Solubilized extracellular matrix from brain and urinary bladder elicits distinct functional and phenotypic responses in macrophages

Meng, F. W.; Slivka, Peter F.; Dearth, Christopher L.; Badylak, Stephen F.

doi:10.1016/j.biomaterials.2014.12.044

Cited by 71 publications

(61 citation statements)

References 82 publications

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“…No adverse immune response was shown after ECM hydrogels were injected in the heart [55, 60, 75–81], fat [43, 45, 47, 50, 67], liver [57], brain [21, 22, 24] skeletal muscle [23, 63, 64, 83], tendon [26, 59, 84], spinal cord [82], lung [49], cartilage [70], or colon [51, 71], and these studies included both homologous and heterologous ECM hydrogels. The findings in vivo are consistent with in vitro studies that have shown the pepsin-digested ECM (“pre-gel”) promotes a regulatory (“M2-like”) macrophage activation state, which is associated with a constructive remodeling response in vivo [71, 90, 91]. For example, macrophages activated toward an M2-like phenotype with solubilized ECM promoted downstream effects such as stimulating the migration and myogenesis of skeletal muscle progenitor cells [90].…”

Section: In Vivo Applications Of Ecm Hydrogelssupporting

confidence: 86%

Extracellular matrix hydrogels from decellularized tissues: Structure and function

et al. 2017

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Extracellular matrix (ECM) bioscaffolds prepared from decellularized tissues have been used to facilitate constructive and functional tissue remodeling in a variety of clinical applications. The discovery that these ECM materials could be solubilized and subsequently manipulated to form hydrogels expanded their potential in vitro and in vivo utility; i.e. as culture substrates comparable to collagen or Matrigel, and as injectable materials that fill irregularly-shaped defects. The mechanisms by which ECM hydrogels direct cell behavior and influence remodeling outcomes are only partially understood, but likely include structural and biological signals retained from the native source tissue. The present review describes the utility, formation, and physical and biological characterization of ECM hydrogels. Two examples of clinical application are presented to demonstrate in vivo utility of ECM hydrogels in different organ systems. Finally, new research directions and clinical translation of ECM hydrogels are discussed.

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Section: In Vivo Applications Of Ecm Hydrogelssupporting

confidence: 86%

Extracellular matrix hydrogels from decellularized tissues: Structure and function

et al. 2017

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“…These mechanisms include the degradation of the scaffold material with subsequent release of proregenerative components (e.g., matricryptic peptides) that promote repair through modulation of the innate immune response (specifically the macrophage response) and recruitment of endogenous stem/progenitor cells. 16–23 Consistent with previous findings, the bioscaffold in the present study appeared completely degraded by 2 wk and was replaced with site-appropriate colonic epithelium. A recent report shows that a hydrogel form of ECM has the ability to mitigate the proinflammatory environment in a rodent model of inflammatory bowel disease.…”

Section: Discussionsupporting

confidence: 92%

Bioscaffold-mediated mucosal remodeling following short-segment colonic mucosal resection

Dziki

Keane

Shaffiey

et al. 2017

Journal of Surgical Research

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Precancerous or cancerous lesions of the gastrointestinal tract often require surgical resection via endomucosal resection. Although excision of the colonic mucosa is an effective cancer treatment, removal of large lesions is associated with high morbidity and complications including bleeding, perforation, fistula formation, and/or stricture, contributing to high clinical and economic costs and negatively impacting patient quality of life. The present study investigates the use of a biologic scaffold derived from extracellular matrix (ECM) to promote restoration of the colonic mucosa following short segment mucosal resection. Six healthy dogs were assigned to ECM-treated (tubular ECM scaffold) and mucosectomy only control groups following transanal full circumferential mucosal resection (4 cm in length). The temporal remodeling response was monitored using colonoscopy and biopsy collection. Animals were sacrificed at 6 and 10 wk, and explants were stained with hematoxylin and eosin (H&E), Alcian blue, and proliferating cell nuclear antigen (PCNA) to determine the temporal remodeling response. Both control animals developed stricture and bowel obstruction with no signs of neomucosal coverage after resection. ECM-treated animals showed an early mononuclear cell infiltrate (2 weeks post-surgery) which progressed to columnar epithelium and complex crypt structures nearly indistinguishable from normal colonic architecture by 6 weeks after surgery. ECM scaffold treatment restored colonic mucosa with appropriately located PCNA+ cells and goblet cells. The study shows that ECM scaffolds may represent a viable clinical option to prevent complications associated with endomucosal resection of cancerous lesions in the colon.

