SPARC-modified mesenchymal stem cells promote recovery of β-cells and insulin secretion by calcium ion homeostasis

Abstract

Introduction Type 1 diabetes (T1D) results from the destruction of pancreatic β-cells, leading to insulin deficiency. As insulin therapy does not affect disease progression, advancements in immune regulation therapies have emerged, including the reconstitution of the insulin secretory system. Cysteine-rich acidic secretory protein (SPARC) is an extracellular matrix glycoprotein that regulates cell adhesion, facilitating cell migration, and mediating interactions between cells and their extracellular matrix. SPARC is overexpressed during tissue repair and is involved in β-cells survival. However, the potential of SPARC-modified mesenchymal stem cells (MSCs) to improve insulin secretion has not been thoroughly investigated. This study investigated the therapeutic effects of SPARC-MSCs in vivo and in vitro and assessed whether SPARC enhances survival and insulin secretion after β-cells injury. Methods In vivo, we established T1D models in mice and canine using SPARC-MSCs for cell transplantation. In vitro, MIN6 cells were damaged with STZ, and SPARC-MSC supernatant was co-cultured with MIN6 for various assays. Results Our study demonstrated that SPARC enhanced the regenerative capacity and migratory efficiency of MSCs after H2O2 injury and improved their morphology. In STZ-induced canine and mice diabetes models, SPARC-MSCs therapy significantly reduced hyperglycemia, improved oral glucose tolerance test (OGTT), and reversed weight loss in canine. Biochemical analyses showed improved liver function, and histological examination revealed restored islet area was significantly restored. Transcriptome and proteome sequencing indicated significant enrichment in calcium binding and cell migration pathways. Co-culturing SPARC-MSC supernatant with MIN6 cells after STZ injury restored their regenerative ability, enhancing insulin secretion and ATP content under high glucose stimulation. SPARC treatment also significantly increased intracellular Ca2+ levels in MIN6 cells. Conclusion SPARC significantly promotes cell regeneration and stimulates insulin secretion by increasing intracellular ATP and Ca2+ influx. In diabetic canine and mice models, it alleviated hyperglycemia, improved glucose tolerance, and enhanced pancreatic islet area and insulin secretion.

1. Introduction

Diabetes mellitus is a metabolic disorder characterized by hyperglycemia, which arises from defects in insulin secretion, impaired insulin function or both. The overt symptoms of hyperglycemia include polyuria, polyphagia, and weight loss, while long-term complications encompass retinopathy, nephropathy, foot ulcers, and neuropathy [1]. Type 1 diabetes mellitus (T1DM) is an autoimmune disease that predominantly affects children and adolescents, leading to the destruction of pancreatic beta cells and resulting in an inability to produce insulin [2, 3]. However, treatment with insulin alone does not ameliorate the disease process, hyperglycemia, immune dysregulation, and inflammatory responses further damage pancreatic β-cells and activate various stress pathways, including oxidative stress, endoplasmic reticulum (ER) stress, mitochondrial dysfunction, apoptosis, and necrosis [4–6]. Consequently, therapeutic approaches that emphasize immunomodulation, such as restoring pancreatic β-cells function and re-establishing the insulin secretion system, may prove effective in preventing and reversing the progression of diabetes [7].

Mesenchymal stem cells (MSCs) exhibit several critical functions, including immunomodulation, the secretion of biomolecules such as growth factors and cytokines, evasion of innate immunity, antioxidant and anti-apoptosis [8]. Numerous studies have demonstrated the role of MSCs in diabetes, demonstrating their capacity to prevent β-cells destruction, safeguard the affected β-cells populations, and promote endogenous β-cells regeneration [9]. For instance, Bassi's team discovered that the transplantation of allogeneic MSCs into diabetic non-obese diabetic (NOD) mice significantly alleviates the symptoms of autoimmune diabetes, mitigates the Th1 immune response, and consequently supports the maintenance of functional β-cells [10]. In the context of islet transplantation for diabetes, MSCs have shown promise in improving graft survival and function.