MAPK/ERK signaling governs the diverging healing outcome of skin and elastic cartilage towards regeneration and fibrosis in adult mammals
Antonio Tomasso, PhD, MS; Kerstin Bartscherer, PhD, MS; Ashley W. Seifert, PhD, MS; Derrick C Wan, MD, FACS; Michael T Longaker, MD, MBA, FACS
Introduction: Skin and elastic cartilage surgery represents a clinical challenge owing to their poor regenerative capacity. In contrast to most mammals, including humans, spiny mice regenerate skin and complex musculoskeletal tissues, including hair follicles, glands, nerves, muscles and elastic cartilage. However, the mechanisms underlying mammalian tissue regeneration are poorly understood. The identification of pro-regenerative core signaling pathways is clinically relevant.
Methods: We performed interspecies comparative analysis of ear pinna punches, used as a wound model for skin and elastic cartilage. Immunohistochemistry, bulk and scRNA-seq, loss- and gain-of-function experiments were deployed to assess the role of specific pathways during skin and cartilage regeneration.
Results: Spiny mice exhibited MAPK/ERK signaling-mediated asymmetric regeneration of the elastic cartilage and hair follicles in the ear pinna. Upon wounding, ERK was immediately induced in keratinocytes, mesenchymal cells, chondrocytes and perichondral cells of both spiny mice (regenerators) and laboratory mice (poor regenerators). However, its activation was sustained over time only during regeneration. We identified ERK upstream regulators and, when ERK was inhibited, spiny mouse skin regeneration shifted toward a fibrotic repair and cartilage growth was arrested. Conversely, the implantation of microbeads releasing growth factors and AAV-mediated gene transfer, yielded a pro-regenerative response, including ECM remodeling, hair follicle neogenesis and an increase in Col2a1+ chondrocytes in the ear punch.
Conclusion: This study demonstrates that cellular ERK activity controls the delicate balance between regeneration and fibrosis in mammals. The regenerative abilities of the spiny mouse constitutes a promising research frontier to enhance the endogenous repair of skin and cartilaginous structures in plastic surgery.