Toward Perfect Skin Regeneration: A Pharmacological Approach

How can damaged tissue regenerate into fully functional, “perfect” skin? This question has guided my research since my early career. As a graduate student, I studied the role of Rho-associated protein kinase (ROCK) in skin development and wound healing, where we found that the two ROCK isoforms, ROCK1 and ROCK2, function redundantly in keratinocytes and are involved in epithelial sheet contraction during eyelid closure in development and skin repair in adults (Shimizu, Thumkeo et al., Journal of Cell Biology, 2005; Thumkeo et al., Genes to Cells, 2005). These studies established a foundation for understanding how coordinated cellular dynamics contribute to tissue integrity.

Building on this background, I have developed a research program aimed at uncovering mechanisms of skin regeneration from a pharmacological perspective when I was promoted as a semi-PI in 2016. We first identified lysophosphatidic acid (LPA) as a potent inducer of keratinocyte differentiation (Sumitomo, Siriwach, Thumkeo et al., Journal of Investigative Dermatology, 2019). Using single-cell RNA sequencing, we further discovered a population of THBS1-positive basal keratinocytes induced by LPA that contributes to wound healing (Siriwach et al., iScience, 2022; STAR Protocols, 2022). These findings highlight how specific signaling pathways can reshape cellular states to promote tissue repair.

In parallel, we have explored small-molecule approaches to control skin regeneration. Through chemical screening, we identified a compound (Compound 8.1) that strongly induces keratinocyte differentiation. Mechanistic studies suggest that its effects are mediated through the aryl hydrocarbon receptor (AHR) signaling pathway (Sumitomo et al., Journal of Pharmaceutical Sciences, 2025). Ongoing work aims to refine such compounds, characterize their molecular effects, and evaluate their therapeutic potential in vivo.

More recently, our analyses of single-cell datasets from skin wound models have revealed dynamic changes not only in keratinocytes but also in immune cell populations. These observations have led us to investigate how immune cells contribute to tissue repair. By integrating single-cell and spatial omics technology, we aim to elucidate how the immune cells in the wounded skin microenvironment contribute to regeneration.

In contrast to conventional approaches such as cell therapy or tissue engineering, our goal is to establish a pharmacological paradigm for tissue regeneration. This direction is still evolving and inherently challenging, but it offers the potential for broadly applicable and accessible therapies.

For this project, we particularly welcome students who are motivated to explore unconventional ideas, think beyond established frameworks, and engage with scientific questions whose answers are not yet clearly defined. Through this work, we aim to uncover previously unsuspected fundamental principles of tissue regeneration and open new avenues for the treatment of skin injury and beyond.