Key result
Tamoxifen-induced Tcf21-iCre shows low recombination efficiency in fibrogenic fibroblasts, minimally reducing Hif1a expression.
Why the study?
Cardiac fibrosis research is challenging due to fibroblast heterogeneity, prompting evaluation of whether Tcf21-iCre can successfully target floxed loci after tamoxifen injections in adult mouse models.
The Tcf21-iCre mouse model exhibits limited recombination efficiency in adult cardiac fibroblasts following intraperitoneal tamoxifen injection, restricting its utility for broad loss-of-function studies in cardiac fibrosis.
Low Tcf21-iCre efficiency limits its utility for adult cardiac fibroblast gene targeting; leaves open need for optimized Cre drivers in fibrosis research.
Cardiac fibrosis plays a crucial role in heart failure, but research in this field remains challenging due to heterogeneity of cardiac fibroblast populations. In the past years, several Cre-drivers have been proposed for cardiac fibroblast-specific deletion of floxed genes in adult mouse research models. Here, we evaluated whether Tcf21-iCre, a tamoxifen-inducible Cre recombinase (iCre) under the endogenous Tcf21 promoter, was able to successfully target two floxed loci (Hypoxia inducible factor 1a (Hif1a) and the fluorescent reporter locus mTmG) after intraperitoneal tamoxifen injections. Six-week-old mice received intraperitoneal tamoxifen injections on five consecutive days to induce Cre activity, and the recombination efficiency was measured in isolated fibroblasts via qPCR, Western Blot and fluorescence microscopy. Recombination efficiency was very low, with minimal reduction in expression of Hif1a. For the mTmG locus, both bi-allelic and mono-allelic recombination was detected, with mono-allelic events suggesting low Cre activity even within Tcf21-expressing fibroblasts. The addition of experimental models of heart failure with reduced or preserved ejection fraction as pro-fibrotic stimuli or an inclusion of an additional round or higher doses of tamoxifen injections did not improve recombination efficiency of the targeted alleles. Thus, Tcf21-iCre targets only a small proportion of fibrogenic fibroblasts following i.p. tamoxifen injection, limiting its usability in loss-of-function studies that require broad fibroblast coverage and highlighting the need for alternative Cre-drivers or delivery strategies to facilitate antifibrotic therapy development.
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Schober et al. (2026) studied Cardiac fibrosis. Tamoxifen vs. Tcf21-iCre- mice was evaluated on Recombination efficiency (Hif1a mRNA reduction and mTmG fluorescence). Tcf21-iCre targets only a small proportion of fibrogenic fibroblasts following intraperitoneal tamoxifen injection, resulting in minimal reduction of Hif1a expression.
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