Pancreas regeneration

Abstract

The pancreas is made from two distinct components: the exocrine pancreas, a reservoir of digestive enzymes, and the endocrine islets, the source of the vital metabolic hormone insulin. Human islets possess limited regenerative ability; loss of islet β-cells in diseases such as type 1 diabetes requires therapeutic intervention. The leading strategy for restoration of β-cell mass is through the generation and transplantation of new β-cells derived from human pluripotent stem cells. Other approaches include stimulating endogenous β-cell proliferation, reprogramming non-β-cells to β-like cells, and harvesting islets from genetically engineered animals. Together these approaches form a rich pipeline of therapeutic development for pancreatic regeneration.

Fig. 1 |. Natural regenerative responses of the endocrine pancreas

The adult endocrine pancreas (islets of Langerhans) is made up of four major endocrine cell types with each secreting a major hormone: insulin (β-cells), glucagon (α-cells), somatostatin (δ-cells), and pancreatic polypeptide (PP cells). Animal studies have shown that β-cell replication is a major mode of regeneration and repair in homeostasis, injury, pregnancy, obesity, and insulin resistance. Conversion of islet δ- and α-cells into β-cells has been reported after extreme β-cell loss using specific ablation methods in animal models. Significant regeneration of the endocrine pancreas is largely restricted to young children and young animals. Adult animals and adult humans have little, if any, ability to regenerate the endocrine pancreas.

Fig. 2 |. Regeneration of the exocrine pancreas

The exocrine pancreas is composed of acinar cells that synthesize and secrete digestive enzymes, ductal cells that funnel the enzymes into the small intestine, and central acinar cells. The exocrine pancreas can regenerate spontaneously and robustly in both animals and humans. Inflammatory injuries to the exocrine pancreas such as acute pancreatitis lead to acinar cell death and acinar dedifferentiation, which is characterized by degranulation and morphological transformation into duct-like cells in a process termed acinar-to-ductal metaplasia. Once inflammation subsides, acinar cells can rapidly regenerate by self-replication and possible redifferentiation of the metaplastic duct-like cells back into a normal and functional acinar state.

Fig. 3 |. Therapeutic strategies for regeneration and repair of the endocrine pancreas.

At present, the most advanced technology for making functional human insulin-secreting cells, and the only one to enter clinical trials, is derivation from human pluripotent stem cells. Other strategies include stimulating proliferation of residual β-cells in vivo, reprogramming of non-β-cells to β-like cells in vivo or in vitro, harvesting islets from genetically engineered pigs, and possibly growing entire human pancreata in animals followed by removal of human islets for transplantation.