# Cell Intrinsic and Extrinsic Factors Driving Maturation in Human PSC-derived Neurons

> **NIH NIH R01** · SLOAN-KETTERING INST CAN RESEARCH · 2024 · $635,667

## Abstract

Project Summary
Human embryonic (hESC) and human induced pluripotent stem cells (hiPSC) offer great promise for basic
research and for applications in disease modeling. The initial challenge for exploiting this potential was to direct
stem cell differentiation towards specific nerve cell or glial fates relevant to disease. Over the last few years, we
have developed many such protocols that now enable researchers to generate > 50 distinct human cell types in
a dish. However, a major remaining challenge is the fetal rather than adult-like features exhibited by the
resulting cells, which limits their usefulness. The reason for their immaturity is unclear but may be linked to a
cell-intrinsic, clock-like mechanism that controls the timing of maturation. While it takes 9 months for a human
baby to develop, from conception to birth, the same process takes only 20 days in a mouse. Those dramatic
timing differences are recapitulated in a dish, where the maturation of human cells may require many months
to reach adult-like properties. Interestingly, we observe such timing differences in both 2D and 3D culture
including in neural organoids. Even after transplanting human cells into the mouse brain, cells continue to
follow a human-specific maturation trajectory, despite being surrounded by an adult host microenvironment.
 Here we will address this challenge by building assays to measure and quantify neuronal and glial
maturation and by developing strategies to override the intrinsic maturation clock. Towards these goals, we
have established a unique stem cell-based assay to produce nerve cells at very high precision and in a
temporally synchronized manner. The resulting cells then progressively mature from fetal to adult-like stages
over a period of several months allowing us to define markers that predict the neuronal maturation state. In Aim
1, we will build on these preliminary data and establish stage-specific “fingerprints” of nerve cell maturation to
determine maturation states at unprecedented precision. In addition, we will characterize the maturation of glial
cells (astrocytes and microglia) in a novel tri-culture system to test whether the presence of glia can improve
neuronal maturation. In Aim 2, we will apply maturation “fingerprints” as a readout for identifying factors that
can accelerate maturation timing. In preliminary studies, we have identified chemicals and genes that are
strong candidates for driving neuronal maturation. We will further validate those findings in the tri-culture
system to determine the combined effect of intrinsic and extrinsic maturation factors. Finally, we will perform
mechanistic studies to understand how those factors induce more adult-like features in human cells. In Aim3,
we will test our optimized maturation strategies in more complex 3D culture systems to assess whether
induced maturation strategies impact other developmental processes such as cell migration and organization.
Finally, we will assess whether “...

## Key facts

- **NIH application ID:** 10890861
- **Project number:** 5R01NS128087-02
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** LORENZ P. STUDER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $635,667
- **Award type:** 5
- **Project period:** 2023-08-01 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10890861

## Citation

> US National Institutes of Health, RePORTER application 10890861, Cell Intrinsic and Extrinsic Factors Driving Maturation in Human PSC-derived Neurons (5R01NS128087-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10890861. Licensed CC0.

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