SCIENCE@home

Material microenvironmental properties couple to induce distinct transcriptional programs in mammalian stem cells

Max C Darnell,Alison O’Neil,Angelo S. Mao,Luo Gu,L. Rubin,D. Mooney

Published 2018 in Proceedings of the National Academy of Sciences of the United States of America

ABSTRACT

Significance Cells have been shown to respond to a host of physical properties of the environments that surround them. However, given that these properties vary considerably across tissues, how these individual properties interact to form unique regulatory environments for cells is largely unknown. This work analyzes the transcriptional responses of cells to unique combinations of microenvironmental material properties to gain broad insights into the coupling among different properties, the magnitude of the transcriptional effects, and the role of cell type. We find significant coupling among these properties, large variation in the magnitude of the transcriptional changes, and qualitative differences in the responses based on cell type, demonstrating the significant context dependence of microenvironmental material sensing. Variations in a multitude of material microenvironmental properties have been observed across tissues in vivo, and these have profound effects on cell phenotype. Phenomenological experiments have suggested that certain of these features of the physical microenvironment, such as stiffness, could sensitize cells to other features; meanwhile, mechanistic studies have detailed a number of biophysical mechanisms for this sensing. However, the broad molecular consequences of these potentially complex and nonlinear interactions bridging from biophysical sensing to phenotype have not been systematically characterized, limiting the overall understanding and rational deployment of these biophysical cues. Here, we explore these interactions by employing a 3D cell culture system that allows for the independent control of culture substrate stiffness, stress relaxation, and adhesion ligand density to systematically explore the transcriptional programs affected by distinct combinations of biophysical parameters using RNA-seq. In mouse mesenchymal stem cells and human cortical neuron progenitors, we find dramatic coupling among these substrate properties, and that the relative contribution of each property to changes in gene expression varies with cell type. Motivated by the bioinformatic analysis, the stiffness of hydrogels encapsulating mouse mesenchymal stem cells was found to regulate the secretion of a wide range of cytokines, and to accordingly influence hematopoietic stem cell differentiation in a Transwell coculture model. These results give insights into how biophysical features are integrated by cells across distinct tissues and offer strategies to synthetic biologists and bioengineers for designing responses to a cell’s biophysical environment.

PUBLICATION RECORD

CITATION MAP

EXTRACTION MAP

CLAIMS

  • No claims are published for this paper.

CONCEPTS

  • No concepts are published for this paper.

REFERENCES

Showing 1-52 of 52 references · Page 1 of 1

CITED BY

Showing 1-100 of 113 citing papers · Page 1 of 2

12
Next