New transgenic mouse models enabling pan-hematopoietic or selective hematopoietic stem cell depletion in vivo

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.

Towards an integrated understanding of inflammatory pathway influence on hematopoietic stem and progenitor cell differentiation

“…[35,36] These changes have been demonstrated to alter the way HSPCs traffic and engraft in BM [35,36] and may affect other aspects of interaction with the BM niche. Therefore, use of less destructive genetic [37,38] or drug-based [39] ablation techniques is preferable to better reflect the normal physiology of HSPC interactions with niche cells. Ideally, future studies would use a combination of transplantation experiments and tissue-specific gene manipulations, whenever available, to test for the contributions of each cell type in situ (Figure 3).…”

Jchain-DTRMice Allow for Diphtheria Toxin-Mediated Depletion of Antibody-Secreting Cells and Evaluation of Their Differentiation Kinetics

“…While species such as humans, simians and mice all express the HB-EGF protein, the mouse version of the protein possesses distinct amino acid differences making this species relatively insensitive to DT 21 . As such, mouse models have been developed in which human or simian HBEGF (referred to throughout as the DTR) expression is driven by cell type-specific genetic elements thus allowing for targeted ablation of that particular cell type [22][23][24] .…”