# Refining iPSC-Based Spinal Cord Model Systems by Fabricating Developmentally Programmed Extracellular Matrix Cues

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2024 · $559,496

## Abstract

ABSTRACT
Cellular reprogramming and induced pluripotent stem cell (iPSC) technologies have provided unprecedented
access to the human central nervous system (CNS). They have enabled the assembly of models for the
investigation of neurodevelopment and neurological disease mechanisms, which have led to significant
advancements in our understanding of these processes. However, culturing iPSC-derived neurons in vitro
remains technically challenging. Neurons grown in cell autonomous systems exhibit insufficient levels of
morphological maturation, synaptic connectivity, metabolic function, and electrophysiological activity, while
transcriptional analyses suggest they resemble neurons of late embryonic to early postnatal stages hindering
the study of adult-onset neurodegenerative diseases. We hypothesize that the lack of a physiological,
developmentally appropriate extracellular matrix (ECM) platform is a major contributor to these limitations. The
ECM is an intricately organized intercellular scaffold of secreted proteins and complex sugars that configures
spatiotemporal microenvironments throughout the CNS. It provides critical structural support to neurons,
astrocytes, and glial cells, serves as a reservoir for soluble factors, and mediates cellular signaling. Through
these actions, the ECM can modulate neuronal development, maturation, and aging. However, the temporal
diversity and functional effects of the matrisome, defined as the ensemble of the ECM and ECM-associated
proteins, in the CNS is poorly characterized. As a result, the design of in vitro platforms for culturing iPSC-derived
neurons that truly recapitulate the physiological ECM is impossible. Here, we will refine iPSC-neuronal model
systems by providing developmentally appropriate ECM cues. In Aim 1 we will utilize biochemical purification
and quantitative mass spectrometry (MS)-based proteomics to define the composition and nature of remodeling
of the in vivo matrisome from extracted mouse spinal cords at 3 developmental stages (postnatal, adult, old). In
Aim 2 we will leverage our combined expertise in iPSC technologies and biomaterials to establish ECM mimetic
matrices that can recapitulate the architecture and modulatory activity of the physiological matrisome to facilitate
the maturation and aging of stem cell derived spinal motor neurons in vitro. In Aim 3 we will improve the
development and reproducibility of 3-D spinal organoids by growing them in structured scaffolds with
incorporated candidate ECM cues. Our proposed aims will shed light into the contribution of the temporal
matrisome on neuronal diversity, development and function and facilitate the establishment of physiological
iPSC-based spinal cord model systems.

## Key facts

- **NIH application ID:** 10852169
- **Project number:** 1R01AG086270-01
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Evangelos Kiskinis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $559,496
- **Award type:** 1
- **Project period:** 2024-09-01 → 2029-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10852169

## Citation

> US National Institutes of Health, RePORTER application 10852169, Refining iPSC-Based Spinal Cord Model Systems by Fabricating Developmentally Programmed Extracellular Matrix Cues (1R01AG086270-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10852169. Licensed CC0.

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