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Rejuvenating Old Stem Cells – miRNA KO is the Way?

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Review of “Abrogation of Age-Induced MicroRNA-195 Rejuvenates the Senescent Mesenchymal Stem Cells by Reactivating Telomerase” from Stem Cells by Stuart P. Atkinson

We have all seen the sensational stories of 90-year-olds running marathons or scaling the highest peaks where even the young and fit don’t dare to pass. How do they do it and what molecular mechanisms are in play? And more to the point, can we apply any knowledge garnered to rejuvenate the elderly and infirm? 

Researchers from the laboratory of Muhammad Ashraf (University of Illinois at Chicago, USA) have been asking themselves similar questions, but directed at mesenchymal stem cells (MSCs). They previously identified a novel subpopulation of young MSCs (YMSCs) in old bone marrow with a promisingly high regenerative potential [1]. Now, in their new study in Stem Cells, they link this potential to the suppression of a specific miRNA in YMSCs which normally mediates the age-related inhibition of telomerase and the onset of cellular senescence [2]. They hope that this finding may allow the construction of potent anti-aging stem cell therapeutics.

The authors discovered differences in miRNA expression with aging after comparing the RNA profiles of YMSCs and old (O)MSCs. Of the miRNAs upregulated and downregulated, the study concentrated on the significant upregulation of miR-195 in OMSCs after discovering that an miR-195 binding site existed in the 3′-UTR of mouse Tert gene.

Further in vitro analysis confirmed that miR-195 directly bound and inhibited Tert mRNA expression in OMSCs suggesting that this miRNA may induce senescence. Interestingly, abrogation of miRNA-195 expression in OMSCs reduced levels of senescence markers, increased telomere lengthening, and reduced apoptosis, all of which suggests that miRNA-195 abrogation rejuvenates OMSCs.

But does this rejuvenation increase their therapeutic potential? To find this out, the group transplanted OMSCs with abrogated miRNA-196 expression onto the infarcted mouse heart and found that this significantly reduced infarction size with better efficacy and improved cardiac function when compared to normal OMSCs (See Figure - Masson trichrome staining).

Not only does this study uncover an important pathway regulating the aging of MSCs, but it may provide us with a means to treat elderly patients in an autologous manner. While only tested for the treatment of myocardial infarction, a common ailment in the elderly, it is likely that these rejuvenated MSCs will have regenerative potential for the treatment of other age-related illnesses. Furthermore, KO of miRNA-195 may act to rejuvenate other aged adult stem cell types and could also help to erase age-related signs in more differentiated cells.

References

  1. Igura K, Okada M, Kim HW, et al. Identification of small juvenile stem cells in aged bone marrow and their therapeutic potential for repair of the ischemic heart. Am J Physiol Heart Circ Physiol 2013;305:H1354-1362.
  2. Okada M, Kim HW, Matsu-Ura K, et al. Abrogation of Age-Induced MicroRNA-195 Rejuvenates the Senescent Mesenchymal Stem Cells by Reactivating Telomerase. Stem Cells 2016;34:148-159.