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

Author(s):Show less -

L. Andreone ; A.F. dos Santos ^[2] ; R.A.M. Wailemann ^[3] ; L.F. Terra ^[4] ; V.M. Gomes ^[5] ; J. Macedo da Silva ^[6] ; L. Rosa-Fernandes ^[7] ; M.C. Sogayar ; G. Palmisano ^[9] ; L. Labriola ^[10] ; M.J. Perone

• Document type: Journal article
• Source: Brazilian Journal of Medical and Biological Research; v. 56, 2023-09-22.

Abstract

Islet transplantation represents a therapeutic option for type 1 diabetes (T1D). Long-term viability of transplanted islets requires improvement. Mesenchymal stromal cells (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 of SphCs in improving 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, intratesticular SphCs administration did not show 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 influenced islets such as cytoprotection, cellular stress, metabolism, and survival. In summary, SphCs improved the performance of transplanted allogeneic islets in an experimental T1D model, without pharmacological immunosuppression. Future research is warranted to identify SphCs-secreted factors responsible for islets' endurance. (AU)

• FAPESP's process: 13/07029-4 - Unveiling the role of HSP25/27 in Prolactin-induced cytoprotection in pancreatic beta cells
• Grantee: Leticia Labriola
• Support Opportunities: Regular Research Grants
• FAPESP's process: 12/50680-5 - Photosensitization in life sciences
• Grantee: Mauricio da Silva Baptista
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 13/07937-8 - Redoxome - Redox Processes in Biomedicine
• Grantee: Ohara Augusto
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 12/16785-4 - Unvealing the signaling pathways involved in the cytotoxic effects of photodynamic therapy in human breast cancer cells
• Grantee: Ancély Ferreira dos Santos
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 16/05311-2 - Regenerative medicine aiming at therapy for chronic degenerative diseases (cancer and diabetes)
• Grantee: Mari Cleide Sogayar
• Support Opportunities: Research Projects - Thematic Grants