fat-covered-islet-transplantation-using-epididymal-white-adipose

Fat-Covered Islet Transplantation Using Epididymal White Adipose Tissue

Islet transplantation is a cellular replacement therapy for severe diabetes mellitus. The intraperitoneal cavity is typically the transplant site for this ...

Fukuoka University

Fukuoka University Hospital

This review demonstrates the unique potential of the spleen as an optimal site for islet transplantation and as a source of mesenchymal stem cells. Islet transplantation is a cellular replacement therapy used to treat severe diabetes mellitus; however, its clinical outcome is currently unsatisfactory. Selection of the most appropriate transplantation site is a major factor affecting the clinical success of this therapy. The spleen has long been studied as a candidate site for islet transplantation. Its advantages include physiological insulin drainage and regulation of immunity, and it has recently also been shown to contribute to the regeneration of transplanted islets. However, the efficacy of transplantation in the spleen is lower than that of intraportal transplantation, which is the current representative method of clinical islet transplantation. Safer and more effective methods of islet transplantation need to be established to allow the spleen to be used for clinical transplantation. The spleen is also of interest as a mesenchymal stem cell reservoir. Splenic mesenchymal stem cells contribute to the repair of damaged tissue, and their infusion may thus be a promising therapy for autoimmune diseases, including type 1 diabetes mellitus and Sjogren&rsquo;s syndrome.

The Spleen as an Optimal Site for Islet Transplantation and a Source of Mesenchymal Stem Cells.

The Frey procedure is an effective surgery for chronic pancreatitis (CP) patients who have pancreatic head lesions with dilation of the main pancreatic duct. However, pancreatic tail lesions can cause relapsing pancreatitis after the procedure. Therefore, additional distal pancreatectomy (DP) might complement the therapeutic effect of the Frey procedure in controlling inflammation of the pancreatic tail. The Frey procedure with DP (Frey + DP) is indicated for inflammatory lesions in the pancreatic head and tail. In this study, we assessed the usefulness of Frey + DP using the retrospective clinical data of our cases.

Combination of longitudinal pancreaticojejunostomy with coring-out of the pancreatic head (Frey procedure) and distal pancreatectomy for chronic pancreatitis.

Type 1 diabetes mellitus (T1DM) is caused by the autoimmune targeting of pancreatic β-cells, and, in the advanced stage, severe hypoinsulinemia due to islet destruction. In patients with T1DM, continuous exogenous insulin therapy cannot be avoided. However, an insufficient dose of insulin easily induces extreme hyperglycemia or diabetic ketoacidosis, and intensive insulin therapy may cause hypoglycemic symptoms including hypoglycemic shock. While these insulin therapies are efficacious in most patients, some additional therapies are warranted to support the control of blood glucose levels and reduce the risk of hypoglycemia in patients who respond poorly despite receiving appropriate treatment. There has been a recent gain in the popularity of cellular therapies using mesenchymal stromal cells (MSCs) in various clinical fields, owing to their multipotentiality, capacity for self-renewal, and regenerative and immunomodulatory potential. In particular, adipose tissue-derived MSCs (ADMSCs) have become a focus in the clinical setting due to the abundance and easy isolation of these cells. In this review, we outline the possible therapeutic benefits of ADMSC for the treatment of T1DM.

Regenerative and Transplantation Medicine: Cellular Therapy Using Adipose Tissue-Derived Mesenchymal Stromal Cells for Type 1 Diabetes Mellitus.

Pancreatic endocrine cells expressing the ghrelin gene and producing the ghrelin hormone were first identified in 2002. These cells, named ε cells, were recognized as the fifth type of endocrine cells. Differentiation of ε cells is induced by various transcription factors, including Nk2 homeobox 2, paired box proteins Pax-4 and Pax6, and the aristaless-related homeobox. Ghrelin is generally considered to be a "hunger hormone" that stimulates the appetite and is produced mainly by the stomach. Although the population of ε cells is small in adults, they play important roles in regulating other endocrine cells, especially β cells, by releasing ghrelin. However, the roles of ghrelin in β cells are complex. Ghrelin contributes to increased blood glucose levels by suppressing insulin release from β cells and is also involved in the growth and proliferation of β cells and the prevention of β cell apoptosis. Despite increasing evidence and clarification of the mechanisms of ε cells over the last 20 years, many questions remain to be answered. In this review, we present the current evidence for the participation of ε cells in differentiation and clarify their characteristics by focusing on the roles of ghrelin.

