Regenerative Medicine and Diabetes: Targeting the Extracellular Matrix Beyond the Stem Cell Approach and Encapsulation Technology

Abstract

According to the Juvenile Diabetes Research Foundation (JDRF), almost 1. 25 million people in the United States (US) have type 1 diabetes, which makes them dependent on insulin injections. Nationwide, type 2 diabetes rates have nearly doubled in the past 20 years resulting in more than 29 million American adults with diabetes and another 86 million in a pre-diabetic state. The International Diabetes Ferderation (IDF) has estimated that there will be almost 650 million adult diabetic patients worldwide at the end of the next 20 years (excluding patients over the age of 80). At this time, pancreas transplantation is the only available cure for selected patients, but it is offered only to a small percentage of them due to organ shortage and the risks linked to immunosuppressive regimes. Currently, exogenous insulin therapy is still considered to be the gold standard when managing diabetes, though stem cell biology is recognized as one of the most promising strategies for restoring endocrine pancreatic function. However, many issues remain to be solved, and there are currently no recognized treatments for diabetes based on stem cells. In addition to stem cell resesarch, several β-cell substitutive therapies have been explored in the recent era, including the use of acellular extracellular matrix scaffolding as a template for cellular seeding, thus providing an empty template to be repopulated with β-cells. Although this bioengineering approach still has to overcome important hurdles in regards to clinical application (including the origin of insulin producing cells as well as immune-related limitations), it could theoretically provide an inexhaustible source of bio-engineered pancreases.

Shaping Pancreatic β-Cell Differentiation and Functioning: The Influence of Mechanotransduction

“…Although we still do not know in detail the biology of their mechanotransduction, the ability of β-cells to respond to biophysical cues has already been largely exploited by tissue engineers to create in vitro cell growing supports or scaffolds for islet transplantation that better foster β-cell survival and function (excellent reviews on islets scaffolds are present in the literature, some examples are [54,62,63,170,171]).…”

“…3D biomimetic scaffolds will be necessary to reproduce the complex geometry of the native niche which fosters the self-assembly of cells in clusters and the establishment of cell-cell interactions, which are essential to drive cell polarity and preserve β-cell function [172][173][174]. Nanostructured materials, possibly functionalised with relevant biomolecules, should coat the scaffold to reproduce the spatial exposition of cells to chemical and mechanical cues, which drive the decision to self-renew or differentiate [54,113,175,176]. Integration of microfluidics into the culture device will allow the reproduction of hemodynamic shear stress and the mimicking of the dynamic temporal and spatial distribution of soluble signaling factors, which is difficult to achieve with traditional cell static cultures [171][172][173][174].…”

“…An incomplete capsule, made of fibroblasts and collagen fibers, and closely associated with matrix proteins of the peri-insular basement membrane (BM), separates the islets from the exocrine tissue [45,52]. Within the islet, human endocrine cells are surrounded by two different types of BM, composed of different collagen, laminins, and fibronectin isoforms [54]: the vascular BM, which is directly associated with the endothelial cells and acts as a reservoir of growth factors [55], and the peri-islet BM, which invaginates into islets following the pervading microvasculature and can directly exchange signals with the endocrine cells [31].…”

“…Since standard culture supports (plastic or glass) have a stiffness in the range of GPa [58] (much higher than that observed in the islet niche) human isolated islets of Langerhans survive poorly and lose their inter-cellular organization in in vitro cultures. Softer matrices such as hydrogels, chitosan, polylactic-coglycolid (PLGA), and poly-L-lactide (PLA) acids, which better mimic the physiological conditions, instead preserve the islet clustering organization and the β-cell function (reviewed in [54,62,63]). Indeed, when human islets are cultured on soft substrates cell-cell interactions dominate, favoring cell coalescence and preserving the cluster-like organization of the native islet; in contrast, when they are cultured on stiff supports, the extracellular-cell interactions are much stronger, causing cell scattering and the loss of islet-like structure [64].…”

“…A 3D environment is crucial for determining the spatial arrangement of pancreatic endocrine cells, which can modulate insulin secretion [46,72,73]. Indeed, in a 3D environment, β-cells are tightly interconnected among each other, promoting an extremely rapid flow of signals, which ensures efficient and coordinated insulin secretion [54,74].…”