Concise Review: Translating Regenerative Biology into Clinically Relevant Therapies: Are We on the Right Path?

Abstract

Despite approaches in regenerative medicine using stem cells, bio‐engineered scaffolds, and targeted drug delivery to enhance human tissue repair, clinicians remain unable to regenerate large‐scale, multi‐tissue defects in situ. The study of regenerative biology using mammalian models of complex tissue regeneration offers an opportunity to discover key factors that stimulate a regenerative rather than fibrotic response to injury. For example, although primates and rodents can regenerate their distal digit tips, they heal more proximal amputations with scar tissue. Rabbits and African spiny mice re‐grow tissue to fill large musculoskeletal defects through their ear pinna, while other mammals fail to regenerate identical defects and instead heal ear holes through fibrotic repair. This Review explores the utility of these comparative healing models using the spiny mouse ear pinna and the mouse digit tip to consider how mechanistic insight into reparative regeneration might serve to advance regenerative medicine. Specifically, we consider how inflammation and immunity, extracellular matrix composition, and controlled cell proliferation intersect to establish a pro‐regenerative microenvironment in response to injuries. Understanding how some mammals naturally regenerate complex tissue can provide a blueprint for how we might manipulate the injury microenvironment to enhance regenerative abilities in humans. Stem Cells Translational Medicine 2018;7:220–231

Comparative regenerative biology of spiny (Acomys cahirinus) and laboratory (Mus musculus) mouse skin

“…On a side note, these results are based on gene expression data generated from microarrays and RT‐PCR data, and from cytokine arrays all designed for mouse. However, Simkin et al pointed out the shortcomings of comparing across species by microarray data analysis . To further explore the differences in molecular expression between Mus and Acomys , Gawriluk et al acquired RNA‐seq data.…”

Complex Tissue Regeneration in Mammals Is Associated With Reduced Inflammatory Cytokines and an Influx of T Cells

“…Despite a rich literature describing the effects of immune cells and their products in non-regenerating wounds [reviewed in (6,7)], our knowledge of the immune response during tissue regeneration remains relatively poor (8)(9)(10). Recent studies in fish, frogs, salamanders, and spiny mice support that immune cells and their products are required for blastema formation and successful regeneration.…”

Connective tissue fibroblasts from highly regenerative mammals are refractory to ROS-induced cellular senescence

“…2 ), it is equally important to understand how quiescent cells become activated and transduce injury signals to trigger cell cycle re-entry and controlled cell proliferation 3 . This last question is particularly relevant when trying to understand how closely related species can differ in their injury response; where active cell cycle progression and proliferation occur during regeneration, in contrast to cell cycle stasis and excessive collagen deposition during fibrotic repair 4,5 .…”