Small intestinal submucosa-derived extracellular matrix bioscaffold significantly enhances angiogenic factor secretion from human mesenchymal stromal cells

Xin Lin,Claus Svane Sondergaard,Mikella Robinson,Tye Petrie,Veronica Spandler,W. Douglas Boyd

doi:10.1186/s13287-015-0165-3

Abstract

IntroductionThe in vivo therapeutic effect of mesenchymal stromal cells (MSCs) is currently believed to be tightly linked to their paracrine secretion ability. However, insufficient or imprecise cell delivery, low cell survival and retention post-transplant, along with harsh donor site microenvironments, are major barriers to the clinical success of MSC therapies. Here we tested a small intestinal submucosa (SIS)-derived extracellular matrix (ECM) bioscaffold augmented with MSCs, with the hypothesis that they will facilitate the precise delivery of increased numbers of MSCs therefore improving cell viability and retention.MethodsIn this study, we evaluated the secretion of angiogenic factors from three human MSC lines cultured on SIS ECM. We used human antibody array and enzyme-linked immunosorbent assay to measure the level of angiogenic factors released from MSCs when cultured on SIS ECM or regular tissue culture plastic. We tested MSCs cultured for three different time points.ResultsWe found that the SIS ECM culture environment can significantly enhance the release of several angiogenic factors when compared to MSCs cultured on standard tissue culture plastic. Specifically, vascular endothelial growth factor and interleukin-8 secretion was significantly increased at 24, 48 and 72 hours postseeding onto SIS ECM whereas vascular endothelial growth factor release for cells cultured on plastic surface remained the same during these time points. We also observed significant donor to donor variation in cytokine production.ConclusionsThis study demonstrates that MSCs transplanted onto a SIS ECM may greatly increase their therapeutic potential through an increase in pro-angiogenic cytokine release.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-015-0165-3) contains supplementary material, which is available to authorized users.

Highlights

The in vivo therapeutic effect of mesenchymal stromal cells (MSCs) is currently believed to be tightly linked to their paracrine secretion ability
Human MSCs can be seeded and cultured on small intestinal submucosa (SIS) extracellular matrix (ECM) at high density Human bone marrow (BM)-derived MSCs were isolated from three individual donors and screened for tri-lineage differentiation potential (Fig. 1a–e) and the presence of putative MSC cell surface markers (Fig. 1g)
We transduced a subset of MSCs with a lentiviral vector carrying the enhanced green fluorescent protein (eGFP) gene to allow visualization of the MSCs once seeded onto the SIS ECM

Summary

Introduction

The in vivo therapeutic effect of mesenchymal stromal cells (MSCs) is currently believed to be tightly linked to their paracrine secretion ability. Mesenchymal stromal cells (MSCs) are one of the few stem cell types to have reached late stage clinical trials for a variety of indications, including multiple trials as therapeutic agents for ischemic tissue repair [1,2,3,4,5] In addition to their multipotent differentiation potential, a strong paracrine effect has been proposed as the principal mechanism that contributes to tissue repair [6,7,8,9]. BM-derived MSCs secrete angiogenic factors such as vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF) and monocyte chemoattractant protein 1 (MCP-1) that are critical for vascular network remodeling [15,16,17] It is this physiological mechanism that led to the use of MSCs to treat IHD.

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