Umbilical cord mesenchymal stromal cells transplantation delays the onset of hyperglycemia in the RIP-B7.1 mouse model of experimental autoimmune diabetes through multiple immunosuppressive and anti-inflammatory responses

Abstract

Type 1 diabetes mellitus (T1DM) is an autoimmune disorder specifically targeting pancreatic islet beta cells. Despite many efforts focused on identifying new therapies able to counteract this autoimmune attack and/or stimulate beta cells regeneration, TD1M remains without effective clinical treatments providing no clear advantages over the conventional treatment with insulin. We previously postulated that both the inflammatory and immune responses and beta cell survival/regeneration must be simultaneously targeted to blunt the progression of disease. Umbilical cord-derived mesenchymal stromal cells (UC-MSC) exhibit anti-inflammatory, trophic, immunomodulatory and regenerative properties and have shown some beneficial yet controversial effects in clinical trials for T1DM. In order to clarify conflicting results, we herein dissected the cellular and molecular events derived from UC-MSC intraperitoneal administration (i.p.) in the RIP-B7.1 mouse model of experimental autoimmune diabetes. Intraperitoneal (i.p.) transplantation of heterologous mouse UC-MSC delayed the onset of diabetes in RIP-B7.1 mice. Importantly, UC-MSC i. p. transplantation led to a strong peritoneal recruitment of myeloid-derived suppressor cells (MDSC) followed by multiple T-, B- and myeloid cells immunosuppressive responses in peritoneal fluid cells, spleen, pancreatic lymph nodes and the pancreas, which displayed significantly reduced insulitis and pancreatic infiltration of T and B Cells and pro-inflammatory macrophages. Altogether, these results suggest that UC-MSC i. p. transplantation can block or delay the development of hyperglycemia through suppression of inflammation and the immune attack.

Efficacy of mesenchymal stromal cells in the treatment of type 1 diabetes: a systematic review

“…MSCs could delay the onset of experimental autoimmune diabetes (EAD) in immunized RIP-B7.1 mice through anti-inflammatory and immunomodulatory responses (Lachaud et al 2023 ). In clinical, the United States Food and Drug Administration (FDA) approved Tzield (teplizumab-mzwv), an anti-CD3-directed antibody, as the first immunomodulatory treatment to delay the onset of stage 3 T1D in adults and pediatric patients aged 8 years and older with stage 2 T1D (Evans-Molina and Oram 2023 ).…”

Multiple treatments with human embryonic stem cell-derived mesenchymal progenitor cells preserved the fertility and ovarian function of perimenopausal mice undergoing natural aging

“…MDSCs have been found in many other abnormal conditions, such as autoimmunity, infection, diabetes and cardiac aging [26][27][28][29][30]. Several studies have reported that increased MDSC numbers contribute to the pathogenesis of these immune-aging-mediated diseases, and the transplantation of mesenchymal progenitor cells (MPCs) obtained from various sources has been shown to have beneficial effects in blocking or delaying disease progression through the suppression of inflammation and immune attack [31][32][33]. Immunosuppression derived from these two cell types (MSCs/MPCs and MDSCs) seems to have an opposite function in fibrosis, but the mechanism has not been well studied.…”

Multiple treatments with human embryonic stem cell-derived mesenchymal progenitor cells preserved fertility and ovarian function of perimenopausal mice undergoing natural aging.

“…These cells suppress innate and adaptive immunity and promote aging-related brosis and have been found in many other abnormal conditions, such as autoimmunity, infection, diabetes and cardiac aging (13,14). Several studies have reported that increased MDSC numbers contribute to the development of these disorders, and the transplantation of mesenchymal progenitor cells (MPCs) obtained from various sources has bene cial effects on blocking or delaying the progression of diseases through suppression of in ammation and immune attack (15)(16)(17).…”