Abstract

Hematopoietic stem cell (HSC) multipotency and self-renewal are typically defined through serial transplantation experiments. Host conditioning is necessary for robust HSC engraftment, likely by reducing immune-mediated rejection and by clearing limited HSC niche space. Because irradiation of the recipient mouse is non-specific and broadly damaging, there is a need to develop alternative models to study HSC performance at steady-state and in the absence of radiation-induced stress. We have generated and characterized two new mouse models where either all hematopoietic cells or only HSCs can be specifically induced to die in vivo or in vitro. Hematopoietic-specific Vav1-mediated expression of a loxP-flanked diphtheria-toxin receptor (DTR) renders all hematopoietic cells sensitive to diphtheria toxin (DT) in “Vav-DTR” mice. Crossing these mice to Flk2-Cre mice results in “HSC-DTR” mice which exhibit HSC-selective DT sensitivity. We demonstrate robust, rapid, and highly selective cell ablation in these models. These new mouse models provide a platform to test whether HSCs are required for long-term hematopoiesis in vivo, for understanding the mechanisms regulating HSC engraftment, and interrogating in vivo hematopoietic differentiation pathways and mechanisms regulating hematopoietic homeostasis.

Details

Title
New transgenic mouse models enabling pan-hematopoietic or selective hematopoietic stem cell depletion in vivo
Author
Rodriguez y Baena Alessandra 1 ; Rajendiran Smrithi 2 ; Manso, Bryce A 2 ; Krietsch Jana 2 ; Boyer, Scott W 1 ; Kirschmann, Jessica 3 ; Camilla, Forsberg E 2 

 University of California-Santa Cruz, Institute for the Biology of Stem Cells, Santa Cruz, USA (GRID:grid.205975.c) (ISNI:0000 0001 0740 6917); University of California-Santa Cruz, Program in Biomedical Sciences and Engineering, Department of Molecular, Cell, and Developmental Biology, Santa Cruz, USA (GRID:grid.205975.c) (ISNI:0000 0001 0740 6917) 
 University of California-Santa Cruz, Institute for the Biology of Stem Cells, Santa Cruz, USA (GRID:grid.205975.c) (ISNI:0000 0001 0740 6917); University of California-Santa Cruz, Biomolecular Engineering, Santa Cruz, USA (GRID:grid.205975.c) (ISNI:0000 0001 0740 6917) 
 University of California-Santa Cruz, Institute for the Biology of Stem Cells, Santa Cruz, USA (GRID:grid.205975.c) (ISNI:0000 0001 0740 6917) 
Publication year
2022
Publication date
2022
Publisher
Nature Publishing Group
e-ISSN
20452322
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2632679649
Copyright
© The Author(s) 2022. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.