Expanding Hematopoietic Stem Cells by Removing Inhibitors
Sunday April 20th, 2008 @ 15:22:22 EST
The desire to expand hematopoietic stem cells is not only a basic research accomplishment but would allow for widespread use of autologous stem cells, as well as expand the utilization of cord blood stem cells which are usually of concern due to the relatively low stem cell content.
Various methods of expanding hematopoietic stem cells exist, for example, treatment with histone deacetylase inhibitors, culture in various cytokine cocktails, or treatment with chelating agents. Unfortunately, besides at a basic level, little is known about the actual mechanisms by which stem cells self renew. Recently Dr. Michael Clarke's group published a paper (Akala et al. Long-term haematopoietic reconstitution by Trp53(-)(/-)p16(Ink4a)(-/-)p19(Arf-)(/-) multipotent progenitors Nature April 2008) shedding some light on this matter. As an aside, this is the same Dr. Clarke whose technologies were commercialized by OncoMed in the area of tumor stem cells.
Dr. Clarke's group previously demonstrated that the polycomb gene Bmi-1 is essential for hematopoietic stem cell renewal (
Park et al. Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells. Nature. 2003 May 15;423(6937):302). Subsequently other groups have demonstrated that Bmi-1 is involved in adult but not embryonic stem cell self-renewal. One of the mechanisms by which Bmi-1 maintains self-renewal is by suppressing the cell cycle inhibitors p16Ink4a (p16) and p19Arf (p19). This is very interesting since both of these genes have been demonstrated to be accurate biomarkers of aging ! (
Krishnamurthy et al. Ink4a/Arf expression is a biomarker of aging. J Clin Invest 114:1299).
In the current paper, Dr. Clarke generated mice that lack p53 as well as p16 and 19. Interesting these mice has a ten fold increase hematopoietic stem cells capable of reconsituting other repients. Additionally this striking increase in hematopoietic stem cell activity was correlated with increased cells expressing the surface phenotype of early hematopoietic stem cells.
This finding is of great interest since it suggests that techniques such as RNA interference may be useful in "suppressing suppressors" of stem cell self renewal and thus allowing for the generation of novel methods of expanding autologous stem cells without inducing differentiation.
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