In Situ Modification of Tissue Stem and Progenitor Cell Genomes

被引：37

作者：

Goldstein, Jill M. ^{[1
,2
,3
]}

Tabebordbar, Mohammadsharif ^{[4
]}

Zhu, Kexian ^{[1
,2
,3
,5
]}

Wang, Leo D. ^{[6
,7
,8
,14
,15
]}

Messemer, Kathleen A. ^{[1
,2
,3
]}

Peacker, Bryan ^{[1
,2
,3
]}

Kakhki, Sara Ashrafi ^{[1
,2
,3
]}

Gonzalez-Celeiro, Meryem ^{[1
,2
,9
]}

Shwartz, Yulia ^{[1
,2
]}

Cheng, Jason K. W. ^{[10
]}

Xiao, Ru ^{[11
,12
,13
]}

Barungi, Trisha ^{[11
,12
,13
]}

Albright, Charles ^{[10
]}

Hsu, Ya-Chieh ^{[1
,2
]}

Vandenberghe, Luk H. ^{[2
,4
,11
,12
,13
]}

Wagers, Amy J. ^{[1
,2
,3
,6
]}

机构：

[1] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA

[2] Harvard Stem Cell Inst, Cambridge, MA 02138 USA

[3] Harvard Med Sch, Paul F Glenn Ctr Biol Aging, Boston, MA 02115 USA

[4] Brd Inst MIT & Harvard, Cambridge, MA 02142 USA

[5] Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA

[6] Joslin Diabet Ctr, Boston, MA 02215 USA

[7] Boston Childrens Hosp, Div Pediat Hematol Oncol, Boston, MA 02215 USA

[8] Dana Farber Canc Inst, Boston, MA 02215 USA

[9] Swiss Fed Inst Technol, Inst Mol Hlth Sci, CH-8093 Zurich, Switzerland

[10] Editas Med Inc, 11 Hurley St, Cambridge, MA 02142 USA

[11] Schepens Eye Res Inst, Grousbeck Gene Therapy Ctr, Boston, MA 02114 USA

[12] Massachusetts Eye & Ear, Boston, MA 02114 USA

[13] Harvard Med Sch, Ocular Genom Inst, Dept Ophthalmol, Boston, MA 02114 USA

[14] City Hope Natl Med Ctr, Dept Pediat, Beckman Res Inst, Duarte, CA 91010 USA

[15] City Hope Natl Med Ctr, Dept Immunooncol, Beckman Res Inst, Duarte, CA 91010 USA

来源：

CELL REPORTS | 2019年 / 27卷 / 04期

关键词：

SKELETAL-MUSCLE; HEMATOPOIETIC STEM; SATELLITE CELLS; GENE-THERAPY; MOUSE MODEL; FIBRO/ADIPOGENIC PROGENITORS; PROGRESS; IDENTIFICATION; ACTIVATION; EXPRESSION;

D O I：

10.1016/j.celrep.2019.03.105

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

In vivo delivery of genome-modifying enzymes holds significant promise for therapeutic applications and functional genetic screening. Delivery to endogenous tissue stem cells, which provide an enduring source of cell replacement during homeostasis and regeneration, is of particular interest. Here, we use a sensitive Cre/lox fluorescent reporter system to test the efficiency of genome modification following in vivo transduction by adeno-associated viruses (AAVs) in tissue stem and progenitor cells. We combine immunophenotypic analyses with in vitro and in vivo assays of stem cell function to reveal effective targeting of skeletal muscle satellite cells, mesenchymal progenitors, hematopoietic stem cells, and dermal cell subsets using multiple AAV serotypes. Genome modification rates achieved through this system reached >60%, and modified cells retained key functional properties. This study establishes a powerful platform to genetically alter tissue progenitors within their physiological niche while preserving their native stem cell properties and regulatory interactions.

引用

页码：1254 / +

页数：18

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