# Tissue Engineered Rostral Migratory Stream for Directed Neuronal Replacement

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2024 · $535,788

## Abstract

PROJECT SUMMARY
Chronic disability due to traumatic brain injury (TBI) affects 2% of the total population, and neuronal loss is
generally considered permanent, owing to limited capacity for neuroregeneration in the adult mammalian brain.
There are currently no approved treatments for improving recovery after TBI, and innovative approaches to
enhance neuroregeneration are desperately needed. Intriguingly, new neurons are generated in the
subventricular zone (SVZ) and then guided to the olfactory bulb/tract (and possibly striatum) via the rostral
migratory stream (RMS) for integration into existing circuitry. Recent publications have demonstrated that SVZ
neuroblasts can be redirected into lesions, differentiate into region-specific neuronal cell types, integrate into
circuitry, and improve functional recovery in adult rodents, but a translational strategy to direct and enhance
neuroblast migration into lesions has yet to be established. To address this challenge, we have assembled a
multi-disciplinary team of stem cell specialists, neurobiologists, clinicians, and tissue engineers to develop the
first anatomically-inspired microtissue designed to structurally and functionally emulate the glial tube of the
RMS. In an exciting breakthrough, our team developed novel microtissue engineering techniques that promote
the self-assembly of astrocytes into longitudinally aligned bundles that recapitulate the organization of the glial
tube of the RMS. To date, we have biofabricated this Tissue Engineered Rostral Migratory Stream (TE-RMS)
using rodent derived astrocytes as well as human stem cell derived astrocytes and, importantly, we have
shown that the TE-RMS directly facilitates the alignment and migration of immature neurons in vitro and in
vivo. In the current proposal, we will first validate the TE-RMS as an in vitro test bed to elucidate mechanisms
of neuronal progenitor migration and cell fate determination (Aim 1). We will then test the ability of the TE-RMS
to divert endogenous neuronal progenitors in vivo and repair damaged cerebral cortex following experimental
TBI in rats (Aim 2). In this Aim, the TE-RMS will be stereotaxically microinjected after the acute injury period to
span from the SVZ into lesioned tissue, and the redirection of migrating neurons to repopulate cortical areas,
functional integration with residual circuitry, and facilitation of behavioral recovery will be assessed. Finally, as
a first step towards clinical translation, we will perform in vitro and in vivo studies to validate the TE-RMS built
using astrocytes derived from stem cells harvested from adult human gingiva to develop methods for the
eventual creation of autologous, patient-derived implants from an easily accessible cell source (Aim 3). The
TE-RMS recapitulates the brain's own method for delivery and integration of new neurons. Thus, the execution
of these Aims will significantly advance a translational bioengineering approach capable of providing targeted
and sust...

## Key facts

- **NIH application ID:** 10825437
- **Project number:** 5R01NS117757-04
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Daniel Kacy Cullen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $535,788
- **Award type:** 5
- **Project period:** 2021-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10825437

## Citation

> US National Institutes of Health, RePORTER application 10825437, Tissue Engineered Rostral Migratory Stream for Directed Neuronal Replacement (5R01NS117757-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10825437. Licensed CC0.

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