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Stem Cell Dynamics in Skin Regeneration and Aging

Tissue stem cells maintain tissue integrity during homeostasis and exhibit remarkable plasticity in response to stresses and injuries. A misregulation of stem cells leads to tissue dysfunction, such as impaired wound healing, chronic inflammation, tumorigenesis, and aging. Emerging evidence suggests that stem cell populations in adult tissues are heterogeneous and play distinct roles in physiological and pathological conditions. 


Our research focuses on elucidating the cellular dynamics and regulatory mechanisms of tissue stem cells during skin regeneration, inflammation and aging processes. We have identified a novel stem cell population in mouse skin epidermis (Sada et al., Nat Cell Biol 2016) and established genetic tools and molecular markers to analyze these cells in vivo. Such stem cell proliferative heterogeneity is shown to be present not only in mouse skin, but also in the other epithelial tissues of the eye and oral mucosa, as well as in human skin. We are now combining cellular and molecular biology methods, mouse genetics, omics analysis, bioengineering, and glycobiology to analyze the function of biomolecules involved in skin stem cell regulation. Our research goal is to identify the drivers and effectors of stem cell dysfunction; targeting these factors will allow us to prevent and treat diseases at the stem cell level, with potential applications in regenerative therapies and future treatments for cancer, aging, and other skin diseases.


Defining Stem Cell Lineages in the Skin Epidermis

The skin barrier function is achieved by proliferation and differentiation of stem cells residing in the epidermis. Epidermal stem cells have been used for clinical purposes since 1980’s, yet their basic knowledge lagged behind until recently due to the lack of molecular markers and tools to define “stem cell” populations. 


A classical model suggests that slow-cycling cells act as long-lived stem cells and place at the top of lineage hierarchy, generating short-lived progenitor cells. The slow-cycling nature is considered to be a mechanism to protect stem cells from replication-induced DNA damage, accumulation of mutations, telomere-shortening, all of which can lead to tumorigenesis and aging. However, true biological functions of slow-cycling cells remain controversial.

​In our previous study, Sada et al. identified novel molecular markers that enable us to distinguish slow-cycling and fast-dividing cells in the skin epidermis and, thereby, to study their localization, kinetics and long-term stem cell potential during homeostasis and regeneration. Contradicting to the classical model, we found that not only slow-cycling cells, but also fast-dividing cells act as long-lived stem cells. Each stem cell population clusters within spatially distinct territories in the skin and can preferentially produce their unique lineages. Following injury, these two stem cell populations can interconvert to each other, demonstrating their plasticity for robust skin regeneration.

Our work re-defines the stem cell populations in the skin epidermis and identifies two discrete stem cells with different cell division frequencies. This opens a new avenue for understanding the heterogeneous stem cell populations in aging, cancer and other diseases. 

We are currently addressing,

  • Does the two stem cell population model apply to human skin or other tissues?

  • How these two stem cell populations are affected during aging? If they divide more, do they age more?

  • When and how these stem cells are established during skin development?

  • How they are regulated (cell-intrinsic or environmentally)?

  • How they behave in culture? Can we engineer 3D skin in vitro?

  • Biomarkers to define different stem cell populations?

Elucidating the Mechanisms of Stem Cell Aging

Aging is the gradual decline of physiological functions over time. The theory of “stem cell aging” proposes that aging is caused by the misregulation or dysfunction of tissue stem cells during aging; however, the crucial drivers for stem cell aging at cellular and molecular levels still remain largely unknown.

Aging epithelial tissues have impaired wound healing and barrier function and an increased risk of cancer. We previously found that epidermal stem cell populations with different cell division frequencies coexist in mouse epidermis (Nat Cell Biol 2016), but the role of these stem cell populations in skin aging was unknown. We recently reported that a rapidly-dividing epidermal stem cell population is declined with age and that maintenance of extracellular matrix integrity is critical for its regulation (EMBO Rep, 20220). We are currently conducting further functional analysis of the environmental and stem cell intrinsic factors that induce stem cell aging and skin dysfunction.

Development and evaluation of bioengineered 3D skin model

The development of in vitro culture of primary keratinocytes and epidermal autografts was the first breakthrough in skin regenerative therapy. Cultured epidermal autografts were successfully transplanted into severe burn patients in the 1980s, and several clinical cases of severely burned patients were subsequently reported. In 2017, genetically modified epidermal stem cells were used to treat junctional epidermolysis bullosa, opening a new avenue for skin regeneration therapy. However, creating a complete skin substitute that mimics physiological 3D tissue structure and cellular composition in vitro remains a major scientific and clinical challenge. In particular, it has not yet been possible to reproduce the proliferative heterogeneity of epidermal stem cells that we found in our mouse experiments under in vitro culture conditions. There is also a lack of markers and tools to assess the quality of 3D skin equivalents.

Our aim is to develop 3D skin models and evaluate their cellular and molecular components. By optimizing culture conditions, we aim to reproduce the heterogeneity patterns of epidermal stem cells and their niche environment in vitro. Future applications of human 3D skin models include regenerative therapy, drug screening, and disease modeling.

The roles of glycans in skin aging and stem cell function

The presence of glycans determines the structure, stability, and localization of glycoproteins. Glycans play essential roles in physiological and pathological conditions such as development, tumorigenesis, and inflammation. They are also required for stem cell regulation by modulating cell-cell and cell-matrix interactions. The study of glycans in mammalian tissue stem cells has been challenging because stem cells are rare and biochemical analysis of glycans requires large amounts of samples.


Using lectin microarrays, a platform for high-throughput glycan structural analysis, we performed comprehensive glycan profiling of mouse epidermal stem cells during skin aging (Aging Cell, 2020). We demonstrated that epidermal stem cells undergo an age-dependent “glycome shift” from high mannose to sialylated complex-type N-glycans. We identified two lectin probes, a mannose-binder rHeltuba and an a2-3 Sia-binder rGal8N, as novel biomarkers that preferentially detect young and old epidermal stem cells, respectively. We are currently addressing how changes in glycans affect protein function and aging phenotype in skin. Glycosylation detected by lectins serves as a molecular marker of aging, and functional studies offer potential intervention strategies for healthy aging and longevity.

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