# Mechanisms of Neural Stem Cell Mechanoregulation

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA BERKELEY · 2021 · $287,816

## Abstract

PROJECT SUMMARY/ABSTRACT
Mechanical forces within the material microenvironment are increasingly recognized as important regulators of
stem cell self-renewal and differentiation. Over the past decade we have been exploring these concepts in the
context of adult hippocampal neural stem cells (NSCs), which generate neurons throughout adult life and play
key roles in learning, memory, and disease processes. In our first period of R01 support, we have shown that
extracellular matrix (ECM) stiffness cues can act through Rho GTPase- and myosin-dependent contractility to
influence lineage commitment within a defined temporal window. Moreover, manipulation of these stiffness-
sensing pathways in vivo can control hippocampal neurogenesis in a manner that is predictable from culture
studies. More recently, we have created reversibly-stiffening oligonucleotide-crosslinked materials and applied
this technology to narrow this window to 12-36 h and to begin elucidating key signals that are activated during
this period to induce lineage commitment. In this renewal application, we now propose to build upon these
advances by tackling two key questions of high general interest within the stem cell field: First, do the
mechanoregulatory signaling relationships observed in simplified 2D systems hold in more complex 3D
microenvironments, particularly ones with dynamic mechanical properties analogous to those encountered in
vivo? Second, precisely how do the signals triggered by mechanical inputs (e.g. Rho GTPase-dependent myosin
contraction) interface with the signals canonically understood to regulate NSC neurogenesis? In Aim 1, we will
investigate mechanosensitive lineage commitment in 3D by applying new click-crosslinked hyaluronic acid
hydrogels with tunable stiffness. We will also innovate upon these materials by incorporating reversible
oligonucleotide-based crosslinks that allow variable degrees of stress relaxation, and then use these materials
to ask if we can shift the time window of mechanosensitive lineage commitment. In Aim 2, we will investigate
integration of mechanotransductive signaling and canonical pro-neurogenic signaling in the control of NSC
neurogenesis. Specifically, we will test the hypothesis that mechanosensitive lineage commitment is controlled
by a master signaling circuit involving YAP, angiomotin, and b-catenin. We will also apply genome-wide CRISPR
gain/loss-of-function screens to identify additional candidates, which we will then characterize and incorporate
into this regulatory framework. Successful completion of these studies will not only dramatically improve the
field’s understanding of how mechanical signals influence NSC lineage commitment but offer a new intellectual
roadmap and set of tools that will be broadly applicable to all stem cell types.

## Key facts

- **NIH application ID:** 10160962
- **Project number:** 5R01NS074831-10
- **Recipient organization:** UNIVERSITY OF CALIFORNIA BERKELEY
- **Principal Investigator:** Sanjay Kumar
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $287,816
- **Award type:** 5
- **Project period:** 2012-05-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10160962

## Citation

> US National Institutes of Health, RePORTER application 10160962, Mechanisms of Neural Stem Cell Mechanoregulation (5R01NS074831-10). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10160962. Licensed CC0.

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