Regeneration in the ears of immunodeficient mice: Identification and lineage analysis of mesenchymal stem cells

Wound healing in the ears of Athymic Nude-nu mice resembles regeneration. Histological analysis of the ear-punched tissues revealed the initial formation of a blastema-like structure followed by dermal, vascular, cartilage, and muscle regrowth exclusively in Athymic Nude-nu mice but not in wild-type controls (C57BL/6J). A subset of stem cells referred to here as ear mesenchymal stem cells (EMSCs) has been isolated from the external ears of regenerative (Athymic Nude-nu) and nonregenerative strains of mice. Morphological, histochemical, and molecular analysis after the induction of EMSC differentiation revealed multiple mesenchymal cell lineages (adipocytes, chondrocytes, and osteocytes) in all murine strains independent of their ability for regeneration. Thus, the absence of regeneration in wounded ears of C57BL/6J wild-type mice is not related to the absence of mesenchymal stem cell differentiation in tissue culture. Because nude mice lack T lymphocytes, it appears that in this model the absence of T lymphocytes in the wounded ears provides a microenvironment conducive to regeneration of mesenchymal tissues. These findings provide a new model to study the influence of the immune system on tissue regeneration.