Organoids in Diabetes Research

Pratiksha Roham

Organoids are 3D in vitro cell culture systems that are generated by differentiating embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs) or adult tissue stem cells (ASCs)1. During differentiation, in addition to culture media and growth factors, stem cells require a scaffold/matrix that contains the basement membrane elements, e.g., Matrigel, for their growth2. These organoids precisely recapitulate the development of the organs and are able to mimic the in vivo tissue architecture and function. Thus, organoids are more reliable than traditional 2D monolayer cultures and animal models due to their high physiological resemblance to human beings1.

Till date, organoids of nearly every organ in the human body have been made and offer a valuable tool in biomedical research to study the normal development and disease biology of inaccessible organs whose studies are lacking due to authentic model systems such as Diabetes Mellitus (DM). Investigations of the pancreas at cellular levels in biomedical research are difficult due to the scarcity of human organ donors 3. Furthermore, the pancreatic β cells of the most commonly used rodent models differ from humans with respect to their composition, arrangement, proliferative capacity, insulin secretion, glucose uptake and gene expression profile4. Distinct types of rodent and human cell lines have also been used in vitro; however, they suffer from the lack of 3-D organization, absence of paracrine communications, altered stress responses, etc. Taken together, these raise a demand for organoids in DM research2.

The main goal of the treatment of DM either Type 1 DM or Type 2 DM is to atone the pancreatic β-cells. Current therapeutics for the management of DM only reduce the symptoms and do not reverse it5. In severe cases, the transplantation of human pancreatic islets is a viable therapeutic alternative that is severely limited by the shortage of cadaveric human islets. Along these lines, stem cell-derived Pancreatic Organoids (PO) present an excellent remedy for large-scale generation of insulin-producing cells which might be used in future for islet replacement therapy in DM3.

Over the past decade, POs have shown promising results in diabetic animal models. For example, POs derived from stem cells have been shown to restore normoglycemia when transplanted into diabetic animal models6. In a recent study, Yoshihara et al. by using CRISPR–Cas9 genome editing technology, have created human islet-like organoids overexpressing PD-L1, which after transplantation in immunocompetent mice were able to maintain normal glucose up to 50 days. Additionally, they have discovered that the non-canonical WNT4 signaling pathway is essential for ex vivo glucose-stimulated insulin secretion7.

There are a few challenges with the use of organoids. They are heterogeneous with respect to their morphology. Additionally, the absence of blood circulation limits their communication with other endocrine cells. Lastly, their finite lifespan limits their potential application in clinical research2. Despite these challenges, POs show promising potential to study islet development, pathophysiology of DM and other pancreas-related disorders, drug testing, and regenerative medicine, to name a few, and this technology needs to be developed further in the future3