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“…In particular, pepsin ECM digests have been found to enhance in vitro cell migration [34], proliferation [66], and macrophage polarization [67], effects influenced by tissue source [68], animal age [69], and fraction [70]. In vivo, ECM-mediated effects on macrophage polarization, and the broader inflammatory response, at least partially explain the benefit of ECMs in promoting constructive remodeling (i.e., improved healing) [71, 72].…”

Section: Discussionmentioning

confidence: 99%

Tissue-specific bioactivity of soluble tendon-derived and cartilage-derived extracellular matrices on adult mesenchymal stem cells

2017

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BackgroundBiological scaffolds composed of tissue-derived extracellular matrix (ECM) can promote homologous (i.e., tissue-specific) cell differentiation through preservation of biophysical and biochemical motifs found in native tissues. Solubilized ECMs derived from decellularized tendon and cartilage have recently been promoted as tissue-specific biomaterials, but whether tissue-specific bioactivity is preserved following solubilization is unknown. This study explored the tissue-specific bioactivity of soluble decellularized tendon and cartilage ECMs on human bone marrow-derived mesenchymal stem cells (MSCs) presented across different culture microenvironments, including two-dimensional (2D) tissue culture plastic, aligned electrospun nanofibers, cell pellets, and cell-seeded photocrosslinkable hydrogels.MethodsTendon and cartilage ECMs were decellularized using established methods and solubilized either via pepsin digestion or urea extraction. The effect of soluble ECMs on cell proliferation and differentiation was initially explored by supplementing basal medium of human MSCs cultured on 2D tissue culture plastic. In subsequent experiments, MSCs were cultured on aligned electrospun nanofibers, ascell pellets, or encapsulated within photocrosslinkable methacrylated gelatin (GelMA) hydrogels. Urea-extracted tendon and cartilage ECMs were added as supplements.ResultsPepsin-digested ECMs did not promote homologous differentiation in human MSCs, whether provided as a medium supplement or three-dimensional (3D) hydrogels. In contrast, urea-extracted ECMs tended to promote tissue-specific differentiation of MSCs cultured in 2D and 3D microenvironments. The application of the small molecule TGF-β signaling inhibitor SB-431542 largely negated the tissue-specific gene expression patterns mediated by tendon and cartilage ECMs. This suggests that the action of endogenous TGF-β was required, but was not sufficient, to impart tissue-specific bioactivity of urea-extracted ECMs. When urea-extracted cartilage ECM was incorporated within a photocurable GelMA hydrogel it independently enhanced chondrogenesis in encapsulated MSCs, and showed additive prochondrogenesis upon TGF-β supplementation in the medium.ConclusionsUrea-extracted ECM fractions of decellularized tendon and cartilage are soluble supplements capable of enhancing tissue-specific differentiation of adult stem cells.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-017-0580-8) contains supplementary material, which is available to authorized users.

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Solubilized extracellular matrix from brain and urinary bladder elicits distinct functional and phenotypic responses in macrophages

Cited by 71 publications

References 82 publications

Extracellular matrix hydrogels from decellularized tissues: Structure and function

Extracellular matrix hydrogels from decellularized tissues: Structure and function

Bioscaffold-mediated mucosal remodeling following short-segment colonic mucosal resection

Tissue-specific bioactivity of soluble tendon-derived and cartilage-derived extracellular matrices on adult mesenchymal stem cells

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