mechanics, which is correlated with its important functions in HSC niche retention and preservation of hematopoietic regeneration capacity.

Citing Articles

Hormonally mediated mechanical remodelling of human haematopoietic stem cells enhances their bone-marrow engraftment.

Nat Biomed Eng. 2025; .

PMID: 39774297 DOI: 10.1038/s41551-024-01310-7.

Enhanced engraftment of human haematopoietic stem cells via mechanical remodelling mediated by the corticotropin-releasing hormone.

Wu M, Yang H, Liu S, Jiang L, Liang T, Wang Y Nat Biomed Eng. 2024; .

PMID: 39715892 DOI: 10.1038/s41551-024-01316-1.

Loss of PTPN21 disrupted mitochondrial metabolic homeostasis and aggravated experimental pulmonary fibrosis.

Lian H, Xu K, Chang A, Wang Y, Ma S, Cheng L Respir Res. 2024; 25(1):426.

PMID: 39633451 PMC: 11619687. DOI: 10.1186/s12931-024-03041-4.

Unveiling the role of hypoxia-inducible factor 2alpha in osteoporosis: Implications for bone health.

Wang L, Lu Z, Luo S, Li Y, Yang Z, Lu H World J Stem Cells. 2024; 16(4):389-409.

PMID: 38690514 PMC: 11056635. DOI: 10.4252/wjsc.v16.i4.389.

Structural analysis of PTPN21 reveals a dominant-negative effect of the FERM domain on its phosphatase activity.

Chen L, Qian Z, Zheng Y, Zhang J, Sun J, Zhou C Sci Adv. 2024; 10(9):eadi7404.

PMID: 38416831 PMC: 10901363. DOI: 10.1126/sciadv.adi7404.

References

Bruns I, Lucas D, Pinho S, Ahmed J, Lambert M, Kunisaki Y . Megakaryocytes regulate hematopoietic stem cell quiescence through CXCL4 secretion. Nat Med. 2014; 20(11):1315-20. PMC: 4258871. DOI: 10.1038/nm.3707. View

Gu Y, Filippi M, Cancelas J, Siefring J, Williams E, Jasti A . Hematopoietic cell regulation by Rac1 and Rac2 guanosine triphosphatases. Science. 2003; 302(5644):445-9. DOI: 10.1126/science.1088485. View

Raab M, Swift J, Dingal P, Shah P, Shin J, Discher D . Crawling from soft to stiff matrix polarizes the cytoskeleton and phosphoregulates myosin-II heavy chain. J Cell Biol. 2012; 199(4):669-83. PMC: 3494847. DOI: 10.1083/jcb.201205056. View

Parsons J, Horwitz A, Schwartz M . Cell adhesion: integrating cytoskeletal dynamics and cellular tension. Nat Rev Mol Cell Biol. 2010; 11(9):633-43. PMC: 2992881. DOI: 10.1038/nrm2957. View

Gilden J, Peck S, Chen Y, Krummel M . The septin cytoskeleton facilitates membrane retraction during motility and blebbing. J Cell Biol. 2012; 196(1):103-14. PMC: 3255977. DOI: 10.1083/jcb.201105127. 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

Gonzalez-Cruz R, Fonseca V, Darling E . Cellular mechanical properties reflect the differentiation potential of adipose-derived mesenchymal stem cells. Proc Natl Acad Sci U S A. 2012; 109(24):E1523-9. PMC: 3386052. DOI: 10.1073/pnas.1120349109. View

Carlucci A, Gedressi C, Lignitto L, Nezi L, Villa-Moruzzi E, Avvedimento E . Protein-tyrosine phosphatase PTPD1 regulates focal adhesion kinase autophosphorylation and cell migration. J Biol Chem. 2008; 283(16):10919-29. DOI: 10.1074/jbc.M707248200. View

Tooley A, Gilden J, Jacobelli J, Beemiller P, Trimble W, Kinoshita M . Amoeboid T lymphocytes require the septin cytoskeleton for cortical integrity and persistent motility. Nat Cell Biol. 2008; 11(1):17-26. PMC: 3777658. DOI: 10.1038/ncb1808. View

10.

DeMay B, Meseroll R, Occhipinti P, Gladfelter A . Regulation of distinct septin rings in a single cell by Elm1p and Gin4p kinases. Mol Biol Cell. 2009; 20(8):2311-26. PMC: 2669037. DOI: 10.1091/mbc.e08-12-1169. View

11.

Rosenbluth M, Lam W, Fletcher D . Analyzing cell mechanics in hematologic diseases with microfluidic biophysical flow cytometry. Lab Chip. 2008; 8(7):1062-70. PMC: 7931849. DOI: 10.1039/b802931h. View

12.

Chowdhury F, Na S, Li D, Poh Y, Tanaka T, Wang F . Material properties of the cell dictate stress-induced spreading and differentiation in embryonic stem cells. Nat Mater. 2009; 9(1):82-8. PMC: 2833279. DOI: 10.1038/nmat2563. View

13.

Fay M, Myers D, Kumar A, Turbyfield C, Byler R, Crawford K . Cellular softening mediates leukocyte demargination and trafficking, thereby increasing clinical blood counts. Proc Natl Acad Sci U S A. 2016; 113(8):1987-92. PMC: 4776450. DOI: 10.1073/pnas.1508920113. View

14.

McBeath R, Pirone D, Nelson C, Bhadriraju K, Chen C . Cell shape, cytoskeletal tension, and RhoA regulate stem cell lineage commitment. Dev Cell. 2004; 6(4):483-95. DOI: 10.1016/s1534-5807(04)00075-9. View

15.

Mostowy S, Cossart P . Septins: the fourth component of the cytoskeleton. Nat Rev Mol Cell Biol. 2012; 13(3):183-94. DOI: 10.1038/nrm3284. View

16.

Holst J, Watson S, Lord M, Eamegdool S, Bax D, Nivison-Smith L . Substrate elasticity provides mechanical signals for the expansion of hemopoietic stem and progenitor cells. Nat Biotechnol. 2010; 28(10):1123-8. DOI: 10.1038/nbt.1687. View

17.

Lichtman M . Cellular deformability during maturation of the myeloblast. Possible role in marrow egress. N Engl J Med. 1970; 283(18):943-8. DOI: 10.1056/NEJM197010292831801. View

18.

Seshagiri S, Stawiski E, Durinck S, Modrusan Z, Storm E, Conboy C . Recurrent R-spondin fusions in colon cancer. Nature. 2012; 488(7413):660-4. PMC: 3690621. DOI: 10.1038/nature11282. View

19.

Orford K, Scadden D . Deconstructing stem cell self-renewal: genetic insights into cell-cycle regulation. Nat Rev Genet. 2008; 9(2):115-28. DOI: 10.1038/nrg2269. View

20.

Cheshier S, Morrison S, Liao X, Weissman I . In vivo proliferation and cell cycle kinetics of long-term self-renewing hematopoietic stem cells. Proc Natl Acad Sci U S A. 1999; 96(6):3120-5. PMC: 15905. DOI: 10.1073/pnas.96.6.3120. View