Development and Characteristics of Pancreatic Epsilon Cells.

Chemoimmunotherapy is a promising treatment for various malignant diseases. In this study, we examined whether first-line chemoimmunotherapy using adoptive immune-cell therapy was effective for metastatic colorectal cancer (mCRC).

Changes in Immunological Status in Patients With Metastatic Colorectal Cancer Treated With First-line Chemoimmunotherapy.

Early rejection is a critical issue to be overcome to achieve successful islet transplantation. NLRP3 inflammasome is a protein complex that mediates the maturation of pro-interleukin (IL)-1β and pro-IL-18 to IL-1β and IL-18, respectively, which induce cellular death. Here, we investigated the impact of NLRP3 inflammasome and the effect of its inhibition by MCC950 in a rodent model of islet transplantation. We assessed the therapeutic effects of MCC950, a specific inhibitor of NLRP3 inflammasome, on gene expression, islet survival ratio and viability, and islet transplantation in mice. NLRP3 inflammasome-related gene (Nlrp3 and Il1b) expression was upregulated in islets stimulated with proinflammatory cytokines and suppressed when incubated with MCC950. Survival ratio and viability of incubated islets were reduced by cytokine stimulation and improved by MCC950. Regarding islet transplantation, the number of apoptotic cells in transplanted islets was reduced by MCC950. Furthermore, the expression of IL-1β in transplanted islets, migration of macrophages around islets, and fluctuation of blood glucose levels were suppressed by MCC950. Our study revealed that NLRP3 inflammasome worsened the therapeutic outcomes of islet transplantation and that MCC950 administration improved glycaemic control in syngeneic mice that underwent islet transplantation by inhibiting inflammation, which suppressed islet death.

Inhibition of NLRP3 inflammasome by MCC950 improves the metabolic outcome of islet transplantation by suppressing IL-1β and islet cellular death.

White adipose tissue (WAT) is a candidate transplantation site for islets. However, the mechanism of islet engraftment in WAT has not been fully investigated. In this study, we attempted to clarify the therapeutic effect and mechanism of islet transplantation into visceral WAT.

Mechanism of Transplanted Islet Engraftment in Visceral White Adipose Tissue.

The clinical utility of stem cell therapy for peripheral artery disease has not been fully discussed, and one obstacle is limited donor supplies. In this study, we attempted to rescue mouse ischemic hind limb by xenotransplantation of neonatal porcine bone marrow-derived mesenchymal stem cells (npBM-MSCs).

Xenotransplantation of neonatal porcine bone marrow-derived mesenchymal stem cells improves murine hind limb ischemia through lymphangiogenesis and angiogenesis.

Article	Year
The Spleen as an Optimal Site for Islet Transplantation and a Source of Mesenchymal Stem Cells. International journal of molecular sciences\| PubMed ID: 29735923	2018
Combination of longitudinal pancreaticojejunostomy with coring-out of the pancreatic head (Frey procedure) and distal pancreatectomy for chronic pancreatitis. Surgery today\| PubMed ID: 30259156	2019
Regenerative and Transplantation Medicine: Cellular Therapy Using Adipose Tissue-Derived Mesenchymal Stromal Cells for Type 1 Diabetes Mellitus. Journal of clinical medicine\| PubMed ID: 30781427	2019
Development and Characteristics of Pancreatic Epsilon Cells. International journal of molecular sciences\| PubMed ID: 31014006	2019
Changes in Immunological Status in Patients With Metastatic Colorectal Cancer Treated With First-line Chemoimmunotherapy. Anticancer research\| PubMed ID: 32727803	2020
Inhibition of NLRP3 inflammasome by MCC950 improves the metabolic outcome of islet transplantation by suppressing IL-1β and islet cellular death. Scientific reports\| PubMed ID: 33087823	2020
Mechanism of Transplanted Islet Engraftment in Visceral White Adipose Tissue. Transplantation\| PubMed ID: 33215898	2020
Xenotransplantation of neonatal porcine bone marrow-derived mesenchymal stem cells improves murine hind limb ischemia through lymphangiogenesis and angiogenesis. Xenotransplantation\| PubMed ID: 33960029	2021

Naoaki Sakata

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