Germ Layer Restricted Wnt And Hedgehog Signaling Regulate Digit Tip Regeneration
Zeshaan N. Maan, MD, MSc, Michael Januszyk, MD, PhD, Janos Barrera, MD, Irving Weissman, MD, Geoffrey Gurtner, MD.
Stanford University School of Medicine, Stanford, CA, USA.
PURPOSE:
The critical function of the hand highlights the need to understand and effectively treat injuries to this vital structure. Surgical repair is often complicated by loss of functional capacity. Reports of “salamander-like” spontaneous regeneration in human fingertips raise the possibility of regenerative approaches for traumatic hand injuries. The discrete signaling mechanisms governing this regenerative process are poorly understood.
METHODS:
Tissue harvested from murine digit tips 7 days after amputation at the regenerative plane (distal to the germinal matrix) or non-regenerative plane (proximal to the germinal matrix) were compared using microarray analysis. Viral knockdown of candidate genes identified by microarray analysis was used to confirm a functional role for these signaling networks in vivo. Tissue specific expression and response patterns of target genes were assessed using gene specific reporter mice.
RESULTS:
Microarray analysis identified 287 differentially regulated genes. Gene set enrichment analysis (GSEA) identified Wnt and Hedgehog (HH) as the top associated signaling networks. Suppression of Wnt signaling, significantly impaired digit tip regeneration compared to control. Wnt overexpression did not accelerate regeneration. Reduced HH signaling significantly impaired digit regeneration. HH overexpression impaired epidermal closure. Wnt and HH signaling originated in the ectodermal layer, but HH responsiveness occurred in the mesodermal layer.
CONCLUSION:
Unbiased microarray analysis combined with in vivo knockdown studies identify a central role for Wnt and HH signaling in digit tip regeneration. Understanding and targeting the cross-talk between these pathways could enable regeneration in normally non-regenerative extremity injuries.
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