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From Epigenetics of Cranial Neural Crest Plasticity to Intervertebral Disc Regeneration

Project description

Novel cell therapies for intervertebral disc regeneration

Lower back pain, primarily caused by intervertebral disc degeneration, is a leading disability cause. Cell therapy treatments present limited clinical efficacy because most cell sources do not regenerate the degenerated tissue. The EU-funded EpiCrest2Reg project proposes to employ nasal chondrocytes (NCs) because of their regenerative capacity and plasticity. However, a better understanding of the molecular mechanisms of NC plasticity is required to support their potential clinical use for intervertebral disc regeneration. Researchers will focus on the epigenetic chromatin signature of NCs and study the role of transcription and chromatin factors in NC plasticity. The knowledge gained, along with assessment of NCs in pre-clinical models, will be important towards a first-in-man application of NCs for treating intervertebral disc degeneration.

Objective

During craniofacial development, Cranial Neural Crest Cells (CNCCs) maintain broad plasticity and patterning competence until they make appropriate cartilage and bone structures in response to local cues. We found that CNCC embryonic plasticity involves a specific epigenetic chromatin signature that maintains genes, including Hox genes, in a transcriptionally silent but poised state, so that they can be readily switched to an active state in response to position-specific environmental signals.

Are there CNCC-derived subpopulations in the adult face cartilage with similar broad plasticity properties that could be used as progenitor source in regenerative medicine? We have shown that Hox-negative adult human CNCC-derived Nasal Chondrocytes (NCs) have cartilage regenerative capacity and plasticity to adapt to heterotopic sites larger than other cell sources, and demonstrated their potential clinical use for articular cartilage repair.

However, lack of understanding of the involved molecular mechanisms limits the broader utilization of adult NCs for the regeneration of other cartilage types, e.g. the intervertebral disc (IVD). This proposal will establish fundamental understanding of the biological processes responsible for the plasticity of adult human NCs and offer a paradigm example of scientific and clinical synergies bridging developmental (epi)genetics and regenerative medicine.

We will:
• Establish whether Hox-negative adult NCs and embryonic CNCCs share similar transcriptomes, epigenomes and 3D chromatin architectures using single cell RNA-seq, ChIP-seq and capture HiC-seq assays.
• Assess whether NCs can epigenetically and transcriptionally adapt to the Hox-positive IVD environment, using co-culture and bioreactor-based organ culture models, and investigate the underlying molecular mechanisms.
• Verify the capacity of adult NCs to repair degenerated IVD cartilage.
• Use human autologous NCs for repair of IVD degeneration in a phase I clinical trial.

Host institution

FRIEDRICH MIESCHER INSTITUTE FOR BIOMEDICAL RESEARCH FONDATION
Net EU contribution
€ 2 670 000,00
Address
MAULBEERSTRASSE 66
4058 Basel
Switzerland

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Region
Schweiz/Suisse/Svizzera Nordwestschweiz Basel-Stadt
Activity type
Research Organisations
Links
Total cost
€ 2 670 000,00

Beneficiaries (3)