# Mechanisms of Neural Stem Cell Mechanoregulation

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA BERKELEY · 2022 · $527,820

## Abstract

PROJECT SUMMARY/ABSTRACT
Biophysical cues encoded in the structure, mechanics, and dimensionality of the stem cell microenvironment are
now appreciated as important regulators of self-renewal and differentiation. For the past 15+ years, including
two periods of R01 support, we have been exploring mechanistic and translational aspects of this regulation in
hippocampal neural stem cells (NSCs), which generate new neurons into adulthood and contribute to
neurological disease and repair. We have made several important contributions to the field’s understanding of
stem cell mechanobiology, including the discovery that NSC lineage decisions are maximally sensitive to
extracellular matrix (ECM) mechanics within a restricted temporal window, during which stiffness cues are
processed by a signaling network that includes RhoA GTPase, actin/myosin, angiomotin, YAP, and β-catenin.
Our discoveries raise two important questions of general interest to the stem cell field, which will serve as the
foundation for our renewal application. First, what molecular mechanisms govern NSC mechanosensitive lineage
commitment in three-dimensional (3D) ECMs, and how do these mechanisms differ from two-dimensional (2D)
ECMs? We will build on our exciting recent discovery that the transcription factor Egr1 is a critical, 3D-specific
regulator of NSC mechanosensitive lineage commitment. Second, how do stem cells dynamically integrate
mechanical inputs on the time scale of minutes to hours to trigger functionally important signaling events? Here
we will leverage our preliminary studies in which we have probed the timing of mechanosensitive signaling events
with mismatched DNA-crosslinked viscoelastic hydrogels and optogenetic reagents that allow timed activation
of RhoA and Cdc42 activation. We have two specific aims: In Aim 1, we will investigate mechanisms through
which Egr1 controls mechanosensitive lineage commitment in 3D matrices using a combination of 2D and 3D
engineered biomaterials, candidate-based molecular studies, and screens to identify Egr1 targets relevant to
neurogenesis. In Aim 2, we will investigate how stiffness cues from 2D ECMs are triggered on the minutes-to-
hours time scale are integrated over hours to days to control lineage commitment. Work in this aim builds on
our observation that timed optogenetic stimulation of RhoA and incorporation of viscous (loss) properties into
elastic ECMs both suppress NSC neurogenesis. We will identify critical regulatory time scales for both
perturbations and determine if they influence lineage commitment through common mechanisms. To integrate
aims, we will investigate the time-dependence of mechanosensitive lineage commitment in 3D ECMs and ask if
RhoA stimulation and stress relaxation act through Egr1 to suppress neurogenesis. Our work will accelerate the
field’s understanding of how stem cells sense and act upon mechanical signals to guide fate decisions, a problem
of high fundamental and translational value. We will ...

## Key facts

- **NIH application ID:** 10446178
- **Project number:** 2R01NS074831-11
- **Recipient organization:** UNIVERSITY OF CALIFORNIA BERKELEY
- **Principal Investigator:** Sanjay Kumar
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $527,820
- **Award type:** 2
- **Project period:** 2012-05-01 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10446178

## Citation

> US National Institutes of Health, RePORTER application 10446178, Mechanisms of Neural Stem Cell Mechanoregulation (2R01NS074831-11). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10446178. Licensed CC0.

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