# Using human IPS cells to study fate, function and neurodegenerative disease

> **NIH NIH R01** · THOMAS JEFFERSON UNIVERSITY · 2020 · $422,918

## Abstract

Human induced pluripotent stem cells (iPSCs), with their potential to generate autologous patient-derived
cells, hold great promise for the study and treatment of a host of devastating diseases, including
Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), to name a few. One of the major
obstacles slowing the translation of this powerful technology to the clinic is the heterogeneity of both
desired and unwanted cell types generated in grafts of iPSCs, even after cells have been directed down
specific differentiation pathways. Similarly in culture, a multitude of cell types are generated after treatment
of iPSCs with lineage-specifying cocktails. These realities, combined with the current lack of suitable cell
surface markers for the selection of specific desired cell types, has significantly impacted the field,
hampering our ability to develop cell replacement therapies or to accurately model diseases in the dish.
One plausible explanation for the observed cell heterogeneity is that presumptive undifferentiated
pluripotent cells sometimes spontaneously initiate the process of differentiation after encountering lineage-
specifying cues in culture, thereby precluding their subsequent directed differentiation by exogenously
added differentiation cocktails. Currently, there are no assured ways to know if iPSCs have begun to
spontaneously differentiate. However, an exciting new discovery made during our previous grant cycle
suggests that the epigenetic state of chromatin shortly after DNA replication serves as a reliable and very
early indicator of the state of differentiation of a stem cell. Our results suggest that it may be possible to
uniformly direct the differentiation of all iPSCs toward a specific cell fate if chromatin can be kept closed
until incubation with exogenous fate-specifying differentiation factors. If these insights are indicative of a
more generalized principle, then it should be possible to generate pure populations of neural progenitors
(NPs) of different subtypes which can give rise to homogeneous populations of various neurons for studies
in culture and in animal models of multiple diseases. With these goals in mind, our Specific Aims for this
proposal are: 1) to assess chromatin status during commitment to a motor neuron phenotype; 2) to
generate pure populations of midbrain dopamine (mDA) and motor NPs and neurons which will be
characterized for phenotype and synaptic function in culture and 3) to further determine whether
homogeneous mDA-committed NPs/neurons can accurately model PD in the dish and be used in
transplants to therapeutically treat PD rat models.

## Key facts

- **NIH application ID:** 9970535
- **Project number:** 5R01NS075839-09
- **Recipient organization:** THOMAS JEFFERSON UNIVERSITY
- **Principal Investigator:** LORRAINE IACOVITTI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $422,918
- **Award type:** 5
- **Project period:** 2012-04-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9970535

## Citation

> US National Institutes of Health, RePORTER application 9970535, Using human IPS cells to study fate, function and neurodegenerative disease (5R01NS075839-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9970535. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*