Autologous Mesenchymal Stem Cell and Islet Cotransplantation: Safety and Efficacy

Hongjun Wang, Charlie Strange, Paul J Nietert, Jingjing Wang, Taylor L Turnbull, Colleen Cloud, Stefanie Owczarski, Betsy Shuford, Tara Duke, Gary Gilkeson, Louis Luttrell, Kathie Hermayer, Jyotika Fernandes, David B Adams, Katherine A Morgan, Hongjun Wang, Charlie Strange, Paul J Nietert, Jingjing Wang, Taylor L Turnbull, Colleen Cloud, Stefanie Owczarski, Betsy Shuford, Tara Duke, Gary Gilkeson, Louis Luttrell, Kathie Hermayer, Jyotika Fernandes, David B Adams, Katherine A Morgan

Abstract

Islet engraftment after transplantation is impaired by high rates of islet/β cell death caused by cellular stressors and poor graft vascularization. We studied whether cotransplantation of ex vivo expanded autologous bone marrow-derived mesenchymal stem cells (MSCs) with islets is safe and beneficial in chronic pancreatitis patients undergoing total pancreatectomy with islet autotransplantation. MSCs were harvested from the bone marrow of three islet autotransplantation patients and expanded at our current Good Manufacturing Practices (cGMP) facility. On the day of islet transplantation, an average dose of 20.0 ± 2.6 ×106 MSCs was infused with islets via the portal vein. Adverse events and glycemic control at baseline, 6, and 12 months after transplantation were compared with data from 101 historical control patients. No adverse events directly related to the MSC infusions were observed. MSC patients required lower amounts of insulin during the peritransplantation period (p = .02 vs. controls) and had lower 12-month fasting blood glucose levels (p = .02 vs. controls), smaller C-peptide declines over 6 months (p = .01 vs. controls), and better quality of life compared with controls. In conclusion, our pilot study demonstrates that autologous MSC and islet cotransplantation may be a safe and potential strategy to improve islet engraftment after transplantation. (Clinicaltrials.gov registration number: NCT02384018). Stem Cells Translational Medicine 2018;7:11-19.

Keywords: Bone marrow; Cell death; Chronic pancreatitis; Glycemic control; Islet transplantation; Mesenchymal stem cell.

© 2017 The Authors Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.

Figures

Figure 1
Figure 1
Patients who had PVT showed higher average islet pellet weight compared with patients without PVT. Islet pellet weights in patients who had PVT or didn't have PVT (no‐PVT) after islet transplantation. Error bars represent standard errors; p values are from Student's t test assuming unequal variances. Abbreviation: PVT, portal vein thrombosis.
Figure 2
Figure 2
MSC patients have reduced insulin requirements and lower blood glucose levels after transplantation. (A): Schematic diagram of MSC preparation, islet transplantation, data collection, and analysis. (B): Percentages of patients that were insulin‐independent at preoperative period (preop) and 6 months and 12 months after TP‐IAT. (C): Daily insulin requirement of MSC (n = 3) and control patients (n = 101), preop, postoperatively on days 1 (POD1), 2 (POD2), 3 (POD3), at discharge, and 6 Mo and 12 Mo after islet transplantation. Mean fasting blood glucose levels (D), HbA1c (E), and C‐peptide levels (F) at preoperative, 6‐month, and 12‐month visits. p values evaluated by Student's t tests and assumed unequal variances. Error bars represent standard errors. Abbreviations: CTR, historical patients; Mo, month; MSC, mesenchymal stem cell; NS, not significant; POD1, postoperatively on day 1; POD2, postoperatively on day 2; POD3, postoperatively on day 3; TP‐IAT, total pancreatectomy with islet autotransplantation.
Figure 3
Figure 3
Results of MMTT at 6 months after islet transplantation in MSC patients (n = 3) and controls (n = 4). (A): Individual patient responses in C‐peptide to a MMTT during a 240 minutes after drinking the BOOST. Solid lines are from controls and dotted lines from MSC patients. (B): Peak C‐peptide level during an MMTT. (C): Mean C‐peptide area under the curve from control and MSC patients. (D): MMSI at 240 mins after MMTT. Error bars represent standard errors, p values are from Student's t test assuming unequal variances. Abbreviations: AUC, area under the curve; CTR, historical patients; MMSI, mixed meal stimulation index; MMTT, mixed‐meal tolerance test; MSC, mesenchymal stem cell.
Figure 4
Figure 4
MSC (n = 3) cases' and historical control patients' (n = 101) morphine use and quality of life (QOL). Daily morphine and equivalent use (A), physical QOL (B), bodily pain (C), and psychological QOL (D) of MSC cases (dotted lines) and historical control patients (solid line) at preop and 6 Mo and 12 Mo postop. Error bars represent standard errors; p values are from Student's t test assuming unequal variances. Abbreviations: CTR, historical patients; Mo, month; MSC, mesenchymal stem cell; NS, not significant; QOL, quality of life.

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