Combinatorial therapy with three-dimensionally cultured adipose-derived stromal cells and self-assembling peptides to enhance angiogenesis and preserve cardiac function in infarcted hearts

Abstract

Even though stem cell therapy is a promising angiogenic strategy to treat ischaemic diseases, including myocardial infarction (MI), therapeutic efficacy is limited by low survival and retention of transplanted cells in ischaemic tissues. In addition, therapeutic angiogenesis depends on stimulating host angiogenesis with paracrine factors released by transplanted cells rather than on direct blood vessel formation by transplanted cells. In the present study, to overcome these limitations and to enhance the therapeutic efficacy of MI treatment, combinatorial therapy with three-dimensional cell masses (3DCMs) and self-assembling peptides (SAPs) was tested in a rat MI model. Spheroid-type 3DCMs, which are vascular differentiation-induced cells, were prepared by culturing human adipose-derived stromal cells on a fibroblast growth factor-immobilized surface. The SAPs were used as the carrier material to increase engraftment of transplanted cells. After coronary artery ligation, 3DCMs were combined with SAPs and were transplanted into ischaemic lesions. The therapeutic potential was evaluated 4 weeks after treatment. By combining 3DCMs and SAPs, survival and retention of transplanted cells increased threefold when compared with treatment with 3DCMs alone and transplanted cells established vascular networks in infarcted hearts. In addition, the size of the infarct in the 3DCM + SAP group was reduced to 6.09 ± 2.83% by the promotion of host angiogenesis and cardiac function was preserved, as demonstrated by a 54.25 ± 4.42% increase in the ejection fraction. This study indicates that combinatorial therapy with 3DCM and SAPs could be a promising strategy for therapeutic angiogenesis to treat MI. Copyright © 2016 John Wiley & Sons, Ltd.

Elastin-Collagen Based Hydrogels as Model Scaffolds to Induce Three-Dimensional Adipocyte Culture from Adipose Derived Stem Cells

“…Hemmrich et al used hyaluronic acid gels to encapsulate preadipocytes and showed adipogenic differentiation in vivo in mouse and pig models over a six-week implantation period [ 47 , 48 ], while Halberstadt et al used RGD-coated alginate scaffolds loaded with ASCs in a sheep model to show adipogenesis over a three-month period [ 49 ]. Researchers have also used peptide-based natural materials to promote differentiation of stem cells [ 13 , 14 , 51 , 52 ]. Kim et al improved angiogenesis in a rat myocardial infarction model using a (arginine-alanine-arginine-alanine-aspartic acid-alanine-aspartic acid-alanine) 2 based hydrogel containing hASCs [ 51 ].…”

“…Researchers have also used peptide-based natural materials to promote differentiation of stem cells [ 13 , 14 , 51 , 52 ]. Kim et al improved angiogenesis in a rat myocardial infarction model using a (arginine-alanine-arginine-alanine-aspartic acid-alanine-aspartic acid-alanine) 2 based hydrogel containing hASCs [ 51 ]. Liu et al used a RAD16 family peptide (RAD16-I) that forms β-sheets in water and self-assembles into scaffolds to support attachment and proliferation of hASCs [ 52 ].…”

Use of Self-Assembling Peptides to Enhance Stem Cell Function for Therapeutic Angiogenesis

“…This was achieved by controlled local delivery of the respective growth factors when combined with RADA, while injection of growth factors or RADA alone did not achieve the desired cardioprotective effects. The combination of stem cells with SAPs has also been studied widely in a variety of different animal models, including ischemic hearts [ 16 ], osteoarthritis [ 17 ], and cartilage defects [ 18 ]. In these studies, the role of SAPs was to act as a carrier to increase engraftment of injected stem cells, thereby improving survival and retention of administered cells and thus improving their desired therapeutic effects.…”

Harnessing the secretome of adipose-derived stem cells in the treatment of ischemic heart diseases

“…Additionally, in MI therapy, the combination of SAPs and 3D-ASCs culture effectively increased the release of paracrine factors. The VEGF production of the combinational group within the infarcted myocardium was nearly tenfolds and twofolds greater compared with monolayer cell and 3D cell groups, respectively [91]. Another example of comprehensive tissue engineering, combined a facile cell sheet with the VEGF overexpression by genetic engineering, conferred robust and prolonged secretion of growth factors from ASCs, primarily due to the enhanced capacity of retention and survival of implanted ASCs [92].…”