# Epigenetic reprogramming to generate novel chondro-osseous stem cells for bone tissue engineering

> **NIH NIH R21** · BAYLOR COLLEGE OF MEDICINE · 2020 · $211,200

## Abstract

Recent studies to harness the capacity of BMP2 to induce de novo bone formation for tissue and/or
limb regeneration resulted in the identification of a novel chondro-osseous progenitor that is primed to engraft
into sites of active bone formation, even when delivered systemically. These cells were identified using lineage
tracing for glial high affinity glutamate transporter GLAST, which has been shown to be restricted to neural
stem cells, astrocytes, and chondrocytes. Transcriptome analysis, using single cell RNAseq, led to the
identification of a highly replicating stem cell that appears to undergo an epithelial to mesenchymal transition
(EMT) to become a cell that expresses a large number of chondrocyte and osteoblast associated transcripts
similar to a recently reported periosteal stem cell. Surprisingly, while the replicating stem cell expressed
GLAST as well as neurogranin, another synaptic protein, and β-tubulin 3/TUJ1; whereas mature chondrocytes
did not express this protein supporting its neural association. In further support several or all clusters also
expressed several Schwann cell markers including N-cadherin, Krox20, and myelin basic protein.
Transcriptome analysis also revealed that this cluster is highly expressing H2A.Z and SET methyltransferase
with decreasing synthesis in other clusters/cells correlating with pseudotime or cell maturation. The data
collectively has led us to hypothesize that Schwann cells upon exposure to BMP2 undergo epigenetic
reprogramming and reactivation of primed tissue specific developmental enhancers leading to a neural crest
progenitor/stem cell phenotype. Further, these stem/progenitors are then able to undergo re-differentiation into
chondrocytes and osteoblasts. To test this hypothesis, we propose to utilize the phospholipid protein 1 (Plp1)
promoter driving Cre recombinase and tomato redfloxSTOPflox mouse to be able to initially label Schwann cells
and allow for reporter expression in downstream reprogrammed cells. GLAST-TR+ cells obtained 48 hours
after delivery of BMP2, will also be included to obtain potential earlier clusters. GLAST-TR+ and/or Plp1-TR+
cells from soft tissues surrounding the region of de novo bone formation 24 hours after delivery of BMP2 and
subjected to single cell RNAseq and single cell ATACseq, which will identify changes in chromatin within the
cell populations that might reflect reprogramming of the cells to the highly replicative stem cell. The resultant
data will be correlated with the scRNAseq data to provide a molecular mechanism for the generation of these
cells. From this data one can then start to envision ex vivo reprogramming of cells to form these chondro-
osseous progenitors that will home to sites of active bone formation.

## Key facts

- **NIH application ID:** 10041588
- **Project number:** 1R21AR077783-01
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Alan ROBERT Davis
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $211,200
- **Award type:** 1
- **Project period:** 2020-07-15 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10041588

## Citation

> US National Institutes of Health, RePORTER application 10041588, Epigenetic reprogramming to generate novel chondro-osseous stem cells for bone tissue engineering (1R21AR077783-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10041588. Licensed CC0.

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