Abstract
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.
Highlights
The mouse digit tip consists of a diverse group of cells and extracellular components organized into tissue compartments that include the terminal phalangeal bone (P3) with marrow, articular cartilage, tendon, blood vessels, and nerve surrounded by connective tissue (CT), epidermis, and the nail rudiment
The CT of the digit tip appears as a loose mesenchyme primarily composed of fibroblasts with blood vessels infiltrating throughout the tissue
The extracellular matrix (ECM) in the mouse digit tip blastema is characterized by focusing on the antigen ER-TR7 which identifies a population of fibroblastic reticular cells (FRCs) involved in compartmentalizing lymph organs during development (Balogh et al, 2008; Katakai, 2012; Katakai et al, 2004b; Link et al, 2007; Van Vliet et al, 1986)
Summary
The mouse digit tip consists of a diverse group of cells and extracellular components organized into tissue compartments that include the terminal phalangeal bone (P3) with marrow, articular cartilage, tendon, blood vessels, and nerve surrounded by connective tissue (CT), epidermis, and the nail rudiment. The major difference between this structure and other similar mammalian extremities is that the digit tip can regenerate following amputation (Borgens, 1982; Muller et al, 1999; Neufeld, 1985). Similar to the epimorphic regenerative response that occurs following amputation of a salamander limb, mouse digit tip regeneration involves a sequence of events that include an inflammatory cascade, histolysis of the bone stump, formation of a wound epidermis, blastema growth, and redifferentiation (Fernando et al, 2011; Simkin et al, 2015). Since fibroblast cells derived from this regeneration-incompetent region are capable of participating in blastema formation (Wu et al, 2013), it seems likely that one difference between regenerative and non-regenerative responses involves the microenvironment associated with blastema formation
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