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Stem Cells – Time is Not Your Friend!

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Review of “Ageing disrupts cell subpopulation dynamics and diminishes the function of mesenchymal stem cells”from Science Reports by Stuart P. Atkinson

Normal ageing is associated with a decreased ability to form blood vessels (neovascularization) [1, 2] and, while mesenchymal stem cell (MSC)-mediated trophic support can promote vessel formation [3, 4], the effects of ageing on cells in this context are relatively unknown. Researchers from the group of Geoffrey C. Gurtner (Stanford University School of Medicine, CA, USAhave now used single cell analysis to demonstrate that increased age leads to a decrease in MSC functionality, which may impact upon their therapeutic application to vascular disease [5].

Initial assessment of MSCs derived from adipose tissue of mice ranging over ages from 3 (young) to 21 (old) months found no differences in frequency, viability or proliferative capacity at the population level. However, single cell analysis using a microfluidic-based gene expression platform [6] did demonstrate that young and old cells differed in the expression of key genes related to cell stemness, vasculogenesis and tissue remodeling. Higher expression of such genes was prevalent in younger cells, so suggesting that older cells may have lost some of their potential. Expression analysis also demonstrated a reduction in inter-cell signaling in aged MSCs. 

The group then assessed MSCs at the functional levels using various techniques related to vasculogenesis and wound repair. An endothelial cell sprouting assay, used as a surrogate for vascular formation, found that aged MSCs had a reduced cytokine stimulatory capacity on human umbilical vein endothelial cells (HUVEC). Likewise, a matrigel plug vascularization assay also found that old MSCs led to less vascularization. Finally, while young MSCs enhanced healing rates in a murine model of excisional cutaneous wounds, older MSCs did not enhance rates or closure times, and this was linked to a reduction in the expression of anti-oxidative and pro-vasculogenic molecules.

Detailed single cell analysis therefore suggests that ageing may affect MSC subpopulation dynamics leading to reduced functionality. Indeed, altered subpopulation dynamics may represent a fundamental mechanism underlying the ageing process. The authors suggest that their data has “considerable implications for new diagnostic and therapeutic approaches in this population”, and may prompt the development of new therapeutic and diagnostic tools.

References

  1. Chang EI, Loh SA, Ceradini DJ, et al. Age decreases endothelial progenitor cell recruitment through decreases in hypoxia-inducible factor 1alpha stabilization during ischemia. Circulation 2007;116:2818-2829.
  2. Felice F, Barsotti MC, Poredos P, et al. Effect of ageing on metabolic pathways in endothelial progenitor cells. Curr Pharm Des 2013;19:2351-2365.
  3. Garg RK, Rennert RC, Duscher D, et al. Capillary force seeding of hydrogels for adipose-derived stem cell delivery in wounds. Stem Cells Translational Medicine 2014;3:1079-1089.
  4. Rustad KC, Wong VW, Sorkin M, et al. Enhancement of mesenchymal stem cell angiogenic capacity and stemness by a biomimetic hydrogel scaffold. Biomaterials 2012;33:80-90.
  5. Duscher D, Rennert RC, Januszyk M, et al. Ageing disrupts cell subpopulation dynamics and diminishes the function of mesenchymal stem cells. Sci Rep 2014;4:7144.
  6. Glotzbach JP, Januszyk M, Vial IN, et al. An information theoretic, microfluidic-based single cell analysis permits identification of subpopulations among putatively homogeneous stem cells. PLoS One 2011;6:e21211.