# hPSC-derived microglia for in vitro modeling of Rett Syndrome

> **NIH NIH F30** · WEILL MEDICAL COLL OF CORNELL UNIV · 2020 · $50,520

## Abstract

Project Summary/Abstract
Human pluripotent stem cells (hPSCs) retain the ability to generate any cell type in the human body, offering
unprecedented access to a wide-array of human cell types. hPSCs are therefore a powerful model to study
human neurodevelopmental diseases in vitro.57,59 Rett Syndrome (RTT), a devastating Autism-Spectrum-
Disorder that affects 1 in 10,000 female births and causes severe regression by 18 months of age, is one such
neurodevelopmental disorder.1,2 Hallmarks of RTT include an imbalance in inhibitory:excitatory synapses as
well as excessive microglial pruning, but how these two pathologies are interconnected has yet to be fully
explored. In this study, my goal is to decipher how inhibitory:excitatory synaptic imbalance in RTT is related to
microglial-neuronal interplay using an iPSC-derived multi-cell type in vitro model containing both neurons and
microglia. While there are established protocols for deriving neurons from hPSCs, to date there have been no
developmentally-based differentiation schema for generating hPSC-derived microglia. Preliminary data shows
that I can generate yolk sac primitive hematopoiesis in vitro to isolate microglial progenitors, and I have
developed two different paradigms to generate microglial-like cells after co-culture with neurons. In this study,
I aim to 1) compare the two paradigms to determine which generates microglial-like cells most similar to
human primary microglia, and 2) use these cells to study the contribution of microglial-neuronal interaction in
an iPSC-model of RTT. Specifically, I will investigate whether the inhibitory:excitatory synaptic imbalance in
RTT is caused by a neuron-only phenotype or whether it is affected by microglial pruning. Through this study, I
hope to generate bonafide human microglia through a novel, developmental paradigm, as well as answer a key
mechanistic question behind RTT synaptic pathology.

## Key facts

- **NIH application ID:** 9998741
- **Project number:** 5F30MH115616-04
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Sudha R Guttikonda
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $50,520
- **Award type:** 5
- **Project period:** 2017-09-01 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9998741

## Citation

> US National Institutes of Health, RePORTER application 9998741, hPSC-derived microglia for in vitro modeling of Rett Syndrome (5F30MH115616-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9998741. Licensed CC0.

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