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Stem Cell Dynamics in Skin Regeneration and Aging

Stem cells maintain the tissue integrity during homeostasis and show remarkable plasticity to quickly respond to various stress or damages of the tissue. Dysfunction or misregulation of stem cells leads to tissue dysfunction, including impaired wound healing, cancer and aging. Emerging evidence suggests the presence of heterogeneous stem cell populations within adult tissues and their specific roles in physiological and pathological conditions. 


Our research focuses on elucidating the cellular dynamics and regulatory mechanisms of tissue-resident stem cells, especially using mouse epithelial tissues (skin, eyes, oral) as a model. We identified a new stem cell populations in the mouse skin epidermis (Sada et al., Nat Cell Biol 2016) and established the genetic tools and molecular markers to analyze these cells in vivo. We are currently studying stem cells in tissue regeneration and aging, by combining cell & molecular biology techniques, genetic-engineering of mice, multi omics analysis, imaging, bioengineering, lectin technology, and so on. 

Our research goal is to reveal the drivers and effectors of stem cell dysfunction. Targeting these factors may prevent or cure diseases at the stem cell level, with implications for applications in regenerative therapy and for future treatments of cancer, aging and other disorders.


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 a gradual decline in physiological functions over a course of time. It still remains largely unknown what are the crucial drivers for aging at cellular and molecular levels. A theory of "stem cell aging" suggests that aging is caused by misregulation or dysfunction of stem cells in aged tissues.


The aged epithelial tissues show reduced wound healing and barrier function, with an increased risk of cancer. Our recent study proposed the co-existence of two distinct stem cell populations – slow-cycling and fast-dividing stem cells – in the mouse epidermis; however, it remains largely unknown how aging affects these stem cell populations and how it contributes to age-associated tissue dysfunction. Considering that fast-dividing stem cells experience three times more divisions than slow-cycling stem cells over the entire life span, they may lose their stem cell ability prematurely or cause malignant transformation due to life-long, repeated cell divisions. 

Our research aims to understand the cellular and molecular basis of stem cell aging in three epithelial tissues, skin, oral and eyes, with implications for future treatments of age-related disorders including cancer. 

Development and evaluation of bioengineered 3D skin model

The development of in vitro culture of primary keratinocytes and transplantation of epidermal autografts led to the first breakthrough for skin tissue engineering. The cultured epidermal autografts were successfully engrafted in severe burn victims in 1980s, followed by several clinical cases on patients with massive burns. In 2017, genetically-corrected epidermal stem cells were used for the treatment of junctional epidermolysis bullosa, opening a new avenue for regenerative therapies in skin. However, it still remains a major scientific and clinical challenge to engineer complete skin substitutes that recapitulate physiological 3D tissue structure and cellular composition in vitro. We also lack the markers and tools to evaluate the quality of 3D skin equivalent.

We aim at developing the 3D skin equivalent and evaluate their molecular components. By optimizing culture conditions, in vivo pattern of stem cell heterogeneity can be reconstituted in vitro. Our work will provide a novel culture platform and an evaluation system of 3D skin models, with future application in transplantation, drug screening, and disease modeling of skin and other organs.

The roles of glycans in skin aging and stem cell function

The presence of glycans determines the structure, stability, and localization of glycoproteins. It plays a crucial role in physiological and pathological conditions, such as development, tumorigenesis, and inflammation. Glycans are required for stem cell regulations by modulating cell-cell and cell-matrix interactions. The study of glycans in mammalian tissue stem cells has been challenging, as stem cells are rare and large amounts of samples are required for the biochemical analysis of glycans.


Using lectin microarray, a platform for high-throughput glycome analysis, our previous study provided a comprehensive glycan profiling of mouse epidermal stem cells during skin aging (Aging Cell, 2020). We demonstrated that old epidermal stem cells undergo an age-related glycan 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 new biomarkers to preferentially detect young and old epidermal stem cells, respectively. We are currently addressing how glycan changes affect protein function and aging phenotypes in the skin. The glycan modifications detected by lectins will serve as molecular markers for aging, and functional studies will provide a potential intervention strategy for healthy aging and longevity.

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