Acquisition of a Unique Mesenchymal Precursor-like Blastema State Underlies Successful Adult Mammalian Digit Tip Regeneration

Dev Cell. 2020 Feb 24;52(4):509-524.e9. doi: 10.1016/j.devcel.2019.12.004. Epub 2020 Jan 2.

Abstract

Here, we investigate the origin and nature of blastema cells that regenerate the adult murine digit tip. We show that Pdgfra-expressing mesenchymal cells in uninjured digits establish the regenerative blastema and are essential for regeneration. Single-cell profiling shows that the mesenchymal blastema cells are distinct from both uninjured digit and embryonic limb or digit Pdgfra-positive cells. This unique blastema state is environmentally determined; dermal fibroblasts transplanted into the regenerative, but not non-regenerative, digit express blastema-state genes and contribute to bone regeneration. Moreover, lineage tracing with single-cell profiling indicates that endogenous osteoblasts or osteocytes acquire a blastema mesenchymal transcriptional state and contribute to both dermis and bone regeneration. Thus, mammalian digit tip regeneration occurs via a distinct adult mechanism where the regenerative environment promotes acquisition of a blastema state that enables cells from tissues such as bone to contribute to the regeneration of other mesenchymal tissues such as the dermis.

Keywords: adult mouse digit tip; blastema; development; lineage tracing; mammalian tissue regeneration; mesenchymal precursors; scRNA-seq.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation*
  • Cell Lineage
  • Cells, Cultured
  • Extremities / embryology
  • Extremities / injuries
  • Extremities / physiology*
  • Female
  • Gene Expression Regulation, Developmental*
  • Male
  • Mesenchymal Stem Cells / cytology*
  • Mesenchymal Stem Cells / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Mice, Knockout
  • Mice, SCID
  • Receptors, Platelet-Derived Growth Factor / physiology*
  • Regeneration*
  • Single-Cell Analysis
  • Transcriptome

Substances

  • Receptors, Platelet-Derived Growth Factor

Grant support