Xiaoyang Wu, Ph.D.

Research Summary


 

Given their pivotal role in tissue homeostasis and regenerative medicine, somatic/adult stem cells are of tremendous interest to both biomedical research field and the public. Skin and its appendages provide a protective barrier that keeps harmful microbes out and essential body fluids in. To perform these functions while confronting the physicochemical traumas from the outside world, human skin must undergo rejuvenation through homeostasis and wound repair. Both processes rely on the essential activities of skin somatic stem cells, including the activation and migration of epidermal stem cells upon wounding, as well as the delicate balance of epidermal stem cell proliferation, self-renewal and differentiation during tissue homeostasis. Understanding the underlying mechanisms is important, because dysregulation of these processes leads to many skin diseases including cancers. Research in my laboratory is dedicated to understanding the dynamics, signaling, and clinical applications of epidermal stem cells. Particularly, we are interested in three fundamental questions in this field:

1) Regenerative medicine and tissue engineering with epidermal stem cells. Cell and gene therapies provide promising therapeutic approaches for many otherwise terminal or severely disabling diseases. As the largest surface organ, human skin provides an ideal site for tissue engineering, as well as the long-term and efficient delivery of therapeutic genes in vivo. Compared to conventional gene therapy approaches, transplantation with autologous skin grafts derived from epidermal stem cells is technically well-established, minimally invasive, and has been successfully used for decades in the treatment of burn wounds. It has also been well documented that therapeutic molecules, including large proteins secreted by skin epidermal cells, can cross the epidermal/dermal barrier and reach the circulation to achieve therapeutic effects in a systemic manner. We have recently resolved the long-standing technical obstacle in the field by establishing a novel mouse skin organotypic culture and transplantation model. With this key technical advancement, we have, and will continue to explore the exciting clinical applications of cutaneous gene therapy as a safe and effective treatment for many human diseases.

2) Migration and cytoskeletal dynamics of epidermal stem/progenitor cells. Skin wound repair and tissue regeneration require activation of quiescent epidermal stem cells and their directional movement toward the wounds. Aberrant cell migration can delay wound repair and have dire consequences for the survival of the organism. Cell migration is also an essential process involved in developmental morphogenesis and tumor metastasis. The intricate, multi-step process of directional cell movement requires the integrated activities of cytoskeleton, membrane, and cell adhesions. A long-standing model in the field, including my own postdoctoral research (Wu, Kodama et al. Cell, 2008, Wu, Shen et al. Cell, 2011), suggests that coordination of microtubule and F-actin dynamics can promote cell adhesion dynamics and cell motility. However, critical questions remain unanswered: how cytoskeletal coordination contributes to cell adhesion dynamics, and how this coordination is regulated spatiotemporally during cell movement. Elucidating these processes will fulfill a significant gap in our understanding of the molecular machinery driving cell migration.

3) Molecular mechanisms controlling stemness and differentiation of epidermal stem cells. Skin tissue homeostasis and regeneration are sustained by epidermal stem cells, which are localized within the basal layer of the skin epithelium and underlie the remarkable resilience of skin. To replenish cells that are lost during tissue turnover or following injury, these cells can exit from their niches at the basement membrane and execute their program of differentiation. Aberrant differentiation of skin cells leads to cutaneous carcinogenesis and many other skin diseases. The mechanisms controlling epidermal differentiation remain unclear. Deciphering the underlying molecular events is of fundamental importance for our understanding of skin development and disease treatments, as well as providing essential groundwork and guidelines for regenerative medicine based on skin tissue engineering.