Thursday September 23, 2021 - 15:00 to 16:15
New abstract graft (TX) of co-microencapsulated human umbilical cord-derived mesenchymal stem (hUCMS) and human pancreatic islet-derived insulin producing cells (hIDC) for treatment of experimental type 1 diabetes
Pia Montanucci1, Teresa Pescara1, Alessia Greco1, Giuseppe Basta1, Riccardo Calafiore1.
1Departement of Medicine, Laboratory for Endocrine Cell Transplants and Biohybrid Organs, University of Perugia, Perugia, Italy
Introduction: We had preliminarily shown that microencapsulated hUCMS grafts restored euglycemia in non-obese diabetic (NOD) mice with recent onset mild, but not severe T1D, which suggested that such TX setting was useful only at an early stage of the disease process with mild hyperglycemia (1). hIDC obtained after in vitro expansion of human whole islets, through development of islet-derived progenitor cells, may de-differentiate, thereafter re-differentiate into insulin producing cells. Hence the two cell types, sharing common stemness properties, may be advantageously combined, for synergistic interaction and crosstalk, and since hIDC produce tracer insulin, could also apply to treatment of long-standing T1D.
Methods: Upon microencapsulation in clinical grade sodium alginate (AG), hUCMS and hIDC were able to form cell co-aggregates that looked well integrated and viable after proper staining. We then grafted intraperitoneally microencapsulated hUCMS/hIDC co-aggregates into non-obese diabetic/severe combined immunodeficient (NOD/SCID) mice, which resulted in an acquired ability by hIDC to produce and store hormones, and in the maintenance by hUCMS of secreting immunomodulatory factors such as IDO1 and HLAG5. Next, we transplanted these microencapsulated cell co-aggregates into NOD mice with spontaneous T1D with also severe hyperglycemia, observing a decline of blood glucose levels throughout 180 days post-TX.
Results: In vitro, we have shown that hUCMS inhibited proliferation of allogeneic polymorphonuclear blood cells from patients with T1D, while promoting expansion of FoxP3+ Tregs. Reversal of hyperglycemia in diabetic NODs seemed to suggest that hUCMS and hIDC, upon co-microencapsulation, anatomically and functionally synergized to accomplish two goals: to maintain basal insulin output by hIDC, and to exploit the immunoregulatory properties of hUCMS. At 180 days post-transplant, the retrieved pancreases showed either intact islets able to secrete insulin and glucagon, or islets crowned by “insulitis,” or islets severely damaged by infiltrating mononuclear cells. This observation confirms other reports on hUCMS enhancing β-cell survival.
Conclusion: We have preliminary gathered evidence about the fact that two adult stem cell types within AG microcapsules, may synergize forming an organoid by promoting trace amounts of insulin production (hIDC), while "freezing" the autoimmune disease process (hUCMS). By taking advantage on establishing a state of acquired immune tolerance while providing an even minimal insulin secretion, the system is applicable to reversal of established, even severe hyperglycemia in not immunosuppressed NOD mice, creating a basis for treatment of longer-standing and not only early onset T1D.
1) Montanucci P et al. Xenotranspl 2019;26:e12476