Ptpn21 Controls Hematopoietic Stem Cell Homeostasis and Biomechanics

• Type of Material: Article
• Authors: Fang Ni, Emory University; Wen-Mei Yu, Emory University; Xinyi Wang, Emory University; Meredith E. Fay, Emory University; Katherine Young, Emory University; Yongzhi Qiu, Emory University; Wilbur Lam, Emory University; Todd A. Sulchek, Georgia Institute of Technology; Tao Cheng, Chinese Academy of Sciences; David T. Scadden, Harvard University; Cheng-Kui Qu, Emory University
• Language: English
• Date: 2019-04-04
• Publisher: Cell Press
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2019 Elsevier Inc.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.stem.2019.02.009
• Title of Journal or Parent Work: Cell Stem Cell
• Volume: 24
• Issue: 4
• Start Page: 608
• End Page: +
• Grant/Funding Information: This work was supported by the National Institutes of Health grants HL130995 and DK092722 (to C.K.Q.).
• Keywords: Science & Technology; Niche; Trafficking; Life Sciences & Biomedicine; Septin cytoskeleton; Migration; Cell Biology; Cell & Tissue Engineering; Require; Maturation
• Research Categories: Biology, Cell; Health Sciences, Oncology; Engineering, Biomedical; Health Sciences, Human Development

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 246 ), 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. Ptpn21, a protein tyrosine phosphatase highly expressed in HSCs, plays an important role in maintaining cellular mechanics and HSC retention in the niche. Knockout of Ptpn21 results in decreased cellular stiffness, enhanced deformability and motility, stem and progenitor cell egress, and defective hematopoietic reconstitution capabilities. Mechanistically, Ptpn21 modulates cell mechanics by dephosphorylating Septin1 (Tyr 246 ).