TY - JOUR
T1 - Cas9-mediated knockout of Ndrg2 enhances the regenerative potential of dendritic cells for wound healing
AU - Henn, Dominic
AU - Zhao, Dehua
AU - Sivaraj, Dharshan
AU - Trotsyuk, Artem
AU - Bonham, Clark Andrew
AU - Fischer, Katharina S.
AU - Kehl, Tim
AU - Fehlmann, Tobias
AU - Greco, Autumn H.
AU - Kussie, Hudson C.
AU - Moortgat Illouz, Sylvia E.
AU - Padmanabhan, Jagannath
AU - Barrera, Janos A.
AU - Kneser, Ulrich
AU - Lenhof, Hans Peter
AU - Januszyk, Michael
AU - Levi, Benjamin
AU - Keller, Andreas
AU - Longaker, Michael T.
AU - Chen, Kellen
AU - Qi, Lei S.
AU - Gurtner, Geoffrey C.
N1 - Publisher Copyright:
© 2023, Springer Nature Limited.
PY - 2023/12
Y1 - 2023/12
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-023-40519-z
DO - 10.1038/s41467-023-40519-z
M3 - Article
C2 - 37550295
AN - SCOPUS:85166786189
SN - 2041-1723
VL - 14
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 4729
ER -