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Fak depletion in both hematopoietic and nonhematopoietic niche cells leads to hematopoietic stem cell expansion
Lu, Jiayun Sun, Yan Nombela-Arrieta, Cesar Du, Karrie P. Park, Shin-Young Chai, Li Walkley, Carl Luo, Hongbo R. Silberstein, Leslie E.
Lu, Jiayun
Sun, Yan
Nombela-Arrieta, Cesar
Du, Karrie P.
Park, Shin-Young
Chai, Li
Walkley, Carl
Luo, Hongbo R.
Silberstein, Leslie E.
Abstract
Hematopoietic stem cells (HSCs) reside in complex bone marrow microenvironments, where niche-induced signals regulate hematopoiesis. Focal adhesion kinase (Fak) is a nonreceptor protein tyrosine kinase that plays an essential role in many cell types, where its activation controls adhesion, motility, and survival. Fak expression is relatively increased in HSCs compared to progenitors and mature blood cells. Therefore, we explored its role in HSC homeostasis. We have used the Mx1-Cre−inducible conditional knockout mouse model to investigate the effects of Fak deletion in bone marrow compartments. The total number as well as the fraction of cycling Lin−Sca-1+c-kit+ (LSK) cells is increased in Fak−/− mice compared to controls, while hematopoietic progenitors and mature blood cells are unaffected. Bone marrow cells from Fak−/− mice exhibit enhanced, long-term (i.e., 20-week duration) engraftment in competitive transplantation assays. Intrinsic Fak function was assessed in serial transplantation assays, which showed that HSCs (Lin−Sca-1+c-kit+CD34−Flk-2− cells) sorted from Fak−/− mice have similar self-renewal and engraftment ability on a per-cell basis as wild-type HSCs. When Fak deletion is induced after engraftment of Fakfl/flMx1-Cre+ bone marrow cells into wild-type recipient mice, the number of LSKs is unchanged. In conclusion, Fak inactivation does not intrinsically regulate HSC behavior and is not essential for steady-state hematopoiesis. However, widespread Fak inactivation in the hematopoietic system induces an increased and activated HSC pool size, potentially as a result of altered reciprocal interactions between HSCs and their microenvironment.
Keywords
Date
2012
Type
Journal article
Journal
Experimental Hematology
Book
Volume
40
Issue
4
Page Range
307-317
Article Number
ACU Department
Mary MacKillop Institute for Health Research
Faculty of Health Sciences
Faculty of Health Sciences
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Relation URI
Source URL
Event URL
Open Access Status
License
All rights reserved
File Access
Controlled