Mesenchymal Stromal Cells as immunomodulators and trophic mediators for the treatment of Type 1 Diabetes and its complications

Zazzeroni, Luca (2019) Mesenchymal Stromal Cells as immunomodulators and trophic mediators for the treatment of Type 1 Diabetes and its complications, [Dissertation thesis], Alma Mater Studiorum Università di Bologna. Dottorato di ricerca in Scienze chirurgiche, 31 Ciclo. DOI 10.48676/unibo/amsdottorato/8749.
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In Type 1 Diabetes (T1D), insulin-producing beta cells are lost due to a T-cell mediated autoimmune attack. We hypothesized that Mesenchymal Stromal Cells (MSCs) derived from Pancreas (P) and Pancreatic Islet (PI) modulate immunity, sustain beta cell function and survival. We confirmed the mesenchymal nature of human PI-MSC via immunophenotypic profiling and in vitro mesenchymal lineages differentiation. A subset of these cells expresses NG2, a marker of pericytes, and HLA-G, a molecule involved in immunomodulation. We studied the immunomodulatory activity of hPI-MSC in vitro, observing that they can inhibit the proliferation of activated Peripheral Blood Mononuclear cells, via mechanisms that include increased expression of HLA-G. hPI-MSCs have a potent effect on T cells, stimulating an expansion of Regulatory T cells. Remarkably, we found that hPI-MSC can boost the glucose-responsive insulin release function of beta cells via releasing soluble factors. We studied the effect of co-transplantation of murine P-MSC with islets in a murine model of autoimmune T1D, via transplantation in the anterior chamber of the eye. This allowed us to perform in vivo imaging. We performed a longitudinal study on the changes occurring in islets, GFP-tagged P-MSCs, revascularization, and immune cell trafficking. We observed a remodeling of the vascular structures, with contribution from mP-MSC. Ongoing in vivo experiments are focused on long-term analyses of islet survival and immune cell trafficking. These finding indicate that pancreas and pancreatic islets represent a source of MSC that modulate immunity, sustain beta cell function, and promote survival of islet endocrine cells in T1D. In a separate project, we analyzed the effect of the secretome of placenta-derived MSCs in an in vitro Scratch Wound assay. The supernatant from one tissue source (undisclosed due to intellectual property rights) significantly accelerated wound healing. This could have important potential for translational applications in the treatment of diabetic ulcers.

Tipologia del documento
Tesi di dottorato
Zazzeroni, Luca
Dottorato di ricerca
Settore disciplinare
Settore concorsuale
Parole chiave
type 1 diabetes, MSC, mesenchymal, beta cell replacement, cell therapy, stem cells, pancreatic islet
Data di discussione
10 Aprile 2019

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