Research Article: Wild-type and SAMP8 mice show age-dependent changes in distinct stem cell compartments of the interfollicular epidermis

Date Published: May 15, 2019

Publisher: Public Library of Science

Author(s): Gopakumar Changarathil, Karina Ramirez, Hiroko Isoda, Aiko Sada, Hiromi Yanagisawa, Jyotshna Kanungo.


Delayed wound healing and reduced barrier function with an increased risk of cancer are characteristics of aged skin and one possible mechanism is misregulation or dysfunction of epidermal stem cells during aging. Recent studies have identified heterogeneous stem cell populations within the mouse interfollicular epidermis that are defined by territorial distribution and cell division frequency; however, it is unknown whether the individual stem cell populations undergo distinct aging processes. Here we provide comprehensive characterization of age-related changes in the mouse epidermis within the specific territories of slow-cycling and fast-dividing stem cells using old wild-type, senescence-accelerated mouse prone 1 (SAMP1) and SAMP8 mice. During aging, the epidermis exhibits structural changes such as irregular micro-undulations and overall thinning of the tissue. We also find that, in the old epidermis, proliferation is preferentially decreased in the region where fast-dividing stem cells reside whereas the lineage differentiation marker appears to be more affected in the slow-cycling stem cell region. Furthermore, SAMP8, but not SAMP1, exhibits precocious aging similar to that of aged wild-type mice, suggesting a potential use of this model for aging study of the epidermis and its stem cells. Taken together, our study reveals distinct aging processes governing the two epidermal stem cell populations and suggests a potential mechanism in differential responses of compartmentalized stem cells and their niches to aging.

Partial Text

Aging is a gradual decline in physiological functions over a course of time. It still remains a mystery what are the crucial drivers for aging at cellular and molecular levels. Among a myriad of hypotheses proposed, a theory of stem cell aging suggests that aging is caused by the inability of adult stem cells to replenish tissues due to depletion or accumulation of molecular and cellular defects [1–3].

The mouse IFE is maintained by two distinct populations of epidermal stem cells that divide at a different rate [12]. Our current study focused on the age-dependent changes of slow-cycling and fast-dividing stem cells located in the interscale and scale IFE of tail skin, respectively. Considering that fast-dividing stem cells experience three times more divisions than slow-cycling stem cells over the entire life span [12], they may lose their stem cell property prematurely due to life-long, repeated cell divisions. Our observations revealed compartment-specific changes of epidermal stem cells during aging that were marked by distinct parameters. We found that fast-dividing stem cells showed a significant decrease in proliferation with age (Fig 4B and 4C), along with structural changes in the form of irregular micro-undulations and overall thinning of the epidermis (Fig 1B–1D). In contrast, the differentiation process is found to be more affected in the slow-cycling stem cell lineage (Fig 6B and 6C). These results suggest that distinct stem cell populations and their niches may react differently to aging. Further experiments are needed to address detailed cellular and molecular mechanisms of epidermal stem cell aging.