# Preserving chromatin nano-structure to enhance chondrocyte therapeutic potential for cartilage repair

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2022 · $417,075

## Abstract

Summary
 There is a gap in the knowledge about how chondrocytes lose their phenotype and matrix production
capacity during in vitro expansion. This gap in knowledge stems from the paucity of studies that directly
interrogate chondrocyte genome architecture and transcriptional profiles in single cells to capture the inherent
heterogeneity of cell differentiation. To fill this unmet gap, we will use state-of-the-art super-resolution imaging,
single cell RNA Sequencing (RNA-Seq), high-throughput RNA-FISH (MERFISH) and metabolic labeling
(FUNCAT) technologies to relate, on a cell-by-cell level, the chromatin nano-structure, transcriptional output,
epigenetic modifications and matrix production capacity of single chondrocytes expanded in culture under
different epigenetic and chemo-physical cues. We will further develop machine learning models to predict
chondrocyte phenotype using super-resolution images of chondrocyte chromatin nano-structure. Our central
hypothesis is that there are distinct chromatin nano-structural arrangements and transcriptional signatures
associated with chondrocytes that have high matrix production capacity, and that chromatin nano-structure can
be manipulated in a predictive manner via the combination of epigenetic and chemo-physical cues to improve
chondrocyte therapeutic potential. The basis for this hypothesis is our preliminary super-resolution data of
chromatin nano-structure in in vitro expanded chondrocytes and mesenchymal stem cells grown on substrates
of varying stiffness and subjected to various chemical cues. The proposed work is significant as it will generate
new knowledge about how chromatin nano-structure and epigenetic landscape regulates matrix production
capacity of chondrocytes and how this capacity can be enhanced through manipulation of chromatin and
epigenetic states. Our Aims are:
matrix
 whether chromatin nano-structure and transcription are predictive of chondrocyte
production capacity
Aim 1: Determine
 Aim 2: Determine how chemo-physical and epigenetic cues impact transitions in chromatin nano-
structure and matrix production in chondrocytes
 Aim 3: Determine whether predicted cues improve chondrocyte therapeutic efficacy
In summary, we expect to contribute to the identification of new in vitro expansion conditions that maintain
naïve chondrocyte phenotype and enhance their therapeutic potential. The proposed research is innovative as
it represents a drastic departure from the status quo by applying multi-faceted, single-cell based imaging and
sequencing technologies to determine the relationship between chondrocyte chromatin and epigenetic state,
transcriptional activities, and matrix production. If successful, this work may change clinical practice by providing
improved cell populations for cartilage repair.

## Key facts

- **NIH application ID:** 10365877
- **Project number:** 1R01AR079224-01A1
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Su Chin Heo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $417,075
- **Award type:** 1
- **Project period:** 2022-09-20 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10365877

## Citation

> US National Institutes of Health, RePORTER application 10365877, Preserving chromatin nano-structure to enhance chondrocyte therapeutic potential for cartilage repair (1R01AR079224-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10365877. Licensed CC0.

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