Fibroblast reticular cells engineer a blastema extracellular network during digit tip regeneration in mice

The regeneration blastema which forms following amputation of the mouse digit tip is composed of undifferentiated cells bound together by an organized network of fibers. A monoclonal antibody (ER‐TR7) that identifies extracellular matrix (ECM) fibers produced by fibroblast reticular cells during lymphoid organogenesis was used to characterize the ECM of the digit, the blastema, and the regenerate. Digit fibroblast reticular cells produce an ER‐TR7(+) ECM network associated with different tissues and represent a subset of loose connective tissue fibroblasts. During blastema formation there is an upregulation of matrix production that returns to its pre‐existing level and anatomical pattern in the endpoint regenerate. Co‐localization studies demonstrate a strong spatial correlation between the ER‐TR7 antigen and collagen type III (COL3) in histological sections. ER‐TR7 and COL3 are co‐induced in cultured digit fibroblasts following treatment with tumor necrosis factor alpha and a lymphotoxin beta receptor agonist. These results provide an initial characterization of the ECM during digit regeneration and identify a subpopulation of fibroblasts involved in producing the blastema provisional matrix that is remodeled during the regeneration response.