Regeneration linked miRNA modify tumor phenotype and can enforce multi-lineage growth arrest in vivo

Regulated cell proliferation is an effector mechanism of regeneration, whilst dysregulated cell proliferation is a feature of cancer. We have previously identified microRNA (miRNA) that regulate successful and failed human liver regeneration. We hypothesized that these regulators may directly modify tumor behavior. Here we show that inhibition of miRNAs -503 and -23a, alone or in combination, enhances tumor proliferation in hepatocyte and non-hepatocyte derived cancers in vitro, driving more aggressive tumor behavior in vivo. Inhibition of miRNA-152 caused induction of DNMT1, site-specific methylation with associated changes in gene expression and in vitro and in vivo growth inhibition. Enforced changes in expression of two miRNA recapitulating changes observed in failed regeneration led to complete growth inhibition of multi-lineage cancers in vivo. Our results indicate that regulation of regeneration and tumor aggressiveness are concordant and that miRNA-based inhibitors of regeneration may constitute a novel treatment strategy for human cancers.

Aging delays epimorphic regeneration in mice

Epimorphic regeneration is a multi-tissue regeneration process where amputation does not lead to scarring, but blastema formation and patterned morphogenesis for which cell plasticity and concerted cell-cell interactions are pivotal. Tissue regeneration declines with aging, yet if and how aging impairs epimorphic regeneration is unknown. Here we show for the first time that aging derails the spatiotemporal regulation of epimorphic regeneration in mammals, first, by exacerbating tissue histolysis and delaying wound closure, and second, by impairing blastema differentiation and skeletal regrowth. Surprisingly, aging did not limit stem cell availability in the blastema, but reduced osteoblast-dependent bone formation. Our data suggest that aging delays regeneration not by stem cell exhaustion, but functional defects of differentiated cells that may be driven by an aged wound environment and alterations in the spatiotemporal regulation of regeneration events. Our findings emphasize the importance of accurate timing of signaling events for regeneration, and highlight the need for carefully timed interventions in regenerative medicine.

Endocrine Regulation of Epimorphic Regeneration

Studies aiming to uncover primary mechanisms of regeneration have predominantly focused on genetic pathways regulating specific stages in the regeneration process: wound healing, blastema formation, and pattern formation. However, studies across organisms show that environmental conditions and the physiological state of the animal can affect the rate or quality of regeneration, and endocrine signals are likely the mediators of these effects. Endocrine signals acting directly on receptors expressed in the tissue or via neuroendocrine pathways can affect regeneration by regulating the immune response to injury, allocation of energetic resources, or by enhancing or inhibiting proliferation and differentiation pathways involved in regeneration. This review discusses the cumulative knowledge in the literature about endocrine regulation of regeneration and its importance in future research to advance biomedical research.

Circadian Regulation in Tissue Regeneration

Circadian rhythms regulate over 40% of protein-coding genes in at least one organ in the body through mechanisms tied to the central circadian clock and to cell-intrinsic auto-regulatory feedback loops. Distinct diurnal differences in regulation of regeneration have been found in several organs, including skin, intestinal, and hematopoietic systems. Each regenerating system contains a complex network of cell types with different circadian mechanisms contributing to regeneration. In this review, we elucidate circadian regeneration mechanisms in the three representative systems. We also suggest circadian regulation of global translational activity as an understudied global regulator of regenerative capacity. A more detailed understanding of the molecular mechanisms underlying circadian regulation of tissue regeneration would accelerate the development of new regenerative therapies.