Co-transplantation of mesenchymal stem cells and endothelial cells with islet grafts: A strategy to improve post-tx engraftment of pancreatic islets
Main Article Content
Abstract
Though islet transplantation is now being considered as a gold standard to cure type 1 diabetes in patients without the threat of unaware hypoglycemia and severe hypoglycemia episode, post-transplantation islet loss due to the loss of intra-islet vasculature during the islet isolation process compromises the full functionality of the transplanted islet mass. Therefore, besides instant blood-mediated inflammatory reaction (IBMIR) induced loss within the first 60 minutes in intraportal vein, two weeks avascular window, prior to adequate vascularization, is responsible for further loss of islets due to hypoxia induced necrosis. Burgeoning evidences demonstrated that using omentum or kidney capsules we can overcome the IBMIR. This review first summarizes the post -transplantation islet loss till day 14 due to the absence of islet vascularization and then elucidates the methods used to restore the post-IBMIR islet loss. Co-transplantation of mesenchymal stem cells and endothelial cells with the islets appeared to be a better approach to overcome the challenges in islet transplantation.
Keywords:
Type 1 diabetes (T1D), Islet transplantation, Co-transplantation, Mesenchymal stem cells (MSCs), Endothelial cells (ECs), Instant blood mediated immune reaction (IBMIR), Post-transplantation islet loss
Article Details
How to Cite
NAQVI, Raza Ali et al.
Co-transplantation of mesenchymal stem cells and endothelial cells with islet grafts: A strategy to improve post-tx engraftment of pancreatic islets.
Medical Research Archives, [S.l.], v. 13, n. 2, feb. 2025.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/6230>. Date accessed: 17 mar. 2025.
doi: https://doi.org/10.18103/mra.v13i2.6230.
Section
Review Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
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[2]. G. A. Gregory, T. I. G. Robinson, S. E. Linklater, et al., “Global incidence, prevalence, and mortality of type 1 diabetes in 2021 with projection to 2040: a modelling study,” Lancet Diabetes Endocrinology, vol. 10, no. 10, pp 2022 741-760. doi: 10.1016/S22 13-8587(22)00218-2. Epub 2022 Sep 13. Erratum in: Lancet Diabetes Endocrinology, Oct 7, 2022; PMID: 36113507.
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[6]. DIAMOND Project Group, Incidence and trends of childhood Type 1 diabetes worldwide 1990-1999, Diabetic Medicine, vol. 23, no. 8. pp 857–866, 2006.
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[8]. A. M. Shapiro, J. R. Lakey, E. A. Ryan, et al., “Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen,” New England Journal of Medicine, vol. 343, no. 4, pp 230-238, 2000.
[9]. A. M. Shapiro, C. Ricordi, B. J. Hering et al., “International trial of the Edmonton protocol for islet transplantation,” New England Journal of Medicine, vol. 355, no. 13, pp 1318-1330, 2006.
[10]. E. Oetjen, D. Baun, S. Beimesche, et al., "Inhibition of human insulin gene transcription by the immunosuppressive drugs cyclosporin A and tacrolimus in primary, mature islets of transgenic mice,” Molecular Pharmacology, vol. 63, pp 1289–1295, 2003.
[11]. I. Hernández-Fisac, J. Pizarro-Delgado, C. Calle, et al., “Tacrolimus-induced diabetes in rats courses with suppressed insulin gene expression in pancreatic islets,” American Journal of Transplantation, vol. 7, pp 2455–2462, 2007.
[12]. N. Rostambeigi, I.R. Lanza, P. P. Dzeja, et al., “Unique cellular and mitochondrial defects mediate FK506-induced islet β-cell dysfunction,” Transplantation, vol. 9, pp 615–623, 2011.
[13]. R. Nishimura, S. Nishioka, I. Fujisawa, et al., “Tacrolimus inhibits the revascularization of isolated pancreatic islets,” PLoS One, vol. 8, no. 4, e56799, 2013.
[14]. B. L. Gala-Lopez, A. R. Pepper, R. L. Pawlick, et al., “Antiaging Glycopeptide Protects Human Islets Against Tacrolimus-Related Injury and Facilitates Engraftment in Mice,” Diabetes, vol. 65, no. 2, pp 451-462, 2016.
