Adult: Coronary: Basic Science
Adipose-derived stem cell sheet under an elastic patch improves cardiac function in rats after myocardial infarction

https://doi.org/10.1016/j.jtcvs.2020.04.150Get rights and content

Abstract

Objectives

Although adipose-derived stem cells (ADSCs) have shown promise in cardiac regeneration, stable engraftment is still challenging. Acellular bioengineered cardiac patches have shown promise in positively altering ventricular remodeling in ischemic cardiomyopathy. We hypothesized that combining an ADSC sheet approach with a bioengineered patch would enhance ADSC engraftment and positively promote cardiac function compared with either therapy alone in a rat ischemic cardiomyopathy model.

Methods

Cardiac patches were generated from poly(ester carbonate urethane) urea and porcine decellularized cardiac extracellular matrix. ADSCs constitutively expressing green fluorescent protein were established from F344 rats and transplanted as a cell sheet over the left ventricle 3 days after left anterior descending artery ligation with or without an overlying cardiac patch. Cardiac function was serially evaluated using echocardiography for 8 weeks, comparing groups with combined cells and patch (group C, n = 9), ADSCs alone (group A, n = 7), patch alone (group P, n = 6) or sham groups (n = 7).

Results

Much greater numbers of ADSCs survived in the C versus A groups (P < .01). At 8 weeks posttransplant, the percentage fibrotic area was lower (P < .01) in groups C and P compared with the other groups and vasculature in the peri-infarct zone was greater in group C versus other groups (P < .01), and hepatocyte growth factor expression was higher in group C than in other groups (P < .05). Left ventricular ejection fraction was higher in group C versus other groups.

Conclusions

A biodegradable cardiac patch enhanced ADSC engraftment, which was associated with greater cardiac function and neovascularization in the peri-infarct zone following subacute myocardial infarction.

Graphical abstract

Enhancement of functional preservation with adipose-derived stem cell (ADSC) therapy by poly(ester carbonate urethane) urea (PECUU) cardiac patch with extracellular matrix (ECM). Combining a biodegradable, elastic cardiac patch that incorporates a cardiac ECM-derived hydrogel with ADSC sheet therapy enhanced cardiac function over individual therapy, and was associated with greater engraftment of ADSCs and neovascularization with greater cell recruitment following subacute myocardial infarction.

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Section snippets

Materials and Methods

All procedures were performed in accordance with the Revised Guide for the Care and Use of Laboratory Animals (National Institutes of Health, Bethesda, Md). Experimental protocols were approved by the Ethics Review Committee for Animal experimentation of the University of Pittsburgh (reference No. 17101554).

Generation of ADSCs Sheets from GFP Transgenic Rats and PECUU Cardiac Patch

ADSCs sheets were successfully generated from GFP gene transgenic F344 rats according to the protocol outlined in Figure 1, A. As assessed by hematoxylin and eosin and Masson's trichrome staining, the generated ADSCs sheets were layered with a few ADSCs and entirely stained with GFP antibody, whereas cardiac patches were formed by 3 layers of ADSC sheets, ECM, and PECUU sheet (Figure 1, B). Porcine heart ECM gel was entirely stained with hematoxylin in the region of the patch where PECUU fibers

Discussion

This study explored whether an ADSC sheet, implanted in concert with PECUU/ECM cardiac patch therapy, would enhance cell survival and therapeutic efficacy compared with single therapy of an ADSC sheet or patch alone. The results demonstrated that significantly more ADSCs could be engrafted on the surface of the LV, and LV contractility and remodeling were improved at the 8-week end point compared with single therapy with an ADSC sheet or patch. By histological assessment, LV wall thickness was

Conclusions

ADSC sheet and cardiac patch therapies represent promising approaches to preserve cardiac function following myocardial infarction. Combining a biodegradable, elastic cardiac patch that incorporates a cardiac ECM-derived hydrogel with ADSC sheet therapy enhanced cardiac function over individual therapy, and was associated with greater engraftment of ADSCs and neovascularization in the peri-infarct zone following subacute myocardial infarction. This multifaceted strategy may contribute to

References (27)

Cited by (17)

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    In recent years, cell sheets have been studied at various transplantation sites, and several reports indicated that MSC sheets and similar tissue-engineered constructs can be transplanted without a carrier to the transplantation site, where they could serve as a scaffold.32,33 ADSC sheets, which are expected to remain in place even without a scaffold and fixation, have been used for regeneration of the heart, esophagus, skin, and other organs.34-36 In orthopedics, ADSC sheets were utilized in nerve, cartilage, and ligament reconstructions.12,13,37

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    For example, CSs placed on a denuded tooth root surface were surrounded with β-tricalcium phosphate [122]. Cell sheets delivered to the retina were reported to be spread and fixed by oil/gas tamponade when the eye chamber is filled with oil or gas to provide temporary pressure [49,55,121]. The process cycle of obtaining CSs and CS-based tissue-engineered constructs, from harvesting initial cell cultures to manufacturing and delivering the final therapy product, is very time-consuming.

  • Engineering stem cell therapeutics for cardiac repair

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    For example, the use of a PEGylated 3D fibrin patch for MSC delivery has been shown to increase cell viability and modulate cell function [141]. It is also reported that a bioengineered cardiac patch that combined a biodegradable, elastic poly(ester carbonate urethane) urea (PECUU) with a cardiac ECM-derived hydrogel and ADSC sheet enhances cardiac function over the treatment with a patch or ADSCs alone [142]. Using scaffolds of various elasticities for stem cell MI therapy may affect outcomes, by influencing cardiac differentiation, and hindering or supporting the mechanical dynamics of the heart [143–145].

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This work was financially supported by Japan Heart Foundation/Bayer Yakuhin Research Grant Abroad and the Uehara Memorial Foundation Research Fellowship.

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