Cas9-Mediated Knockout of Ndrg2 Enhances the Regenerative Potential of Dendritic Cells for Wound Healing

Cas9-Mediated Knockout of Ndrg2 Enhances the Regenerative Potential of Dendritic Cells for Wound Healing. Henn, D., Zhao, D., Chen, K., Trotsyuk, A., Bonham, C. A., Fischer, K. S., Kehl, T., Fehlmann, T., Sivaraj, D., Greco, A. H., Moortgat Illouz, S. E., Padmanabhan, J., Barrera, J. A., Kneser, U., Lenhof, H., Januszyk, M., Levi, B., Keller, A., Longaker, M. T., Qi, L. S., & Gurtner, G. C. bioRxiv, Cold Spring Harbor Laboratory, 2022.

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Chronic wounds impose a significant healthcare burden to a broad patient population. Cell based therapies, while having shown benefits for the treatment of chronic wounds, have not achieved widespread adoption into clinical practice. Here, we developed a novel CRISPR/Cas9 approach to precisely edit dendritic cells (DCs) to enhance their therapeutic potential for healing chronic wounds. Using single-cell RNA sequencing (scRNA-seq) of tolerogenic DCs, we discover N-myc downregulated gene 2 (Ndrg2), which marks a specific population of DC progenitors, as a promising target for CRISPR knockout (KO). Ndrg2-KO alters the transcriptomic profile of DCs and preserves an immature cell state with a strong, pro-angiogenic and regenerative capacity. We then incorporated our CRISPR-based cell engineering within a hydrogel technology for in vivo cell delivery and developed a highly effective translational approach for DC based immunotherapy that accelerated healing of full-thickness wounds in both non-diabetic and diabetic mouse models. These findings could open the door to future clinical trials using safe gene editing in DCs for treating various types of chronic wounds.Competing Interest StatementThe authors have declared no competing interest.

@article {Henn2022.03.14.484360,
	author = {Henn, Dominic and Zhao, Dehua and Chen, Kellen and Trotsyuk, Artem and Bonham, Clark Andrew and Fischer, Katharina S. and Kehl, Tim and Fehlmann, Tobias and Sivaraj, Dharshan and Greco, Autumn H. and Moortgat Illouz, Sylvia E. and Padmanabhan, Jagannath and Barrera, Janos A. and Kneser, Ulrich and Lenhof, Hans-Peter and Januszyk, Michael and Levi, Benjamin and Keller, Andreas and Longaker, Michael T. and Qi, Lei S. and Gurtner, Geoffrey C.},
	title = {Cas9-Mediated Knockout of Ndrg2 Enhances the Regenerative Potential of Dendritic Cells for Wound Healing},
	elocation-id = {2022.03.14.484360},
	year = {2022},
	doi = {10.1101/2022.03.14.484360},
	publisher = {Cold Spring Harbor Laboratory},
	abstract = {Chronic wounds impose a significant healthcare burden to a broad patient population. Cell based therapies, while having shown benefits for the treatment of chronic wounds, have not achieved widespread adoption into clinical practice. Here, we developed a novel CRISPR/Cas9 approach to precisely edit dendritic cells (DCs) to enhance their therapeutic potential for healing chronic wounds. Using single-cell RNA sequencing (scRNA-seq) of tolerogenic DCs, we discover N-myc downregulated gene 2 (Ndrg2), which marks a specific population of DC progenitors, as a promising target for CRISPR knockout (KO). Ndrg2-KO alters the transcriptomic profile of DCs and preserves an immature cell state with a strong, pro-angiogenic and regenerative capacity. We then incorporated our CRISPR-based cell engineering within a hydrogel technology for in vivo cell delivery and developed a highly effective translational approach for DC based immunotherapy that accelerated healing of full-thickness wounds in both non-diabetic and diabetic mouse models. These findings could open the door to future clinical trials using safe gene editing in DCs for treating various types of chronic wounds.Competing Interest StatementThe authors have declared no competing interest.},
	URL = {https://www.biorxiv.org/content/early/2022/03/15/2022.03.14.484360},
	eprint = {https://www.biorxiv.org/content/early/2022/03/15/2022.03.14.484360.full.pdf},
	journal = {bioRxiv}
}

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