Aging disrupts cell subpopulation dynamics and diminishes the function of mesenchymal stem cells

Abstract

Advanced age is associated with an increased risk of vascular morbidity, attributable in part to impairments in new blood vessel formation. Mesenchymal stem cells (MSCs) have previously been shown to play an important role in neovascularization and deficiencies in these cells have been described in aged patients. Here we utilize single cell transcriptional analysis to determine the effect of aging on MSC population dynamics. We identify an age-related depletion of a subpopulation of MSCs characterized by a pro-vascular transcriptional profile. Supporting this finding, we demonstrate that aged MSCs are also significantly compromised in their ability to support vascular network formation in vitro and in vivo. Finally, aged MSCs are unable to rescue age-associated impairments in cutaneous wound healing. Taken together, these data suggest that age-related changes in MSC population dynamics result in impaired therapeutic potential of aged progenitor cells. These findings have critical implications for therapeutic cell source decisions (autologous versus allogeneic) and indicate the necessity of strategies to improve functionality of aged MSCs.

Adult Human Mesenchymal Stem Cell Differentiation at the Cell Population and Single-Cell Levels Under Alternating Electric Current

“…To date, the Fluidigm single-cell analysis method has been used with various stem cells types, such as, mouse hematopoietic stem cells, 19,20 mouse embryonic stem, 21 human cancer stem cells, 16 and human 22 and mouse 23 mesenchymal stem cells mostly in the presence of bioactive chemicals but not under a biophysical stimulus. Exposure of hMSCs to the optimal alternating electric current conditions examined in the present study provided evidence of homogeneous (defined as the uniform expression of a specific gene between 5 and 15; Fig.…”

Dermal white adipose tissue renewal is regulated by the PDGFA/AKT axis

“…Interestingly, the pro-healing effects were not observed if ASC from aged mice and failed to enhance wound healing rates. The authors of this study postulated that this effect was due to a depletion of a functional subset of ASC expressing anti-oxidative and pro-regenerative cytokines (10). Thus, decreased levels of PDGFA and thus reduced CD24+ASC numbers in aged mice might define the mechanism underlying this observation.…”

“…Thus it would be interesting to address as to whether/how molecular mechanisms regulating CD24+ ASC self-renewal as shown by Rivera-Gonzales et al (2), also contribute to dermal wound healing and scarring. Of note, a study investigating the effects of ASC on dermal wound healing in mice has already demonstrated that transplantation of ASC harvested from young mice improved wound healing in aged mice (10). Interestingly, the pro-healing effects were not observed if ASC from aged mice and failed to enhance wound healing rates.…”

Finding a needle in a “needlestack”

“…2 Other subpopulations are able to perform supportive roles such as growth factor release, extracellular matrix production and enrichment of the cell niche. 3 Finally, there are those cell subsets that demonstrate undesirable properties such as activation of fibrosis or unwanted inflammatory cascades. 4 Interestingly, in some disease states changes occur within these subgroups.…”

“…Although the total number of cells remain constant, important subgroups disappear while other less functional subgroups increase in numbers to compensate. 3,5 Traditional population-level assays have been blind to capturing these complex relationships within populations and have failed at sorting out these cell subsets. We have recently demonstrated a robust methodology using single cell transcriptional and protein analyses that can distinguish between seemingly similar cells, identify cellular subsets and isolate each subset based on distinct surface markers.…”