Generating β cells from stem cells-the story so far

Abstract

Despite intensive research, a treatment for diabetic patients that completely restores normoglycemia for an indefinite period of time remains elusive. Although islet transplantation temporarily confers normoglycemia to patients, the lack of a renewable source of insulin-producing β cells hampers the use of this treatment option. Although significant hurdles remain, recent advances in stem cell biology indicate that generation of fully matured β cells from uncommitted progenitor cells, including human embryonic stem cells and induced pluripotent stem cells derived from somatic cell populations, is becoming an achievable goal.

Figure 1.

Signaling pathways controlling embryonic pancreas development and hESC-β-cell differentiation. (A) Depiction of signaling pathways that guide differentiation of pancreatic cells from inner cell mass (ICM) cells present in the blastocyst stage. Pathways with positive activities at the indicated stages are shown in green. Hedgehog signaling (Hh) impairs pancreas organogenesis and is depicted in red during the transition from primitive gut to posterior foregut. (B) Signaling factors used to guide the differentiation from hESCs to pancreatic β cells. Note that while β cells form on transplantation of pancreatic endoderm cells into recipient mice, the factors required to promote full differentiation into functional β cells in cell culture have not been identified. (C) Immunofluorescence images showing the expression of markers for the stages shown in B. The efficiency of cell differentiation is reduced toward the later stages of the protocol with not all cells coexpressing NKX6.1 and PDX1. Also note that the majority of insulin-producing cells derived under cell culture conditions also express glucagon, indicating that they are not fully matured (modified from Guo and Hebrok 2009; reproduced, with permission, from the author).

Figure 2.

Plasticity of adult pancreatic epithelial cells. (A) The adult mammalian pancreas harbors a number of specialized cell types, including the enzyme-producing acinar cells, centroacinar and connecting duct cells, as well as endocrine cells located within the islets of Langerhans. (B) On injury, e.g., duct ligation, duct or duct-associated cells can reactivate Ngn3 and transdifferentiate toward a β-cell state. (C) Acinar cells are reprogrammed toward a β-cell fate on ectopic expression of a set of three transcription factors, Pdx1, Ngn3, and MafA. (Modified from Puri and Hebrok 2010; reproduced, with permission, from the author.)