HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Thorén, L. A. Articles by Jacobsen, S.-E. W. PubMed PubMed Citation Articles by Thorén, L. A. Articles by Jacobsen, S.-E. W.

Kit Regulates Maintenance of Quiescent Hematopoietic Stem Cells¹

Lina A. Thorén^*, Karina Liuba^*, David Bryder, Jens M. Nygren^*, Christina T. Jensen^*, Hong Qian^*, Jennifer Antonchuk^2,* and Sten-Eirik W. Jacobsen^3,*

^* Hematopoietic Stem Cell Laboratory, Lund Strategic Research Center for Stem Cell Biology and Cell Therapy, and Immunology Unit, Institution for Experimental Medical Science, Lund University, Lund, Sweden

Hematopoietic stem cell (HSC) numbers are tightly regulated and maintained in postnatal hematopoiesis. Extensive studies have supported a role of the cytokine tyrosine kinase receptor Kit in sustaining cycling HSCs when competing with wild-type HSCs posttransplantation, but not in maintenance of quiescent HSCs in steady state adult bone marrow. In this study, we investigated HSC regulation in White Spotting 41 (Kit^W41/W41) mice, with a partial loss of function of Kit. Although the extensive fetal HSC expansion was Kit-independent, adult Kit^W41/W41 mice had an almost 2-fold reduction in long-term HSCs, reflecting a loss of roughly 10,000 Lin^–Sca-1⁺Kit^high (LSK)CD34^–Flt3^– long-term HSCs by 12 wk of age, whereas LSKCD34⁺Flt3^– short-term HSCs and LSKCD34⁺Flt3⁺ multipotent progenitors were less affected. Whereas homing and initial reconstitution of Kit^W41/W41 bone marrow cells in myeloablated recipients were close to normal, self-renewing Kit^W41/W41 HSCs were progressively depleted in not only competitive but also noncompetitive transplantation assays. Overexpression of the anti-apoptotic regulator BCL-2 partially rescued the posttransplantation Kit^W41/W41 HSC deficiency, suggesting that Kit might at least in the posttransplantation setting in part sustain HSC numbers by promoting HSC survival. Most notably, accelerated in vivo BrdU incorporation and cell cycle kinetics implicated a previously unrecognized role of Kit in maintaining quiescent HSCs in steady state adult hematopoiesis.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the Swedish Research Council, the Juvenile Diabetes Research Foundation, the Swedish Foundation for Strategic Research, and the European Union Project CT-2003-503005 (EuroStemCell). The Lund Stem Cell Center is supported by a Center of Excellence grant from the Swedish Foundation for Strategic Research.

² Current address: Institute for Stem Cell Research, University of Edinburgh, West Mains Road, Edinburgh EH9 3JQ, U.K.

³ Address correspondence and reprint requests to Dr. Sten-Eirik W. Jacobsen, Hematopoietic Stem Cell Laboratory, Lund Strategic Research Center for Stem Cell Biology and Cell Therapy, Lund University, Lund 221 84, Sweden. E-mail address: sten.jacobsen{at}med.lu.se

⁴ Abbreviations used in this paper: HSC, hematopoietic stem cell; BM, bone marrow; FL, fetal liver; LSK, lineage^–Sca-1⁺Kit^high; MPP, multipotent progenitor; WT, wild type.