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

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.

journal_name

Nat Commun

journal_title

Nature communications

authors

Srifa W,Kosaric N,Amorin A,Jadi O,Park Y,Mantri S,Camarena J,Gurtner GC,Porteus M

doi

10.1038/s41467-020-16065-3

subject

Has Abstract

pub_date

2020-05-18 00:00:00

pages

2470

issue

1

issn

2041-1723

pii

10.1038/s41467-020-16065-3

journal_volume

11

pub_type

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