Comparative effects of acute inflammatory challenge on hematopoietic stem cell differentiation in mouse models of clonal hematopoiesis.

Hanna Kodama

Document Type

Article

Publication Date

Summer 2022

Keywords

JMG

JAX Location

In: Student Reports, Summer 2022, The Jackson Laboratory

Abstract

Clonal hematopoiesis (CH) is an age-related condition characterized by the selective advantage and expansion of mutant hematopoietic stem cells (HSCs). One of the proposed mechanisms by which CH-associated mutations are thought to cause a selective advantage of HSCs is through resistance to inflammation. To support investigation of this and other potential mechanisms, a Cre-inducible mouse model of a common human CH mutation in the gene DNMT3A was developed by the Trowbridge lab. In this study, Dnmt3aR878H/+ (Dnmt3amut) was induced using two different Cre recombinase expression models; the Mx1-Cre model which results in expression across all HSCs, and the Fgd5-CreERT2 model which is expressed predominantly in stress-resistant HSCs. We hypothesize that if the Dnmt3amut causes a selective advantage by stress/inflammation resistance, then inducing the mutation in an already stress-resistant HSC population would mask their selective growth advantage. This project tests the hypothesis that the effect of Dnmt3a mutation on HSCs under inflammatory stress will be greater when using the Mx1-Cre model compared to when using the Fgd5-CreERT2 model. While we were unable to draw comparisons between the mouse models, we show that in vitro acute LPS and Pam3CSK4 stimulation does not induce a stress response significant enough for a visible phenotypic change in HSPC differentiation, and we may need to stimulate in vivo.

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