Abstract:
:In the human hematopoietic system, rare self-renewing multipotent long-term hematopoietic stem cells (LT-HSCs) are responsible for the lifelong production of mature blood cells and are the rational target for clinical regenerative therapies. However, the heterogeneity in the hematopoietic stem cell compartment and variable outcomes of CRISPR/Cas9 editing make functional interrogation of rare LT-HSCs challenging. Here, we report high efficiency LT-HSC editing at single-cell resolution using electroporation of modified synthetic gRNAs and Cas9 protein. Targeted short isoform expression of the GATA1 transcription factor elicit distinct differentiation and proliferation effects in single highly purified LT-HSC when analyzed with functional in vitro differentiation and long-term repopulation xenotransplantation assays. Our method represents a blueprint for systematic genetic analysis of complex tissue hierarchies at single-cell resolution.
journal_name
Nat Communjournal_title
Nature communicationsauthors
Wagenblast E,Azkanaz M,Smith SA,Shakib L,McLeod JL,Krivdova G,Araújo J,Shultz LD,Gan OI,Dick JE,Lechman ERdoi
10.1038/s41467-019-12726-0subject
Has Abstractpub_date
2019-10-18 00:00:00pages
4730issue
1issn
2041-1723pii
10.1038/s41467-019-12726-0journal_volume
10pub_type
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