PT  - JOURNAL ARTICLE
AU  - Feini Qu
AU  - Ilan C. Palte
AU  - Paul M. Gontarz
AU  - Bo Zhang
AU  - Farshid Guilak
TI  - Transcriptomic analysis of bone and fibrous tissue morphogenesis during digit tip regeneration in the adult mouse
AID  - 10.1101/643361
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 643361
4099  - http://biorxiv.org/content/early/2019/05/20/643361.short
4100  - http://biorxiv.org/content/early/2019/05/20/643361.full
AB  - Humans have limited regenerative potential of musculoskeletal tissues following limb or digit loss. The murine digit has been used to study mammalian regeneration, where stem/progenitor cells (the ‘blastema’) regrow the digit tip after distal, but not proximal, amputation. However, the molecular mechanisms responsible for this response remain to be determined. We hypothesized that regeneration is initiated and maintained by a gene regulatory network that recapitulates aspects of limb development, whereas a non-regenerative response exhibits fibrotic wound healing and minimal bone remodeling. To test these hypotheses, we evaluated the spatiotemporal formation of bone and fibrous tissues after level-dependent amputation of the murine terminal phalanx and quantified the transcriptome of the repair tissue. We show that digit regeneration is a level-dependent and spatiotemporally controlled process, with distal and proximal amputations showing significant differences in gene expression and tissue regrowth over time. Regeneration is characterized by the transient upregulation of genes that direct skeletal system development and limb morphogenesis, including distal Hox genes. By identifying the molecular pathways regulating regeneration, this work will lead to novel therapies that restore complex tissues after injury.Summary Statement Murine digit tip regeneration after distal amputation is orchestrated through a transient, limb-specific gene network by blastema cells. Proximal amputation activates an alternate transcriptional program that results in scar formation.