Hypoxia mediates low cell-cycle activity and increases the proportion of long-term-reconstituting hematopoietic stem cells during in vitro culture.
2010 (English)In: Experimental Hematology, ISSN 0301-472X, E-ISSN 1873-2399, Vol. 38, no 4, 301-310 p.Article in journal (Refereed) Published
Objective. Recent evidence suggests that hematopoietic stem cells (HSCs) in the bone marrow (BM) are located in areas where the environment is hypoxic. Although previous studies have demonstrated positive effects by hypoxia, its role in HSC maintenance has not been fully elucidated, neither has the molecular mechanisms been delineated. Here, we have investigated the consequence of in vitro incubation of HSCs in hypoxia prior to transplantation and analyzed the role of hypoxia inducible factor (HIF)-1α.
Materials and Methods. HSC and progenitor populations isolated from mouse BM were cultured in 20% or 1% O2, and analyzed for effects on cell cycle, expression of cyclindependent kinase inhibitors (CDKI) genes, and reconstituting ability to lethally irradiated mice. The involvement of HIF-1α was studied using methods of protein stabilization and gene silencing.
Results. When long-term FLT3-CD34- Lin-Sca-1+c-Kit+ (LSK) cells were cultured in hypoxia, cell numbers were significantly reduced in comparison to normoxia. This was due to a decrease in proliferation and more cells accumulating in G0. Moreover, the proportion of HSCs with long-term engraftment potential was increased. Whereas the expression of CDKI genes p21cip1, p27Kip1, and p57Kip2 increased in LSK cells by hypoxia, only p21cip1 was upregulated in FLT3-CD34-LSK cells. We could demonstrate that expression of p27Kip1 and p57Kip2 was dependent of HIF-1 . Surprisingly, overexpression of constitutively active HIF-1 or treatment with the HIF stabilizer agent FG-4497 led to a reduction in HSC reconstituting ability. Conclusion. Our results imply that hypoxia, in part via HIF-1 , maintain HSCs by decreasing proliferation and favouring quiescence.
Place, publisher, year, edition, pages
2010. Vol. 38, no 4, 301-310 p.
Hematopoietic stem cells, mouse, bone marrow, hypoxia, hypoxia-inducible factor-1 alpha, proliferation, cell cycle, transplantation
National CategoryMedical and Health Sciences
IdentifiersURN: urn:nbn:se:liu:diva-65541DOI: 10.1016/j.exphem.2010.01.005OAI: oai:DiVA.org:liu-65541DiVA: diva2:396560
On the day of the defence date the title of this article was "Hypoxia, via hypoxia-inducible factor (HIF)-1, mediates low cell cycle activity and preserves the engraftment potential of mouse hematopoietic stem cells" and one of the authors is no longer included in the article.
When finally published online the title of this article changde name to Hypoxia mediates low cell-cycle activity and increases the proportion of long-term-reconstituting hematopoietic stem cells during in vitro culture.2011-02-102011-02-102015-10-20