Cas9-mediated knockout of Ndrg2 enhances the regenerative potential of dendritic cells for wound healing

Dominic Henn, Dehua Zhao, Dharshan Sivaraj, Artem Trotsyuk, Clark Andrew Bonham, Katharina S. Fischer, Tim Kehl, Tobias Fehlmann, Autumn H. Greco, Hudson C. Kussie, Sylvia E. Moortgat Illouz, Jagannath Padmanabhan, Janos A. Barrera, Ulrich Kneser, Hans-Peter Lenhof, Michael Januszyk, Benjamin Levi, Andreas Keller, Michael T. Longaker, Kellen Chen, Lei S. Qi () and Geoffrey C. Gurtner ()
Additional contact information
Dominic Henn: Stanford University
Dehua Zhao: Stanford University
Dharshan Sivaraj: Stanford University
Artem Trotsyuk: Stanford University
Clark Andrew Bonham: Stanford University
Katharina S. Fischer: Stanford University
Tim Kehl: Saarland University
Tobias Fehlmann: Saarland University
Autumn H. Greco: Stanford University
Hudson C. Kussie: Stanford University
Sylvia E. Moortgat Illouz: Stanford University
Jagannath Padmanabhan: Stanford University
Janos A. Barrera: Stanford University
Ulrich Kneser: Ruprecht-Karls-University of Heidelberg
Hans-Peter Lenhof: Saarland University
Michael Januszyk: Stanford University
Benjamin Levi: University of Texas Southwestern Medical Center
Andreas Keller: Saarland University
Michael T. Longaker: Stanford University
Kellen Chen: Stanford University
Lei S. Qi: Stanford University
Geoffrey C. Gurtner: Stanford University

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: 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 yet achieved widespread adoption into clinical practice. We developed a CRISPR/Cas9 approach to precisely edit murine dendritic cells to enhance their therapeutic potential for healing chronic wounds. Using single-cell RNA sequencing of tolerogenic dendritic cells, we identified N-myc downregulated gene 2 (Ndrg2), which marks a specific population of dendritic cell progenitors, as a promising target for CRISPR knockout. Ndrg2-knockout alters the transcriptomic profile of dendritic cells and preserves an immature cell state with a strong pro-angiogenic and regenerative capacity. We then incorporated our CRISPR-based cell engineering within a therapeutic hydrogel for in vivo cell delivery and developed an effective translational approach for dendritic cell-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 dendritic cells for treating various types of chronic wounds.

Date: 2023
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DOI: 10.1038/s41467-023-40519-z

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