[15]. D. J. van der Windt, R. Bottino, G. M. Kumar, et al., “Clinical islet xenotransplantation: how close are we?” Diabetes, vol. 61, no. 12, pp 3046-3055, 2012.
[16]. D. K. Cooper, B. Gollackner, and D. H. Sachs, “Will the pig solve the transplantation backlog?” Annual Review of Medicine, vol. 53, pp 133, 2002.
[17]. C. Ricordi, C. Socci, A. M. Davalli, et al., “Isolation of the elusive pig islet,” Surgery, vol. 107, pp 688–694, 1990.
[18]. B. Hering, and N. Walawalkar, “Pig-to-nonhuman primate islet xenotransplantation,” Transplantation Immunology, vol. 21, pp 81-86, 2009.
[19]. K. Cardona, G. S. Korbutt, Z. Milas, et al., “Long-term survival of neonatal porcine islets in nonhuman primates by targeting costimulation pathways,” Nature Medicine, vol. 12, no. 3, pp 304-306, 2006.
[20]. J. Denner, “Why was PERV not transmitted during preclinical and clinical xenotransplantation trials and after inoculation of animals?” Retrovirology, vol. 15, pp 28, 2018.
[21]. G. Mattsson, L. Jansson, and P. O. Carlsson, Decreased vascular density in mouse pancreatic islets after transplantation. Diabetes, vol. 51, pp 1362 –1366, 2002.
[22]. F. C. Brunicardi, J. Stagner, S. Bonner-Weir, et al., “Microcirculation of the islets of Langerhans,” Diabetes, vol. 45, pp 385 –392, 1996.
[23]. L. Jansson, “The regulation of pancreatic islet blood flow,” Diabetes Metabolism Reviews, vol.10, pp 407 –416,1994.
[24]. P.O. Carlsson, P. Liss, A. Andersson, and L. Jansson, “Measurements of oxygen tension in native and transplanted rat pancreatic islets,” Diabetes, vol. 47, pp 1027 –1032,1998.
[25]. P. O. Carlsson, F. Palm, A. Andersson, and P, Liss, “Chronically decreased oxygen tension in rat pancreatic islets transplanted under the kidney capsule,” Transplantation, vol. 69, pp 761 –766, 2000.
[26]. P. O. Carlsson, F. Palm, A. Andersson, and P. Liss, “Markedly decreased oxygen tension in transplanted rat pancreatic islets irrespective of the implantation site,” Diabetes, vol. 50, pp 489 –495, 2001.
[27]. A. Boker, L. Rothenberg, C. Hernandez et al., “Human islet transplantation: update,” World Journal of Surgery, vol. 25, pp 481 –486, 2001.
[28]. P. Vajkoczy, A. M. Olofsson, H. A. Lehr, et al., Histogenesis and ultrastructure of pancreatic islet graft microvasculature, Evidence for graft revascularization by endothelial cells of host origin,” American Journal Pathology, vol. 146, no. 6, pp 1397-1405, 1995.
[29]. J. O. Sandberg, B. Margulis, L. Jansson, R. Karlsten, and O. Korsgren, “Transplantation of fetal porcine pancreas to diabetic or normoglycemic nude mice. Evidence of a rapid engraftment process demonstrated by blood flow and heat shock protein 70 measurements,” Transplantation, vol. 59, no. 12, pp 1665-1669,1995.
[30]. A. M. Davalli, L, Scaglia, D. H. Zangen, J. Hollister, S. Bonner-Weir, and G. C. Weir, “Vulnerability of islets in the immediate posttransplantation period. Dynamic changes in structure and function,” Diabetes vol. 45, no. 9, pp 1161-1167, 1996.
[31]. E. M. Conway, D. Collen, and P. Carmeliet, “Molecular mechanisms of blood vessel growth,” Cardiovascular Research, vol. 49, pp 507 –521, 2001.
[32]. M. Brissova, A. Shostak, M. Shiota, et al., “Pancreatic islet production of vascular endothelial growth factor--a is essential for islet vascularization, revascularization, and function,” Diabetes, vol. 55, no. 11, pp 2974-2985, 2006.
[33]. E. Lammert, O. Cleaver, and D. Melton, “Induction of pancreatic differentiation by signals from blood vessels,” Science, vol. 294, no. 5542, pp 564-567, 2001.
[34]. Q. Cai, M. Brissova, R. B. Reinert, et al., Enhanced expression of VEGF-A in β cells increases endothelial cell number but impairs islet morphogenesis and β cell proliferation., Developmental Biology, vol. 367, pp 40–54, 2012.
