Table 2.

Studies documenting fibroblast-mediated signaling in repair and remodeling of the infarcted heart using fibroblast-specific targeting approaches.

Mediator	Fibroblast-Specific Approach	Role in Repair and Remodeling of the Infarcted Heart	Role in Modulation of Fibroblast Phenotype	Proposed Mechanism	Ref.
IL1-R1	Tamoxifen-inducible Col1a2 CreERT mice were used for fibroblast- specific deletion of IL1-R1.	Fibroblast-specific IL1-R1 drives adverse cardiac remodeling and promotes ventricular wall thinning and collagen deposition in a model of non-reperfused infarction.	IL1-R1 promotes a pro-fibrotic and matrix-degrading phenotype in fibroblasts.	IL1-α interacts with IL1-R1 to activate p38 and NFκB signaling, leading to increased expression of IL6, MMP3, and MMP9 and secretion of IL-6 and MMP-3.	[85]
Smad3	Myofibroblast-specific deletion used Postn-Cre mice.	Myofibroblast-specific Smad3 protects from cardiac rupture in the non-reperfused infarction model and attenuates chamber dilation.	Smad3 limits fibroblast proliferation and promotes collagen synthesis. It also mediates the formation of organized myofibroblast arrays.	Smad3 regulates fibroblast function via integrin-mediated NOX-2 expression. Moreover, Smad3-dependent activation of the GTPase RhoA dictates fibroblast alignment via the regulation of cell polarity pathways.	[108,110]
Smad7	Postn-Cre mice were used for myofibroblast-specific knockout of Smad7.	Myofibroblast Smad7 protects the infarcted heart from adverse remodeling and from heart failure-related death. Smad7 limits post-infarction fibrosis in the border zone and in the papillary muscles.	Smad7 attenuates myofibroblast activation and the synthesis of structural and matricellular ECM proteins.	Smad7 inhibits the TGFβ response via the inactivation of Smad2/3. Smad7 also binds to ErbB2 and restrains the activation of ErbB1/2 in a TGF-β-independent manner to suppress the expression of fibrogenic genes.	[5]
GSK3β	Postn-Cre mice and tamoxifen-inducible Col1a2-Cre mice were used for deletion in myofibroblasts and fibroblasts, respectively.	Myofibroblast-specific GSK3β negatively regulates fibrosis to limit adverse ventricular remodeling in the infarcted heart.	GSK3β functions to suppress myofibroblast activation and pro-fibrotic signaling.	GSK3β inhibits TGF-β-dependent Smad3 transcriptional activation to limit fibrogenic signaling.	[163]
P38α	TCF-21 or Postn-MCM mouse models were used to generate fibroblast and myofibroblast-specific p38α KO mice.	P38α-dependent signaling in fibroblasts drives fibrosis to promote adverse post-infarction remodeling.	P38 mediates cardiac fibroblast activation.	P38 transduces mechanical and cytokine signals via serum response factor and calcineurin to promote myofibroblast differentiation.	[140]
GRK2	Myofibroblast-specific GRK2 deletion was achieved using Postn-MCM mice.	GRK2 signaling contributes to pathological cardiac remodeling via promoting fibrosis and infarct expansion, leading to cardiac dysfunction.	GRK2 promotes myofibroblast activation and collagen deposition in vivo.	GRK2 interacts with Gβγ, promoting the downregulation of fibroblast β-adrenergic receptors. This decreases downstream cAMP production, resulting in the activation of pro-fibrotic signals.	[164]
Lats1/2	Tcf21-MCM mice were used for fibroblast-specific Lats1/2 deletion.	Lats1/2 limit pro-fibrotic signaling.	Lats1/2 maintain the resting fibroblast phenotype and prevents activation to myofibroblast.	Lats1/2 act to maintain the quiescent fibroblast cell state via inhibiting the YAP-induced activation of pro-fibrogenic genes.	[31]
YAP	Tcf21-MCM and Col1a1 CreERT mice were used for YAP deletion in fibroblasts.	YAP promotes post-infarction fibrosis.	YAP activation in fibroblasts promotes myofibroblast proliferation and differentiation and ECM gene expression.	YAP activation induces MRTF-A expression to facilitate myofibroblast differentiation and profibrotic gene expression.	[162]
5-HT2B	Tcf21-MCM and Postn-MCM were used to delete 5-HT2B in resting and activated fibroblasts, respectively.	5-HT2B expression directly contributes to excessive scar formation, leading to adverse cardiac remodeling and impaired cardiac function post-MI.	5-HT2B promotes fibroblast proliferation and migration and the expression of ECM remodeling genes.	5-HT2B-dependent fibroblast responses are mediated via Dnajb4 expression and Src phosphorylation.	[165]
Hsp47	Postn-MCM mice were used for the generation of myofibroblast-specific Hsp47 KO mice.	Hsp47 expression in myofibroblasts mediates scar formation post-MI.	HSP47 promotes fibroblast proliferation and mediates the expression of collagens without affecting the expression of α-SMA.	HSP47 enhances the expression of Snail and Zeb1 to transcriptionally activate ECM-related genes. It also downregulates the expression of cell cycle inhibitory kinases to facilitate cell proliferation.	[32]
Sox9	Postn-MCM mice were used for myofibroblast-specific KO.	Myofibroblast-specific Sox9 facilitates MI-induced left ventricular dysfunction, inflammation, and tissue scarring.	Sox9 activity promotes fibroblast activation, proliferation, migration, and contractile function.	Sox9 up-regulates ECM-related gene synthesis, inflammation, and proteolysis.	[166]
AMPKα1	Postn-Cre was used for the deletion of AMPKα1 in myofibroblasts.	AMPKα1 activation in myofibroblasts limits adverse post-infarction remodeling post-MI.	Myofibroblast-specific AMPKα1 inhibits fibroblast proliferation in response to injury.	AMPKα1 inhibits fibroblast activation and proliferation via the miR-125b-5p-dependent silencing of connexin-43.	[167]
Muscleblind-like1 (MBNL1)	Tcf21-MCM was used for the fibroblast-specific deletion and overexpression of MBNL1. Postn-MCM was used for the deletion of MBNL1 in activated fibroblasts.	Myofibroblast-specific MBNL1 facilitates the acute wound-healing response post-MI and promotes tissue fibrosis.	MBNL1 promotes myofibroblast transition and contractile function in fibroblasts.	The RNA-binding protein MBNL1 binds to and stabilizes mRNA encoding CnAβ and SRF, promoting myofibroblast differentiation and profibrotic gene expression.	[168]
Fibronectin	Tcf21-MCM was used for the ablation of fibronectin in fibroblasts.	Fibronectin polymerization facilitates adverse cardiac remodeling and fibrosis post I/R injury.	Polymerized FN promotes fibroblast proliferation and migration and collagen matrix deposition.	Fibronectin activates c-myc signaling, leading to integrin β1 activation and the downstream phosphorylation of FAK.	[169]