Enhancing human islet xenotransplant survival and function in diabetic immunocompetent mice through LRH-1/NR5A2 pharmacological activation

Front Immunol. 2024 Sep 27:15:1470881. doi: 10.3389/fimmu.2024.1470881. eCollection 2024.

Abstract

The intricate etiology of type 1 diabetes mellitus (T1D), characterized by harmful interactions between the immune system and insulin-producing beta cells, has hindered the development of effective therapies including human islet transplantation, which requires strong immunosuppressants that impair beta cell survival and function. As such alternative immunomodulating therapies are required for successful transplantation. The discovery that pharmacological activation of the nuclear receptor LRH-1/NR5A2 can reverse hyperglycemia in mouse models of T1D by altering, and not suppressing the autoimmune attack, prompted us to investigate whether LRH-1/NR5A2 activation could improve human islet function/survival after xenotransplantation in immunocompetent mice. Human islets were transplanted under the kidney capsule of streptozotocin (STZ)-induced diabetic mice, and treatment with BL001 (LRH-1/NR5A2 agonist) or vehicle was administered one week post-transplant. Our study, encompassing 3 independent experiments with 3 different islet donors, revealed that mice treated for 8 weeks with BL001 exhibited lower blood glucose levels correlating with improved mouse survival rates as compared to vehicle-treated controls. Human C-peptide was detectable in BL001-treated mice at both 4 and 8 weeks indicating functional islet beta cells. Accordingly, in mice treated with BL001 for 8 weeks, the beta cell mass was preserved, while a significant decrease in alpha cells was observed compared to mice treated with BL001 for only 4 weeks. In contrast, vehicle-treated mice exhibited a reduction in insulin-expressing cells at 8 weeks compared to those at 4 weeks. These results suggest that BL001 significantly enhances the survival, engraftment, and functionality of human islets in a STZ-induced diabetic mouse model.

Keywords: LRH-1; NR5A2; human islet; nuclear receptor; pharmacological treatment; type 1 diabetes; xenotranplantation.

MeSH terms

  • Animals
  • Blood Glucose / metabolism
  • Diabetes Mellitus, Experimental* / immunology
  • Diabetes Mellitus, Experimental* / therapy
  • Diabetes Mellitus, Type 1* / immunology
  • Graft Survival* / drug effects
  • Humans
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / metabolism
  • Islets of Langerhans / drug effects
  • Islets of Langerhans / immunology
  • Islets of Langerhans / metabolism
  • Islets of Langerhans Transplantation*
  • Male
  • Mice
  • Receptors, Cytoplasmic and Nuclear* / agonists
  • Receptors, Cytoplasmic and Nuclear* / metabolism
  • Transplantation, Heterologous*

Substances

  • Receptors, Cytoplasmic and Nuclear
  • NR5A2 protein, human
  • Blood Glucose

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. The authors are supported by grants from the Consejería de Salud y Consumo, Fundación Pública Andaluza Progreso y Salud, Junta de Andalucía (PI-0727-2010 and PI-0001-2020 to BRG), the Consejería de Economía, Innovación y Ciencia (P10.CTS.6359 to BRG), the Ministerio de Ciencia E Innovación (BFU2017-83588-P, PID2021-123083NB-I00 financed by MCIN/AEI/10.13039/501100011033 and by FEDER, UE to BRG), The DiabetesCERO Foundation (BRG), the Spanish Diabetes Society and the Juvenile Diabetes Research Foundation (17-2013-372, 2-SRA-2019-837-S-B, 3-SRA-2023-1307-S-B to BRG).