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Abstract
Background: Stem cells (SC) divide to produce either a SC and a more differentiated committed progenitor (asymmetric SC self-renewal) or two SCs (symmetric SC self-renewal). Aged keratinocyte SCs are less proliferative and undergo less asymmetric SC divisions but more symmetric self-renewal divisions than adult. These changes are relevant, given asymmetric SC self renewal is associated with epidermal thickness and symmetric SC self-renewal with cancer in many circumstances.
Aim: To further examine proliferative defects with age and test whether a small molecule/ peptide can ameliorate these defects.
Method: We used time-lapse photograpy in vitro to examine the proliferation kinetics of aged (73-92y) and adult (34-49y) passage zero human keratinocytes. We then incubated aged keratinocytes with an exogenous peptide, P199 (purported to improve keratinocyte proliferation), or vehicle. Lineage trees of cell divisions were constructed, to determine cell cycle duration (CCD) and the proliferation/differentiation outcomes of each division.
Results: Aged keratinocytes generated smaller colonies than adult. A higher proportion of divisions resulted in terminal differentiation and the median CCD was longer. P199 rescued the increased terminal differentiation as well as the extended CCD. P199 also increased asymmetric SC self-renewal in aged keratinocytes.
Conclusion: Aging results in decreased asymmetric SC self-renewal, increased CCD, and increased terminal differentiation. P199 rescues these changes in SCs, resulting in levels similar to adult samples, but committed progenitors are relatively unaffected. Understanding defects in proliferation with aging at a granular level will allow us to design targeted therapeutics. These studies further indicate that extrinsic factors can successfully rejuvenate specific age-related SC behaviors.