# Regionalized Human Motor Neuron Therapies

> **NIH NIH F32** · UNIVERSITY OF WISCONSIN-MADISON · 2021 · $35,229

## Abstract

Stem cell replacement therapies are a promising, curative alternative to the long-term management
approaches associated with locomotor deficits from trauma or neurodegeneration. However, while cell
therapies for spinal cord regeneration are promising, studies to date have suffered from poor neuronal
integration and/or variable functional outcomes. One reason for this may be regional phenotype mismatch.
Studies in the brain have highlighted the importance of regional specification of human pluripotent stem cell
(hPSC)-derived neural progenitors to alleviate Parkinson's, Huntington's, and Epilepsy" symptoms in rodent
models. Comparable studies in the spinal cord have been hindered by a limited capacity to control the regional
phenotype of hPSC-derived spinal populations. The fundamental hypothesis of this proposal is that
genetic specification of hPSC-derived neuronal transplants to discrete spinal cord regions significantly
affects engraftment efficacy and subsequently patients' functional recovery.
 This work focuses on motor neurons (MNs), which are specifically targeted in a number of
neurodegenerative diseases and are damaged following spinal cord injury. During neural tube development,
colinear HOX expression results in spatial patterning of neuronal phenotypes along the R/C axis of the spinal
cord. The Ashton lab has established protocols recapitulate this Hox progression in hPSCs, generating neural
stem cells with discrete Hox profiles. When combined with morphogens for ventral patterning, this protocol
enables the derivation of a full rostrocaudal spectrum of progenitor MNs (pMNs) and MNs that can serve as
region-specific populations for transplantation. Aim 1 focuses on the generation and characterization of these
regionalized MN cultures representative of high cervical, mid cervical, brachial, thoracic, lumbar, and sacral
anatomical segments. In addition to characterization by molecular and functional assays, single cell RNA-seq
will be performed to determine columnar and motor pool identities within regionalized MN populations prior to
transplantation. Aims 2 and 3 test the hypothesis that regionalized hPSC-derived pMNs differentially integrate
into host circuits and selectively enhance functional recovery in vivo. Aim 2 examines whether pMNs
preferentially engraft into their region-matched spinal cord segment and selectively project axons onto
coordinate musculature in a developmental chick model. Aim 3 seeks to determine whether regionalized pMNs
contribute to functional recovery following transplantation into an adult rat that has been selectively ablated of
phrenic MNs. The expectation is that behavioral gains are mitigated upon transplant silencing. Together, these
aims establish clinically relevant MN populations for transplantation, advance a mechanistic understanding of
human MN diversification and establish the role of regional specificity on neuronal integration into the central
nervous system. The findings can guide future cl...

## Key facts

- **NIH application ID:** 10267676
- **Project number:** 5F32NS106740-04
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Nisha Iyer
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $35,229
- **Award type:** 5
- **Project period:** 2018-09-14 → 2022-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10267676

## Citation

> US National Institutes of Health, RePORTER application 10267676, Regionalized Human Motor Neuron Therapies (5F32NS106740-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10267676. Licensed CC0.

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