دورية أكاديمية
Hypoxia mediates low cell-cycle activity and increases the proportion of long-term-reconstituting hematopoietic stem cells during in vitro culture.
| العنوان: | Hypoxia mediates low cell-cycle activity and increases the proportion of long-term-reconstituting hematopoietic stem cells during in vitro culture. |
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| المؤلفون: | Eliasson, Pernilla, Rehn, Matilda, Hammar, Petter, Larsson, Peter, 1963, Sirenko, Oksana, Flippin, Lee A., Cammenga, Jörg, Jönsson, Jan-Ingvar |
| المساهمون: | Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell hematologi, Originator, Linköpings universitet, Hälsouniversitetet, Originator, Linköpings universitet, Institutionen för medicin och hälsa, Medicinsk radiofysik, Originator |
| المصدر: | Experimental Hematology. 38(4):301-310 |
| مصطلحات موضوعية: | Medical and Health Sciences, Medicin och hälsovetenskap, Hematopoietic stem cells, mouse, bone marrow, hypoxia, hypoxia-inducible factor-1 alpha, proliferation, cell cycle, transplantation, MEDICINE, MEDICIN |
| الوصف: | 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. |
| وصف الملف: | |
| الوصول الحر: | http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-65541Test |
| قاعدة البيانات: | SwePub |
Full Text Finder | تدمد: | 0301472X 18732399 |
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| DOI: | 10.1016/j.exphem.2010.01.005 |