Reprogramming of old HSCs reverses functional defects associated with aging

HSCs must continuously self-renew to replenish the pool of mature blood cells throughout the life an adult.  One requirement for extensive self-renewal is high telomerase activity to prevent telomere shortening.  HSCs isolated from adult bone marrow have shorter telomeres than cells from fetal liver or umbilical cord blood 1, suggesting that proliferative potential may decrease with age.  Also, HSC aging is associated with decreased lymphoid potential, as well as an up-regulation of genes involved in leukemic transformation 2.  Consequently, “aging” HSCs may have functional defects that might be detrimental for therapeutic strategies involving genetic manipulation and transplantation of HSCs for the treatment of various blood disorders.

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Previous studies have demonstrated that during reprogramming, developing iPSCs express epigenetic features of ESCs, and lose those of the starting somatic cell 3.  In addition, a previous study reported a significant elongation of telomeres in derived iPSCs compared to the starting somatic cell 4.  Thus, it may be possible that reprogramming reverses functional defects associated with HSC aging.

Recently, in Blood, Wahlestedt et al examined whether characteristics of aging HSCs are reversible 5.  First, they derived iPSCs from young and aged murine HSCs.  To examine their differentiation potential, they injected the derived iPSCs into murine blastocysts and analyzed the engraftment of the donor cells in the developing chimeric embryos.  Overall, iPSCs derived from aged HSCs demonstrated similar differentiation potential compared to that of younger HSCs.  The engraftment of bone marrow mononuclear cells from primary chimeric mice in a competitive transfer experiment was comparable to that of young HSCs.  Aged HSCs, on the other hand, demonstrated a significant reduction in repopulation capacity.  Interestingly, aged iPSC-derived HSCs also generated naïve T cells at similar levels as young HSCs.

Next, the authors examined telomere length following re-differentiation of the young and aged iPSCs.  Telomeres in aged HSCs were ~11% shorter compared to young HSCs.  However, telomeres of the HSCs derived from the aged iPSCs demonstrated a 2-fold elongation compared to blastocyst control HSCs.  This 2-fold elongation was maintained even after transplantation.  Overall, these results indicate that iPSC induction from HSCs results in elongation of telomeres.

In short, Wahlestedt et al demonstrated that reprogramming does indeed reverse some of the functional defects associated with chronologically aged HSCs, including decreased differentiation potential and shortened telomeres.  However, the study did not address whether the iPSCs derived from aged HSCs had an increased DNA mutation frequency, since HSC aging is also associated with a higher mutation rate.  It would also be interesting to determine whether the above phenomena are also observed in reprogramming of aged human HSCs.  If iPSC induction does indeed result in an “epigenetic reset,” then HSCs derived from iPSCs may have unique characteristics favorable for use in clinical settings.

 

References

1          Vaziri, H. et al. Evidence for a mitotic clock in human hematopoietic stem cells: loss of telomeric DNA with age. Proc Natl Acad Sci U S A 91, 9857-9860 (1994).

2          Rossi, D. J. et al. Cell intrinsic alterations underlie hematopoietic stem cell aging. Proc Natl Acad Sci U S A 102, 9194-9199, doi:10.1073/pnas.0503280102 (2005).

3          Maherali, N. et al. Directly reprogrammed fibroblasts show global epigenetic remodeling and widespread tissue contribution. Cell Stem Cell 1, 55-70, doi:10.1016/j.stem.2007.05.014 (2007).

4          Marion, R. M. et al. Telomeres acquire embryonic stem cell characteristics in induced pluripotent stem cells. Cell Stem Cell 4, 141-154, doi:10.1016/j.stem.2008.12.010 (2009).

5          Wahlestedt, M. et al. An epigenetic component of hematopoietic stem cell aging amenable to reprogramming into a young state. Blood, doi:10.1182/blood-2012-11-469080 (2013).

About Karina Palomares

Karina Palomares is a Postdoctoral Fellow at UC San Diego with a research interest in differentiation of human ES cells into cardiomyocytes. She graduated from UCLA focusing on the role of ephrinB2 in human ES cell fate.