[35]. J. Magenheim, O. Ilovich, A. Lazarus, et al., “Blood vessels restrain pancreas branching, differentiation and growth,” Development, vol. 138, pp 4743–4752, 2011.
[36]. F. W. Sand, A. Hörnblad, J. K. Johansson, et al., “Growth-limiting role of endothelial cells in endoderm development,” Developmental Biololgy, vol. 352, pp 267–277, 2011.
[37]. N. Zhang, A. Richter, J. Suriawinata, et al., “Elevated vascular endothelial growth factor production in islets improves islet graft vascularization,” Diabetes, vol. 53, no. 4, pp 963-970, 2004.
[38]. M. Brissova, K. Aamodt, P. Brahmachary, et al., Islet microenvironment, modulated by vascular endothelial growth factor-A signaling, promotes β cell regeneration,” Cell Metabolism, vol. 19, no. 3, pp 498-511, 2014.
[39]. M. Brissova, M. Fowler, P. Wiebe, et al., “Intraislet endothelial cells contribute to revascularization of transplanted pancreatic islets,” Diabetes, vol. 53, no. 5, pp 1318-1325, 2004.
[40]. T. Asahara, T. Murohara, A. Sullivan, et al., “Isolation of putative progenitor endothelial cells for angiogenesis,” Science, vol. 275, no. 5302, pp 964-967,1997.
[41]. K. Naruse, Y. Hamada, E. and Nakashima, et al., “Therapeutic neovascularization using cord blood-derived endothelial progenitor cells for diabetic neuropathy,” Diabetes, vol. 54, no. 6, pp 1823-1828, 2005. Erratum in: Diabetes, vol. 55, no. 5, pp 1534, 2006.
[42]. V. Mathews, P. T. Hanson, E. Ford, J. Fujita, K. S. Polonsky, and T. A. “Graubert. Recruitment of bone marrow-derived endothelial cells to sites of pancreatic beta-cell injury,” Diabetes, vol. 53, no. 1, pp 91-98, 2004.
[43]. S. Kang, H. S. Park, A. Jo, et al., “Endothelial progenitor cell cotransplantation enhances islet engraftment by rapid revascularization,” Diabetes, vol. 61, no. 4, pp 866-876, 2012.
[44]. V. Coppens, Y. Heremans, G. Leuckx, et al., “Human blood outgrowth endothelial cells improve islet survival and function when co-transplanted in a mouse model of diabetes,” Diabetologia, vol. 56, no. 2, pp 382-390, 2013.
[45]. P. Quaranta, S. Antonini, S. Spiga, et al., “Co-transplantation of endothelial progenitor cells and pancreatic islets to induce long-lasting normoglycemia in streptozotocin-treated diabetic rats,” PLoS One, vol. 9, no. 4, e94783, 2014.
[46]. M. L. da Silva, P. C. Chagastelles, and N. B. Nardi, Mesenchymal stem cells reside in virtually all post-natal organs and tissues, Journal of Cell Science, vol. 119, pp 2204–2213, 2006.
[47]. Y. X. Xu, L. Chen, R. Wang et al., “Mesenchymal stem cell therapy for diabetes through paracrine mechanisms,” Medical Hypotheses, vol. 71, pp 390–393, 2008.
[48]. Y. L. Tang, Q. Zhao, Y. C. Zhang, et al., “Autologous mesenchymal stem cell transplantation induce VEGF and neovascularization in ischemic myocardium,” Regulatory Peptides, vol 117, pp 3-10, 2004).
[49]. E. J. Kim, R. K. Li, R. D. Weisel, et al., Angiogenesis by endothelial cell transplantation, The Journal of Thoracic and Cardiovascular Surgery, vol. 122, no. 5, pp 963–971, 2001.
[50]. M. Figliuzzi, R. Cornolti, N. Perico, et al. Bone marrow-derived mesenchymal stem cells improve islet graft function in diabetic rats, Transplant Proceedings, vol. 41, no. 5, pp 1797-1800, 2009.
[51]. T. Ito, S. Itakura, I. Todorov, et al., “Mesenchymal stem cell and islet co-transplantation promotes graft revascularization and function,” Transplantation, vol. 89, no. 12, pp 1438-1445, 2010.
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