Recruitment of Progenitor Cells by an Extracellular Matrix Cryptic Peptide in a Mouse Model of Digit Amputation

Abstract

Biologic scaffolds composed of extracellular matrix (ECM) have been used successfully in preclinical models and humans for constructive remodeling of functional, site-appropriate tissue after injury. The mechanisms underlying ECM-mediated constructive remodeling are not completely understood, but scaffold degradation and sitedirected recruitment of both differentiated and progenitor cells are thought to play critical roles. Previous studies have shown that degradation products of ECM scaffolds can recruit a population of progenitor cells both in vitro and in vivo. The present study identified a single cryptic peptide derived from the a subunit of the collagen III molecule that is chemotactic for a well-characterized perivascular stem cell in vitro and causes the site-directed accumulation of progenitor cells in vivo. The oligopeptide was additionally chemotactic for human cortical neural stem cells, rat adipocyte stem cells, C2C12 myoblast cells, and rat Schwann cells in vitro. In an adult murine model of digit amputation, treatment with this peptide after mid-second phalanx amputation resulted in a greater number of Sox2 + and Sca1 + ,Lin -cells at the site of injury compared to controls. Since progenitor cell activation and recruitment are key prerequisites for epimorphic regeneration in adult mammalian tissues, endogenous site-directed recruitment of such cells has the potential to alter the default wound healing response from scar tissue toward regeneration.

Implantation of Brain-derived Extracellular Matrix Enhances Neurological Recovery after Traumatic Brain Injury

“…Since tissue repair is severely impeded after destruction of the ECM, native ECM represents an ideal scaffold for tissue-specific reconstruction. Bioengineered scaffold materials composed of ECM have been shown to accelerate post-injury remodeling and repair in various tissues and organs, through mechanisms involving the recruitment of endogenous progenitor cells 12,25 and modulation of innate immune responses. 13 Brain ECM possesses tissuespecific effects in promoting CNS remodeling compared to ECM derived from other tissues.…”

Extracellular Matrix as an Inductive Scaffold for Functional Tissue Reconstruction

“…186 Degradation products of ECM scaffolds have also been shown to be chemoattractants for progenitor and non-progenitor cell populations. [44][45][46]160,161,181 remodeling is facilitated, it must be noted that variations in outcomes have also been reported. 37,173,186,187 As discussed above, although the mechanisms of constructive remodeling are only partially understood, there are certain aspects of preparation and use of ECM bioscaffolds that may account for variable results.…”

“…[155][156][157][158][159] In addition, during in vivo remodeling, it is thought that the progenitor cells recruited to the site of ECM remodeling will differentiate into site appropriate cells in the presence of local mechanical cues. [160][161][162][163][164][165] Several in vitro studies have shown that mechanical loading can induce progenitor cells to differentiate into fibroblasts, smooth muscle cells, and osteoblasts. [166][167][168] Lastly, and as described above, mechanical loading of the ECM may lead to the exposure of cryptic sites and thereby initiate ECM multimerization and cell responses that lead to constructive remodeling.…”

“…186 Degradation products of ECM scaffolds have also been shown to be chemoattractants for progenitor and non-progenitor cell populations. [44][45][46]160,161,181 An ECM scaffold that cannot degrade (ie, is chemically cross-linked) may not release bioactive degradation products, including those bioactive molecules that may be responsible for modulating the host response toward constructive remodeling. Furthermore, surface characterization studies have demonstrated that chemical cross-linking alters the ligand landscape of the material potentially altering ligand-receptor interactions important in determining cell-scaffold interactions.…”

“…The process is mediated by inflammatory cells, such as macrophages, which produce oxidants as well as proteolytic enzymes that aid in the degradation of the matrix. Another study utilizing 14 C-labeled ECM scaffolds showed that peripheral blood monocytes are required for the early and rapid degradation of both ECM scaffolds, and that cross- 43,44,46,[160][161][162][181][182][183][184] Studies have shown antimicrobial activity associated with the degradation products of ECM scaffolds 43,185 ; however, in the absence of degradation, antimicrobial activity was not seen, suggesting that some of the bioactive properties of the ECM are derived from its degradation products, rather than from whole molecules present in the ECM. 186 Degradation products of ECM scaffolds have also been shown to be chemoattractants for progenitor and non-progenitor cell populations.…”