Cas9-AAV6-engineered human mesenchymal stromal cells improved cutaneous wound healing in diabetic mice

Waracharee Srifa, Nina Kosaric, Alvaro Amorin, Othmane Jadi, Yujin Park, Sruthi Mantri, Joab Camarena, Geoffrey C. Gurtner and Matthew Porteus ()
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Waracharee Srifa: Stanford University School of Medicine
Nina Kosaric: Stanford University School of Medicine
Alvaro Amorin: Stanford University School of Medicine
Othmane Jadi: Stanford University School of Medicine
Yujin Park: Stanford University School of Medicine
Sruthi Mantri: Stanford University School of Medicine
Joab Camarena: Stanford University School of Medicine
Geoffrey C. Gurtner: Stanford University School of Medicine
Matthew Porteus: Stanford University School of Medicine

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: Abstract Human mesenchymal stromal cells (hMSCs) are a promising source for engineered cell-based therapies in which genetic engineering could enhance therapeutic efficacy and install novel cellular functions. Here, we describe an optimized Cas9-AAV6-based genome editing tool platform for site-specific mutagenesis and integration of up to more than 3 kilobases of exogenous DNA in the genome of hMSCs derived from the bone marrow, adipose tissue, and umbilical cord blood without altering their ex vivo characteristics. We generate safe harbor-integrated lines of engineered hMSCs and show that engineered luciferase-expressing hMSCs are transiently active in vivo in wound beds of db/db mice. Moreover, we generate PDGF-BB- and VEGFA-hypersecreting hMSC lines as short-term, local wound healing agents with superior therapeutic efficacy over wildtype hMSCs in the diabetic mouse model without replacing resident cells long-term. This study establishes a precise genetic engineering platform for genetic studies of hMSCs and development of engineered hMSC-based therapies.

Date: 2020
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DOI: 10.1038/s41467-020-16065-3

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