Ptpn21 Controls Hematopoietic Stem Cell Homeostasis and Biomechanics

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

doi:10.1016/j.stem.2019.02.009

Ptpn21 Controls Hematopoietic Stem Cell Homeostasis and Biomechanics

Cell Stem Cell. 2019 Apr 4;24(4):608-620.e6. doi: 10.1016/j.stem.2019.02.009. Epub 2019 Mar 14.

Authors

Affiliations

¹ Division of Hematology/Oncology, Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Winship Cancer Institute, Children's Healthcare of Atlanta, Emory University, Atlanta, GA 30322, USA.
² Division of Hematology/Oncology, Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Winship Cancer Institute, Children's Healthcare of Atlanta, Emory University, Atlanta, GA 30322, USA; The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA.
³ Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332, USA.
⁴ The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA; Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332, USA.
⁵ State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences, Tianjin 300020, China.
⁶ Center for Regenerative Medicine and MGH Cancer Center, Massachusetts General Hospital, Department of Stem Cell and Regenerative Biology and Harvard Stem Cell Institute, Harvard University, Boston, MA 02114, USA.
⁷ Division of Hematology/Oncology, Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Winship Cancer Institute, Children's Healthcare of Atlanta, Emory University, Atlanta, GA 30322, USA. Electronic address: cheng-kui.qu@emory.edu.

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 (Tyr²⁴⁶), 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.

Keywords: Ptpn21; biomechanics; cytoskeleton; hematopoietic stem cell; niche; protein tyrosine phosphatase; septin.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Hematopoietic Stem Cells / cytology*
Hematopoietic Stem Cells / metabolism*
Homeostasis*
Mice
Mice, Inbred C57BL
Mice, Knockout
Phosphorylation
Protein Tyrosine Phosphatases, Non-Receptor / deficiency
Protein Tyrosine Phosphatases, Non-Receptor / metabolism*
Septins / metabolism*
Stem Cell Niche

Substances

Protein Tyrosine Phosphatases, Non-Receptor
Ptpn21 protein, mouse
Sept1 protein, mouse
Septins

Abstract

Publication types

MeSH terms

Substances

Grants and funding