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Inadequate Processing of Decellularized Dermal Matrix Reduces Cell Viability In Vitro and Increases Apoptosis and Acute Inflammation In Vivo.

ABSTRACT: Decellularized tissue scaffolds are commonly used in the clinic because they can be used as substitutes for more traditional biomaterials, while imparting additional physiological effects. Nevertheless, reports of complications associated with their use are widespread and poorly understood. This study probes possible causes of these complications by examining cell viability and apoptosis in response to eluents from decellularized dermis. Using multiple sources of decellularized dermis, this study shows that typical decellularized scaffolds (prepared with commonly used laboratory techniques, as well as purchased from commercial sources) contain soluble components that are cytotoxic and that these components can be removed by extensive washes in cell culture media. In addition, this study demonstrates that these observed in vitro phenotypes correlate with increased apoptosis and acute inflammation when implanted subcutaneously in mice.

SUBMITTER: Morris AH

PROVIDER: S-EPMC4948200 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Inadequate Processing of Decellularized Dermal Matrix Reduces Cell Viability In Vitro and Increases Apoptosis and Acute Inflammation In Vivo.

Morris Aaron H AH Chang Julie J Kyriakides Themis R TR

BioResearch open access 20160701 1

Decellularized tissue scaffolds are commonly used in the clinic because they can be used as substitutes for more traditional biomaterials, while imparting additional physiological effects. Nevertheless, reports of complications associated with their use are widespread and poorly understood. This study probes possible causes of these complications by examining cell viability and apoptosis in response to eluents from decellularized dermis. Using multiple sources of decellularized dermis, this stud ...[more]

PMID: 27500014

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Project description:There is an unmet clinical need for novel wound healing strategies to treat full thickness skin defects, especially in diabetic patients. We hypothesized that a scaffold could perform dual roles of a biomechanical support and a favorable biochemical environment for stem cells. Human umbilical cord perivascular cells (HUCPVCs) have been recently reported as a type of mesenchymal stem cell that can accelerate early wound healing in skin defects. However, there are only a limited number of studies that have incorporated these cells into natural scaffolds for dermal tissue engineering. The aim of the present study was to promote angiogenesis and accelerate wound healing by using HUCPVCs and decellularized dermal matrix (DDM) in a rat model of diabetic wounds. The DDM scaffolds were prepared from harvested human skin samples and histological, ultrastructural, molecular and mechanical assessments were carried out. In comparison with the control (without any treatment) and DDM alone group, full thickness excisional wounds treated with HUCPVCs-loaded DDM scaffolds demonstrated an accelerated wound closure rate, faster re-epithelization, more granulation tissue formation and decreased collagen deposition. Furthermore, immunofluorescence analysis showed that the VEGFR-2 expression and vascular density in the HUCPVCs-loaded DDM scaffold treated group were also significantly higher than the other groups at 7days post implantation. Since the rates of angiogenesis, re-epithelization and formation of granulation tissue are directly correlated with full thickness wound healing in patients, the proposed HUCPVCs-loaded DDM scaffolds may fulfil a role neglected by current treatment strategies. This pre-clinical proof-of-concept study warrants further clinical evaluation.Statement of significanceThe aim of the present study was to design a novel tissue-engineered system to promote angiogenesis, re-epithelization and granulation of skin tissue using human umbilical cord perivascular stem cells and decellularized dermal matrix natural scaffolds in rat diabetic wound models. The authors of this research article have been working on stem cells and tissue engineering scaffolds for years. According to our knowledge, there is a lack of an efficient system for the treatment of skin defects using tissue engineering strategy. Since the rates of angiogenesis, re-epithelization and granulation tissue are directly correlated with full thickness wound healing, the proposed HUCPVCs-loaded DDM scaffolds perfectly fills the niche neglected by current treatment strategies. This pre-clinical study demonstrates the proof-of-concept that necessitates clinical evaluations.

Project description:Angiotensin II (AngII) is a central signaling molecule of the renin‑angiotensin system that serves a vital role in myocardial fibrosis (MF). The present study aimed to investigate the effects of matrix metalloproteinase (MMP)3 on MF progression. To induce cellular fibrosis, H9C2 rat myocardial cells were treated with AngII for 24 h. Subsequently, cells were treated with levocarnitine, or transfected with small interfering (si)RNA‑negative control or siRNA‑MMP3 (1/2/3). Cell viability, apoptosis and migration were assessed by performing Cell Counting Kit‑8, flow cytometry and Transwell assays, respectively. Reverse transcription‑quantitative PCR (RT‑qPCR) and western blotting were performed to determine the expression levels of MF biomarkers, including disease‑, apoptosis‑ and oxidative stress‑related genes. Compared with the control group, AngII significantly inhibited H9C2 cell viability and migration, and significantly increased H9C2 cell apoptosis (P<0.05). However, compared with AngII‑treated H9C2 cells, MMP3 knockdown significantly inhibited fibrotic H9C2 cell viability and migration, but increased fibrotic H9C2 cell apoptosis (P<0.05). The RT‑qPCR results demonstrated that MMP3 knockdown significantly downregulated the expression levels of AXL receptor tyrosine kinase, AngII receptor type 1, α‑smooth muscle actin and Collagen I in AngII‑treated H9C2 cells (P<0.05). Moreover, compared with AngII‑treated cells, MMP3 knockdown significantly decreased Bcl‑2 expression levels , but significantly increased caspase‑3 and p53 expression levels in AngII‑treated cells (P<0.05). Additionally, compared with AngII‑treated cells, MMP3 knockdown significantly decreased MMP3, MMP9, STAT3, p22Phox and p47Phox expression levels in AngII‑treated cells (P<0.05). The present study indicated that MMP3 knockdown altered myocardial fibroblast cell viability, migration and apoptosis by regulating apoptosis‑ and oxidative stress‑related genes, thus delaying MF progression.

Dataset Information

Inadequate Processing of Decellularized Dermal Matrix Reduces Cell Viability In Vitro and Increases Apoptosis and Acute Inflammation In Vivo.

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Inadequate Processing of Decellularized Dermal Matrix Reduces Cell Viability In Vitro and Increases Apoptosis and Acute Inflammation In Vivo.

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