Tissue engineering 2.0: guiding self-organization during pluripotent stem cell differentiation

Abstract

Human pluripotent stem cell (hPSC) differentiation aims to mimic development using growth factors or small molecules in a time-dependent and dose-dependent manner. However, the cell types produced using this approach are predominantly fetal-like in phenotype and function, limiting their use in regenerative medicine. This is particularly true in current efforts to produce pancreatic beta cells, wherein robust pancreatic progenitor maturation can only be accomplished upon transplantation into mice. Recent studies have suggested that hPSC-derived cells are capable of self-organizing in vitro, revealing a new paradigm for creating mature cells and tissues. Tissue engineering strategies that provide subtle and dynamic signals to developmentally naïve cells may be applied to mimic in vitro the self-organization aspects of pancreatic development.

Figure 1

In vivo and in vitro beta cell development and additional cues for incorporation. a) In vivo development is characterized by pancreatic endoderm formation during interaction with the dorsal aorta, followed by branching morphogenesis and delamination/migration of endocrine progenitors. b) In vitro beta cell development currently follows a soluble-factor protocol in 2D. c) Potential additions to the in vitro differentiation of beta cells. Adapted from [91,92].

Figure 2

Self-organization in vitro. a) Pluripotent stem cell aggregates self-organize into optic cup-like (top) or anterior pituitary-like tissues (bottom). b) hPSC derived intestinal tissue buds off a monolayer of posterior endoderm-like cells and matures into an lumen-containing organoid containing all major intestinal cell types in the proper architecture. c) Pdx1-expressing pancreatic progenitors branch and differentiate when embedded in Matrigel. LEN = laminin, entactin, Nodal signaling. Adapted from [88], [89].