# Modulating the Stem Cell Niche Set Point to Improve Skeletal Muscle Regeneration

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA-IRVINE · 2024 · $473,377

## Abstract

Abstract
Human pluripotent stem cells (hPSCs) transplantation therapies offer an appealing avenue to
combat skeletal muscle diseases. Directed differentiation of hPSCs to skeletal muscle is among
the few robust in vitro systems able to increase PAX7 expression by 1,000-fold. However, a
drawback of these hPSC-derived muscle cells is that they are functionally immature compared
to true adult muscle stem cells. Just as adult stem cells are dynamically regulated by their niche,
embryonic niches formed in development equivalently control cell fate decisions to mature from
an early precursor or progenitor and eventually to an adult quiescent stem cell. Importantly,
embryonic niches also change over developmental stages, but for hPSCs which form muscle
the niche is understudied or has never been studied. My work is significant because niches
which support muscle stem cells during the repair process, also develop in parallel with the
maturation of progenitor and stem cells from development through to adulthood. This proposal
consists of complementary in vitro and in vivo aims with the overall goal of supporting PAX7 cell
functions and numbers from hPSCs. In Aim 1, we will interrogate how muscle cells arise in the
first place and develop through key functional hallmarks of myogenesis. To accomplish this aim
we will use a lineage tracer built of a key myogenic commitment factor, SIX1, and test whether
SIX1 co-factors lead to functional maturation of hPSC myogenic cells. When hPSCs
differentiate to muscle they also produce impure cultures containing non-myogenic lineages that
we hypothesize support the muscle cells in culture. We will use genetic inhibition of master
transcription factors of these non-myogenic lineages to test their need in the support and
generation of hPSC muscle. Aim 2, seeks to understand how to support hPSC muscle cells
once they are made. We will build a simplified in vitro niche made of myotubes, extracellular
matrix taken from human tissue muscle, and PAX7 muscle progenitors, and over express key
ligands and receptors that we have already identified by spatial RNA seq to test their potential to
support PAX7 cells. We will also test the key role of hypoxia in hPSC PAX7 cell support in vitro.
Lastly, in Aim 3, we will pivot to in vivo systems using a mouse model available in the Hicks lab
that inducible ablates the mouse Pax7 cells and enables improved engraftment by hPSC PAX7
cells. We will first perform a series of in-depth time course experiments to identify the timing of
skeletal muscle stem cell niche formation following hPSC PAX7 cell transplantation. We will
then use an inducible overexpression system to test the function of a key hPSC muscle niche
factor, MEGF10, for enabling gain-of-function in at multiple stages of PAX7 niche formation.
Finally, we will test whether MEGF10 induction can improve the ability of hPSC PAX7 cells to
repopulate new myofibers and re-establish in vivo niches after injuries once transplanted.
Success...

## Key facts

- **NIH application ID:** 10860851
- **Project number:** 1R01AR084027-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Michael Ryan Hicks
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $473,377
- **Award type:** 1
- **Project period:** 2024-08-16 → 2029-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10860851

## Citation

> US National Institutes of Health, RePORTER application 10860851, Modulating the Stem Cell Niche Set Point to Improve Skeletal Muscle Regeneration (1R01AR084027-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10860851. Licensed CC0.

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