Epimorphic regeneration approach to tissue replacement in adult mammals

Abstract

Urodeles and fetal mammals are capable of impressive epimorphic regeneration in a variety of tissues, whereas the typical default response to injury in adult mammals consists of inflammation and scar tissue formation. One component of epimorphic regeneration is the recruitment of resident progenitor and stem cells to a site of injury. Bioactive molecules resulting from degradation of extracellular matrix (ECM) have been shown to recruit a variety of progenitor and stem cells in vitro in adult mammals. The ability to recruit multipotential cells to the site of injury by in vivo administration of chemotactic ECM degradation products in a mammalian model of digit amputation was investigated in the present study. Adult, 6- to 8-week-old C57/BL6 mice were subjected to midsecond phalanx amputation of the third digit of the right hind foot and either treated with chemotactic ECM degradation products or left untreated. At 14 days after amputation, mice treated with ECM degradation products showed an accumulation of heterogeneous cells that expressed markers of multipotency, including Sox2, Sca1, and Rex1 (Zfp42). Cells isolated from the site of amputation were capable of differentiation along neuroectodermal and mesodermal lineages, whereas cells isolated from control mice were capable of differentiation along only mesodermal lineages. The present findings demonstrate the recruitment of endogenous stem cells to a site of injury, and/or their generation/proliferation therein, in response to ECM degradation products.

Tissue-Specific Effects of Esophageal Extracellular Matrix

“…Another potential contributing cell population is the multipotent perivascular stem cell. 22,29 Perivascular stem cells are found surrounding the endothelium of normal tissue and are likely to be present in the vasculature within the esophagus. A number of studies have reported the chemotactic and mitogenic potential of ECM for the perivascular stem cell population.…”

Restoring Mucosal Barrier Function and Modifying Macrophage Phenotype with an Extracellular Matrix Hydrogel: Potential Therapy for Ulcerative Colitis

“…Specifically, ECM materials derived via decellularization of a variety of allogeneic or xenogeneic source tissues have been shown to induce a phenotypic transition from the proinflammatory macrophage and lymphocyte phenotype toward a regulatory, "anti-inflammatory" and healing phenotype [9,31,32,33], and to promote endogenous stem/progenitor cell activation and recruitment [11,29,34,35].…”

“…14 C-labeled ECMH was prepared as stated above with the intestines of pigs that were injected with 14 C-tagged proline, as previously described [15]. FITC-labeled ECMH was prepared with a protein labeling kit (Thermo PierceNet) per manufacturer's instructions [11].…”

“…Intact and solubilized/hydrogel forms of ECM have been shown to facilitate a rapid and dramatic transition away from an M1-like, pro-inflammatory macrophage phenotype toward an M2-like, pro-healing/regulatory macrophage phenotype [9,10]. Simultaneously, naturally occurring cryptic peptide motifs released or exposed during in-vivo degradation of the ECM material, combined with the secreted products of ECM-exposed alternatively activated macrophages, promote stem/progenitor cell chemotaxis, proliferation, and differentiation [11,12]. The objective of the present study was to determine if the above-mentioned ECM-induced biologic effects could influence outcomes in an inducible rodent model of UC.…”

Endoscopic Deployment of MatriStem for Treatment of a Colorectal Anastomotic Leak

“…5,6 The mechanisms of action are not fully understood, but site-appropriate remodeling is hypothesized to be a consequence of immune modulation, promotion of angiogenesis, and recruitment of progenitor cells. Despite a high risk of poor healing and a permanent stoma associated with the magnitude of this anastomotic defect, 2,3,5 it appears that the salutary properties of MatriStem 7,8,9 enabled successful healing of this anastomotic defect. The defect healed rapidly and was associated with healthy vascularized tissue with no evidence of scarring or stricture that typically occurs after an anastomotic leak.…”