Regenerative medicine of pancreatic islets

The pancreas became one of the first objects of regenerative medicine, since other possibilities of dealing with the pancreatic endocrine insufficiency were clearly exhausted. The number of people living with diabetes mellitus is currently approaching half a billion, hence the crucial relevance of new methods to stimulate regeneration of the insulin-secreting beta-cells of the islets of Langerhans. Natural restrictions on the islet regeneration are very tight; nevertheless, the islets are capable of physiological regenerationvia beta-cell self-replication, direct differentiation of multipotent progenitor cells and spontaneous alpha- to beta- or delta- to beta-cell conversion (trans-differentiation). The existing preclinical models of beta-cell dysfunction or ablation (induced surgically, chemically or genetically) have significantly expanded our understanding of reparative regeneration of the islets and possible ways of its stimulation. The ultimate goal, sufficient level of functional activity of beta-cells or their substitutes can be achieved by two prospective broad strategies: beta-cell replacement and beta-cell regeneration. The "regeneration" strategy aims to maintain a preserved population of beta-cells throughin situexposure to biologically active substances that improve beta-cell survival, replication and insulin secretion, or to evoke the intrinsic adaptive mechanisms triggering the spontaneous non-beta- to beta-cell conversion. The "replacement" strategy implies transplantation of beta-cells (as non-disintegrated pancreatic material or isolated donor islets) or beta-like cells obtainedex vivofrom progenitors or mature somatic cells (for example, hepatocytes or alpha-cells) under the action of small-molecule inducers or by genetic modification. We believe that the huge volume of experimental and clinical studies will finally allow a safe and effective solution to a seemingly simple goal-restoration of the functionally active beta-cells, the innermost hope of millions of people globally.