Senescent Cells with Augmented Cytokine Production for Microvascular Bioengineering and Tissue Repairs

Abstract

Controlled delivery of cytokines and growth factors has been an area of intense research interest for molecular and cellular bioengineering, immunotherapy, and regenerative medicine. This study shows that primary human lung fibroblasts chemically induced to senescence (cell cycle arrest) can act as a living source to transiently produce factors essential for promoting vasculogenesis or angiogenesis, such as vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), and interleukin 8 (IL‐8). Coculture of senescent fibroblasts with human umbilical vein endothelial cells in a fibrin gel demonstrate accelerated formation and maturation of microvessel networks in as early as three days. Unlike the usage of nonsenescent fibroblasts as the angiogenesis‐promoting cells, this approach eliminates drawbacks related to the overproliferation of fibroblasts and the subsequent disruption of tissue architecture, integrity, or function. Coculture of mouse pancreatic islets with senescent fibroblasts and endothelial cells in a gel matrix maintains the viability and function of islets ex vivo for up to five days. Applying senescent fibroblasts to wound repair in vivo leads to increased blood flow in a diabetic mouse model. Together, this work points to a new direction for modeling the delivery of cytokines and growth factors that promote microvascular tissue engineering and tissue repairs.