Micro-Engineered Models of Development Using Induced Pluripotent Stem Cells

Abstract

During fetal development, embryonic cells are coaxed through a series of lineage choices which lead to the formation of the three germ layers and subsequently to all the cell types that are required to form an adult human body. Landmark cell fate decisions leading to symmetry breaking, establishment of the primitive streak and first tri-lineage differentiation happen after implantation, and therefore have been attributed to be a function of the embryo's spatiotemporal 3D environment. These mechanical and geometric cues induce a cascade of signaling pathways leading to cell differentiation and orientation. Due to the physiological, ethical, and legal limitations of accessing an intact human embryo for functional studies, multiple in-vitro models have been developed to try and recapitulate the key milestones of mammalian embryogenesis using mouse embryos, or mouse and human embryonic stem cells. More recently, the development of induced pluripotent stem cells represents a cell source which is being explored to prepare a developmental model, owing to their genetic and functional similarities to embryonic stem cells. Here we review the use of micro-engineered cell culture materials as platforms to define the physical and geometric contributions during the cell fate defining process and to study the underlying pathways. This information has applications in various biomedical contexts including tissue engineering, stem cell therapy, and organoid cultures for disease modeling.

Home Away From Home: Bioengineering Advancements to Mimic the Developmental and Adult Stem Cell Niche

“…Additionally, early spatial organization, mechanics, epithelial-mesenchymal transition, and geometry influence the developmentally significant cell fate decisions. These include symmetry-breaking and the emergence of the primitive streak and subsequent gastrulation, suggesting that the 3D environment and interacting signaling pathways play an important role in these processes (Gattazzo et al, 2014;Ahmed, 2016;Blin et al, 2018;Xue et al, 2018;Yoney et al, 2018;Britton et al, 2019;Chhabra et al, 2019;Heemskerk et al, 2019;Srivastava and Kilian, 2019). In vivo, the response of embryonic cells to chemical signals from growth factors, morphogens, metabolites, and biomechanical signals including stretch, pressure, and adhesion result in the proper organization of the embryo (Srivastava and Kilian, 2019;Rossant and Tam, 2021).…”

“…These include symmetry-breaking and the emergence of the primitive streak and subsequent gastrulation, suggesting that the 3D environment and interacting signaling pathways play an important role in these processes (Gattazzo et al, 2014;Ahmed, 2016;Blin et al, 2018;Xue et al, 2018;Yoney et al, 2018;Britton et al, 2019;Chhabra et al, 2019;Heemskerk et al, 2019;Srivastava and Kilian, 2019). In vivo, the response of embryonic cells to chemical signals from growth factors, morphogens, metabolites, and biomechanical signals including stretch, pressure, and adhesion result in the proper organization of the embryo (Srivastava and Kilian, 2019;Rossant and Tam, 2021). Various studies have attempted to replicate the gastrulation-like events in vitro with external developmental cues and self-organizing embryonic stem cells, iPSCs, and epiblast-like cells (Warmflash et al, 2014;Deglincerti et al, 2016;Shao et al, 2017).…”

Microengineered systems with iPSC-derived cardiac and hepatic cells to evaluate drug adverse effects

“…When culturing iPSCs for differentiation in microfluidic devices, as exemplified in Figure 1, there is potential to tune the microenvironment to either enhance or replace signaling factors based on cell–cell interactions and co-cultures of cell lineages. 197 The extracellular matrix (ECM) is also a critical aspect of both in vivo and in vitro cell function and biology and can be experimentally defined both in 2D and 3D culture settings, as well as in devices that facilitate differentiation and maturation stages in 3D. The ECM is known to modulate cell signaling and differentiation cues, for example, ECM-integrin signaling has roles both in early-stage differentiation of iPSCs as well as through later stages of cardiomyocyte differentiation and maturation.…”

Human Pluripotent Stem Cell-Derived Micropatterned Ectoderm Allows Cell Sorting of Meso-Endoderm Lineages

“…Thanks to the development of in vitro culture of human pluripotent stem cells (hPSCs), which can differentiate into the three germ layers, and the use of microtechnologies, researchers have begun to create in vitro structures which can capture some features of early human embryo development (Srivastava and Kilian, 2019;Baillie-benson et al, 2020). Micropatterning technology, which enables geometric confinement of hPSCs in vitro, has emerged as a method of choice for studying signaling dynamics and cell-fate patterning in early human gastrulation (Warmflash et al, 2014), reproducing in vitro the critical stages of gastrulation occurring within the first three pcw of development (Warmflash et al, 2014;Baillie-benson et al, 2020;Minn et al, 2020).…”