Potential of mesenchymal stromal cells for improving islet transplantation outcomes

Highlights

• Mesenchymal stromal cells (MSCs)/their secretome improve islet revascularisation.

• MSC-derived secretory products reduce pathogenic host T cell responses.

• MSCs and their secretory products improve donor islet cell functional survival.

• Harnessing the MSC secretome has potential to improve transplantation efficiency.

Allogeneic islet transplantation as a therapy for Type 1 Diabetes (T1D) is restricted by the limited availability of donor islets, loss of functional islets during pre-transplantation culture in vitro and further extensive loss during the immediate post-transplantation period when islet function and survival is compromised by the hypoxic, inflammatory host environment. In the longer term pathogenic T cell responses drive autoimmunity and chronic allograft rejection. Experimental studies have demonstrated that mesenchymal stromal cells (MSCs) have significant potential to improve the outcomes of clinical islet transplantation. This review explores the potential for MSCs and their ‘secretome’ to influence donor islet cell function and survival, as well as the host niche. We discuss the possibility of harnessing the therapeutic benefits of MSCs in a cell-free strategy to offer a well-defined, cell-free approach to improve the outcomes of clinical islet transplantation.

Introduction

Type 1 diabetes mellitus (T1DM) is an autoimmune disorder in which insulin-secreting pancreatic β-cells are selectively destroyed. The consequent insulin deficiency results in dysregulation of metabolic control with hyperglycemia, hyperlipidemia and ketosis leading to a fatal outcome. People with T1DM have been treated by the administration of exogenous insulin since the first successful isolation of biologically active insulin in 1921. However, insulin therapy treats the symptoms of T1DM rather than offering a cure, and it has become clear over the decades that exogenous insulin often fails to maintain tight glycaemic control, and that the subsequent hyperglycemic excursions are responsible for the progressive development of a range of devastating side effects known as ‘secondary complications’ [1]. Replacement of the damaged β-cells offers the potential for restoring physiological glycemic control and thus avoiding the development of secondary complications. However, pancreas transplantation is surgically invasive and associated with significant co-morbidity [2]. An alternative is to transplant only the endocrine component of the pancreas — the islets of Langerhans-which comprise 2–3% of the total pancreas, and which can be isolated from the intact pancreas by collagenase digestion. Islet transplantation first became a viable therapeutic option with the publication of the landmark ‘Edmonton Protocol’ in 2000 [3], which stimulated human islet transplantation programmes around the world, such that over 1500 people with T1DM have now received islet grafts in 40 centres globally (https://citregistry.org/content/citr-9th-annual-report). Islet transplantation is a safe procedure with little or no co-morbidity [4^••] and the clinical outcomes have improved year-on-year [4^••,5]. Recent figures suggest that approximately 50% of graft recipients remain insulin independent at 5 years and more, making islet transplantation as clinically effective as whole pancreas transplantation [6]. However, the wider adoption of islet transplantation as a therapeutic option is currently limited by a shortage of tissue donors and much effort is currently directed at generating functionally-competent substitutes for primary human islets to expand the available pool of graft material.

Islet β-cells are metabolically active and use glucose metabolism and ATP generation to maintain appropriate rates of insulin secretion for the prevailing extracellular glucose concentrations. Islets deteriorate rapidly during and after their isolation [7], losing 20–50% of the β-cell mass within 24 hours of culture in vitro. The loss of β-cell function continues during the immediate post-transplantation period (24–72 hours) when up to 70% of the graft function is lost because of deleterious responses of the transplanted β-cells to the hypoxic, inflammatory, immunogenic host environment [8]. Strategies which improve the functional survival of islets both before and after transplantation will improve the outcome of individual grafts and enable the limited pool of donor islets to treat many more people with T1DM. One emerging strategy is the use of mesenchymal stromal cells (MSCs) to take advantage of their anti-inflammatory, immunoregulatory, angiogenic and regenerative properties.