Cotransplantation of marginal mass allogeneic islets with 3D culture-derived adult human skin cells improves glycemia in diabetic mice.

ANDREONE, L; SANTOS, AF; WAILEMANN, RAM; TERRA, LF; GOMES, VM; MACEDO DA SILVA, J; ROSA-FERNANDES, L; SOGAYAR, MC; PALMISANO, G; LABRIOLA, L; PERONE, MJ

BRAZILIAN JOURNAL OF MEDICAL AND BIOLOGICAL RESEARCH

ASSOC BRAS DIVULG CIENTIFICA

Lugar: San Pablo; Año: 2023

0100-879X

Islets transplantation represents a therapeutic option for type 1 diabetes (T1D). Long-term viability of transplanted islets requires improvement. MSCs have been proposed as adjuvants for islet transplantation facilitating grafting and functionality. Stem cell aggregation provides physiological interactions between cells and enhances the in situ concentration of modulators of inflammation and immunity.We established a hanging-drop culture of adult human skin fibroblast-like cells as spheroids and skin spheroid-derived cells (SphCs) were characterized. We assessed the potential benefit of SphCs to improve islet functionality by cotransplantation with a marginal mass of allogeneic islets in an experimental diabetic mouse model, and characterized the secretome of SphCs by mass spectrometry-based proteomics.SphCs were characterized as multipotent progenitors and their coculture with anti-CD3 stimulated mouse splenocytes decreased CD4+ T cell proliferation with skewed cytokine secretion through an increase in the Th2/Th1 ratio profile. SphCs conditioned media attenuated apoptosis of islets induced by cytokine challenge in vitro and importantly, SphCs administration (i.t.) showed the absence of tumorigenicity in immune-deficient mice. Moreover, SphCs improved glycemic control when cotransplanted with a marginal mass of allogeneic islets in a diabetic mouse model without pharmacological immunosuppression. SphCs’ protein secretome differed from its paired skin fibroblast-like counterpart in containing 70% of up and downregulated proteins and biological processes that overall positively influence islets such as cytoprotection, cellular stress, metabolism, and survival. In summary, SphCs improve transplanted allogeneic islet performance in an experimental T1D model, without pharmacological immunosuppression. Future research is warranted to identify SphCs-secreted factors responsible for islets’ endurance.