Extracellular Matrix and Growth Factors Improve the Efficacy of Intramuscular Islet Transplantation.

Haruyuki Tsuchiya,Michiaki Unno,Yu Katayose,Gumpei Yoshimatsu,Masahiko Fukase,Naoaki Sakata,Takeshi Aoki,Shinichi Egawa,Masaharu Ishida,Michiya Matsusaki

doi:10.1371/journal.pone.0140910

Abstract

BackgroundThe efficacy of intramuscular islet transplantation is poor despite being technically simple, safe, and associated with reduced rates of severe complications. We evaluated the efficacy of combined treatment with extracellular matrix (ECM) and growth factors in intramuscular islet transplantation.MethodsMale BALB/C mice were used for the in vitro and transplantation studies. The following three groups were evaluated: islets without treatment (islets-only group), islets embedded in ECM with growth factors (Matrigel group), and islets embedded in ECM without growth factors [growth factor-reduced (GFR) Matrigel group]. The viability and insulin-releasing function of islets cultured for 96 h were significantly improved in Matrigel and GFR Matrigel groups compared with the islets-only group.ResultsBlood glucose and serum insulin levels immediately following transplantation were significantly improved in the Matrigel and GFR Matrigel groups and remained significantly improved in the Matrigel group at postoperative day (POD) 28. On histological examination, significantly decreased numbers of TdT-mediated deoxyuridine triphosphate-biotin nick end labeling-positive islet cells and significantly increased numbers of Ki67-positive cells were observed in the Matrigel and GFR Matrigel groups at POD 3. Peri-islet revascularization was most prominent in the Matrigel group at POD 14.ConclusionsThe efficacy of intramuscular islet transplantation was improved by combination treatment with ECM and growth factors through the inhibition of apoptosis, increased proliferation of islet cells, and promotion of revascularization.

Highlights

Islet transplantation has demonstrated utility as a cell replacement therapy for severe diabetes mellitus (DM)
Blood glucose and serum insulin levels immediately following transplantation were significantly improved in the Matrigel and growth factor-reduced (GFR) Matrigel groups and remained significantly improved in the Matrigel group at postoperative day (POD) 28
Significantly decreased numbers of TdT-mediated deoxyuridine triphosphate-biotin nick end labeling-positive islet cells and significantly increased numbers of Ki67-positive cells were observed in the Matrigel and GFR Matrigel groups at POD 3

Summary

Introduction

Islet transplantation has demonstrated utility as a cell replacement therapy for severe diabetes mellitus (DM). Clinical islet transplantation has been predominantly performed using an intraportal approach. Intraportal transplantation is associated with severe complications such as portal hypertension and embolism [4], which can be life threatening [5]. A number of organs have been studied as alternative transplantation sites for islet cells, including the kidney [6], greater omentum [7], bone marrow [8], and pancreas [9]; these sites are regarded as suboptimal transplantation sites in clinical settings. Intramuscular transplantation is technically simple and safe, and it confers a decreased risk of severe complications. The efficacy of intramuscular islet transplantation is poor despite being technically simple, safe, and associated with reduced rates of severe complications. We evaluated the efficacy of combined treatment with extracellular matrix (ECM) and growth factors in intramuscular islet transplantation

Methods

Results

Conclusion