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

Area of Science:

• Biophysics
• Cell Biology
• Biomaterials Science

Background:

• In vivo material microenvironmental properties significantly impact cell phenotype.
• Physical microenvironment features, such as stiffness, can sensitize cells to other properties.
• The broad molecular consequences of biophysical sensing interactions are not well understood.

Purpose of the Study:

• To systematically explore the transcriptional programs affected by combinations of biophysical parameters.
• To investigate how cells integrate multiple substrate properties: stiffness, stress relaxation, and adhesion ligand density.
• To understand the impact of biophysical cues on cell phenotype and differentiation.

Main Methods:

• Utilized a 3D cell culture system enabling independent control of substrate stiffness, stress relaxation, and adhesion ligand density.
• Employed RNA-sequencing (RNA-seq) to analyze transcriptional programs in response to varying biophysical parameters.
• Used Transwell coculture models to assess the influence of hydrogel stiffness on cytokine secretion and stem cell differentiation.

Main Results:

• Demonstrated dramatic coupling among substrate properties in mouse mesenchymal stem cells and human cortical neuron progenitors.
• Identified that the contribution of each biophysical property to gene expression changes varies by cell type.
• Found that hydrogel stiffness regulates cytokine secretion, influencing hematopoietic stem cell differentiation.

Conclusions:

• Cells integrate multiple biophysical cues from their microenvironment, with varying contributions depending on cell type.
• Biophysical properties of the microenvironment significantly influence cell behavior, including gene expression and differentiation.
• Provides insights for designing biomaterials and bioengineering strategies to control cell responses to their physical environment.