In Situ Modification of Tissue Stem and Progenitor Cell Genomes
2019; Cell Press; Volume: 27; Issue: 4 Linguagem: Inglês
10.1016/j.celrep.2019.03.105
ISSN2639-1856
AutoresJill M. Goldstein, Mohammadsharif Tabebordbar, Kexian Zhu, Leo D. Wang, Kathleen A. Messemer, Bryan Peacker, Sara Ashrafi Kakhki, Meryem Gonzalez-Celeiro, Yulia Shwartz, Jason Cheng, Ru Xiao, Trisha Barungi, Charles F. Albright, Ya‐Chieh Hsu, Luk H. Vandenberghe, Amy J. Wagers,
Tópico(s)Pluripotent Stem Cells Research
ResumoHighlights•Multiple AAV serotypes transduce tissue stem cells via systemic or local delivery•AAV-delivered Cre recombinase modifies stem cells in multiple anatomical niches•In vivo AAV transduction does not require stem cell isolation or transplantation•AAV-transduced stem cells retain differentiation and engraftment capacitiesSummaryIn 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.Graphical abstract
Referência(s)