Adult stem cells (SCs) reside in various body sites where they govern tissue homeostasis and orchestrate wound repair. As a group of long-lived and indispensable cells, they inevitably face the challenge of experiencing repeated bouts of inflammation initiated by tissue injury, infection, and noxious agents. Especially during injury repair, tissue SCs must be mobilized to exit their immune privileged niche, and enter a highly inflammatory environment in the center of the wound bed to regenerate the tissue. In order to successfully repair the damage, it is essential for SCs to be equipped with extraordinary abilities to adapt to immune responses. Importantly, our previous work on skin squamous cell carcinomas has found that a group of tumor-initiating cells bearing skin SC features were intrinsically superior to all other tumor populations at persisting through anti-tumor immune responses. This finding further strengthened our speculation that SCs must be endowed with unique capabilities to adapt to inflammation. Cancer and wounds indeed share many characteristics, and cancer has been considered as a wound that never heals. Prior interpretations of this theory mainly pointed to the observations that similar molecular pathways drive stem cell proliferation, differentiation and stress responses in both wound and cancer. The intimate dialogue between stem cells and surrounding immune cells has long been overlooked, but might actually dictate the outcomes of successful tissue regeneration or tumor growth. Therefore, understanding how stem cells communicate with the immune system is vital for not only advancing our knowledge of tissue regeneration, and for develop strategies to improve the defective wound re. Stimulated by our intriguing preliminary observations, we proposed a novel hypothesis that adult stem cells adapt to inflammatory environments by actively reprogramming their immunological niche. Our central vision is to follow the precise analogy that cancer is a wound that never heals, and to simultaneously examine the stem cell-immune cell crosstalk in both wound healing and cancer progression. Our ultimate goal is to understand what process has gone awry during agin, causing the failure of wound repair in aged skin.

Specifically, in this project, we will dissect 1) how do normal skin stem cells sculpt their immune microenvironment to achieve immune adaptation during wound repair? 2) how is the immunological niche spatially and functionally organized to support skin stem cells? 3) how is this immune architecture and immune modulatory program of skin stem cells disrupted during aging, leading to defective wound repair in aged skin?

In this project, my lab will use sophisticated mouse genetic models and use functional (epi)genomics, proteomics, quantitative immunological approaches and advanced imaging techniques, to identify the intrinsic factors for stem cells to reprogram their immunological niche. A major advantage of our propose research program is that we will employ a powerful in utero lentiviral (LV) gene delivery approach to achieve rapid genetic manipulation of stem cells directly in mice. This approach enables the selective transduction of embryonic mouse ectoderm cells that later develop into the epidermis. Once integrated, the DNA carried by the LV is stably propagated specifically in skin cells, allowing for rapid gene overexpression or deletion, and eliminating the need to generate and breed mice, which often takes years. This advantage is especially important for studying human cancer, as rapid functional interrogation of candidate genes in cancer stem cells could be easily achieved directly in autochthonous cancer models, which much more closely resemble the natural tumorigenesis and immune environment of human cancer, compared to conventional tumor cell grafting models. With this powerful platform, we are uniquely positioned to design sophisticated genetic experiments to identify new genes involved in stem cell-immune interactions.

Software provided by the lab: Flowjo, Python, R. ImageJ

AACR annual meeting, SITC annual meeting, symposium and workshop, Keystone Symposium Advances in Cancer Immunotherapy