Comparative Evaluation of Inducible Cre Mouse Models for Fibroblast Targeting in the Healthy and Infarcted Myocardium

Aguado-Alvaro, Laura Pilar; Garitano, Nerea; Abizanda, Gloria; Larequi, Eduardo; Prósper, Felipe; Pelacho, Beatriz

doi:10.3390/biomedicines10102350

Cited by 5 publications

(3 citation statements)

References 48 publications

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“…Interestingly, the exoFB underwent after grafting further differentiation and maturation, as immunostainings revealed decreasing αSMA and increasing PDGFRα levels (Fig 4f). This was comparable to the endoFB and in line with earlier observations by other groups (26, 27). Increased collagen staining at 2 weeks post-surgery showed increasing compaction of the scar in injected and non-injected hearts (Fig 4e).…”

Section: Resultssupporting

confidence: 93%

Efficient targeting of heart lesions with cardiac myofibroblasts: Combined gene and cell therapy enhanced by magnetic steering

Schiffer,

Wagner,

Carls

et al. 2024

Preprint

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1AbstractThe cardiac scar is a collagen-rich area, which is populated by myofibroblasts and has proven little amenable for therapeutic interventions. Herein, we have established an efficient targeting strategy for cardiac lesions by genetically manipulating embryonic cardiac myofibroblasts (mFB)in vitro, load the cells with magnetic nanoparticles and inject these into infarcted mouse hearts using magnetic steering. This yields strongly increased numbers (∼4 fold compared to other cell types) of engrafted mFB. The injected mFB and endogenous myofibroblast (endoFB) population remain separate in the scar, but grafted mFB enhance the proliferation rate of endoFB by ∼4 fold. We also tested the functional impact of this approach by grafting lentiviral (LV)-transduced Connexin43 (Cx43) overexpressing mFB into the cardiac lesion. Prominent engraftment of Cx43+mFB provides strong protection against post-infarct ventricular tachycardia (VT)in vivo, as VT incidence is reduced by ∼50 % at two and eight weeks after cell injection. Thus,ex vivogene and subsequentin vivocell therapy combined with magnetic steering of cardiac mFB enable efficient functional targeting of the cardiac scar.

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Section: Resultssupporting

confidence: 93%

Efficient targeting of heart lesions with cardiac myofibroblasts: Combined gene and cell therapy enhanced by magnetic steering

Schiffer,

Wagner,

Carls

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…These incompatible results may be explained by the different manipulation of myocardial IRX2. Several studies have raised concerns that Col1α2-driven gene deletion was of limited value in deciphering the mechanism of cardiac fibrosis 43 , 44 . The use of Col1α2-driven Irx2 deletion didn’t compromise our main finding that IRX2 is a master regulator of pathological cardiac fibrosis.…”

Section: Discussionmentioning

confidence: 99%

IRX2 regulates angiotensin II-induced cardiac fibrosis by transcriptionally activating EGR1 in male mice

Yao

Fan

et al. 2023

Nat Commun

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Cardiac fibrosis is a common feature of chronic heart failure. Iroquois homeobox (IRX) family of transcription factors plays important roles in heart development; however, the role of IRX2 in cardiac fibrosis has not been clarified. Here we report that IRX2 expression is significantly upregulated in the fibrotic hearts. Increased IRX2 expression is mainly derived from cardiac fibroblast (CF) during the angiotensin II (Ang II)-induced fibrotic response. Using two CF-specific Irx2-knockout mouse models, we show that deletion of Irx2 in CFs protect against pathological fibrotic remodelling and improve cardiac function in male mice. In contrast, Irx2 gain of function in CFs exaggerate fibrotic remodelling. Mechanistically, we find that IRX2 directly binds to the promoter of the early growth response factor 1 (EGR1) and subsequently initiates the transcription of several fibrosis-related genes. Our study provides evidence that IRX2 regulates the EGR1 pathway upon Ang II stimulation and drives cardiac fibrosis.

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“…4D, left). Following backcrossing G0 animals to wildtype mice and validation via genotyping, we crossed the CCR3 fl/fl with the inducible PDGFRa CreERT mice to deplete CCR3 specifically in cardiac fibroblasts 21 . Activation of Cre following 2 weeks of tamoxifen diet feeding led to the depletion of cardiac CCR3 expression specifically in fibroblasts while preserving expression in endothelial cells (Fig.…”

Section: Ccl24 Promotes Fibrosis Through the Ccr3 Receptormentioning

confidence: 99%

Macrophage-derived CCL24 promotes fibrosis and worsens cardiac dysfunction during heart failure

Parthiban,

Barrow,

Nguyen

et al. 2024

Preprint

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Inflammation is a significant risk factor and contributes to cardiovascular disease by driving both adaptive and maladaptive processes. Macrophages are the most abundant immune cells in the heart and play an important role in the remodeling of cardiac tissue. We have previously shown an overall protective function of resident cardiac macrophages after pressure-overloaded injury. However, a subpopulation of resident macrophages also expresses high levels of the profibrotic CC motif chemokine ligand 24 (CCL24), suggesting a dichotomous role in pressure overload-induced cardiac remodeling. Here, we report that following transverse aortic constriction CCL24 knockout (CCL24 KO) mice have improved systolic function, cardiac wall enlargement, as well as increased myocyte surface area and hypertrophy, suggesting that CCL24 disrupts compensatory hypertrophy. TAC-operated CCL24 KO mice also displayed reduced fibrosis and diminished expression of fibrotic genes, implying a pro-fibrotic role for CCL24. Indeed, CCL24 induced the proliferation and activation of primary mouse fibroblasts in a process that required CCR3, the sole G protein-coupled receptor for CCL24. Correspondingly, selective ablation of CCR3 in fibroblasts improved cardiac function and ameliorated fibrosis following pressure overload. Administration of a CCL24 blocking antibody or a CCR3 antagonist both improved cardiac function in pressure-overloaded mice, highlighting the CCL24-CCR3 axis as a potential therapeutic target for heart failure. Finally, CCL24 deficiency improved cardiac function and ameliorated fibrosis during physiological aging. Overall, these results show that macrophage-derived CCL24 aggravates fibrosis via the CCR3 receptor, leading to impaired cardiac function in acute and chronic heart failure.

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Comparative Evaluation of Inducible Cre Mouse Models for Fibroblast Targeting in the Healthy and Infarcted Myocardium

Cited by 5 publications

References 48 publications

Efficient targeting of heart lesions with cardiac myofibroblasts: Combined gene and cell therapy enhanced by magnetic steering

Efficient targeting of heart lesions with cardiac myofibroblasts: Combined gene and cell therapy enhanced by magnetic steering

IRX2 regulates angiotensin II-induced cardiac fibrosis by transcriptionally activating EGR1 in male mice

Macrophage-derived CCL24 promotes fibrosis and worsens cardiac dysfunction during heart failure

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