FIGURE 4.

The role of transitional matrix during limb regeneration. (A) Overview of limb regeneration. (B) After amputation, a wound epithelium is formed through migration of keratinocytes across the wound stump along with the upregulation of MMPs to facilitate degradation of the collagen and laminin-rich ECM. (C) As more cells migrate from the epithelium, the wound epithelium is transformed into the multi-cell layered AEC covering the entire wound stump. The AEC and neurons provide essential FGF and BMP signals to initiate blastema formation. MMP expression remains high during this initial stage of blastema formation. (D) Formation of the blastema requires remodeling of the ECM to form a transitional matrix. TNC, HA, and FN are upregulated in the distal stump and blastema mesenchyme which enhances dedifferentiation of myofibers, followed by migration and proliferation which depend on FGFs and BMPs to sustain the outgrowth of the blastema. (E) ECM regulation of cellular events that occur over during regeneration. Remodeling of the ECM in the old tissue activates cellular reprogramming and migration to form the blastema. Here cells undergo proliferation and differentiation to form the missing tissue. Differences in sulfation levels of HSPG spatially regulate FGF signaling to direct anterior and posterior positional identities. Similar to the limb bud, SHH and FGF8 gradients regulate anterior posterior polarity during later stages of limb regeneration. (F) Model of transitional matrix regulation of muscle regeneration. Upon injury, an upregulation of MMPs degrades the native ECM, while upregulation of TNC, HA in the distal stump and blastema promotes dedifferentiation and migration of muscle. Upregulation of FN in the blastema enhances proliferation and fusion of muscle progenitors into myofibers. When regeneration is complete, the transitional matrix components are downregulated, while collagen and laminin is upregulated. The resulting environment therefore returns to the original native ECM of the uninjured muscle. AEC, apical ectodermal cap; HSPG, heparan sulfate proteoglycan; MMP, matrix metalloproteinase; HA, hyaluronic acid.