Direct Targeting of Myofibroblast Pathways with Peptides

Version	Summary	Created by	Modification	Content Size	Created at	Operation
1		Adam C Midgley	--	1863	2023-08-09 11:34:38	\|
2	format correct	Conner Chen	Meta information modification	1863	2023-08-11 08:10:09	\|

This entry is adapted from the peer-reviewed paper 10.3390/biom13081179

Myofibroblasts are the principal effector cells driving fibrosis, and their accumulation in tissues is a fundamental feature of fibrosis. Essential pathways have been identified as being central to promoting myofibroblast differentiation, revealing multiple targets for intervention. Compared with large proteins and antibodies, peptide-based therapies have transpired to serve as biocompatible and cost-effective solutions to exert biomimicry, agonistic, and antagonistic activities with a high degree of targeting specificity and selectivity.

fibrosis myofibroblast antifibrotic peptides peptide engineering

1. Peptides Targeting the TGF-β Pathway

The TGF-β signaling pathway is considered the consensus canonical pathway in myofibroblast differentiation ^[1]^[2]^[3]^[4]. As such, the TGF-β1 and -β2 pathways have long been popular targets for antifibrotic interventions. Several components and contributors to successful TGF-β pathway activation, signal transduction, and downstream effects have presented opportunities for peptide intervention and interruption of signaling at different cellular locations (Table 1).

Table 1. Emergent peptides and corresponding amino acid sequences in relevance to TGF-β pathway interference. dN = d-Asparagine; nV = Norvaline; dS = d-Serine.

Peptide	Origin/Inspiration	Amino Acid Sequence	Antifibrotic Mechanism	Ref.
CXCL9(74-103)	CXCL9	KKKQKNGKKHQKKKVLKVRKSQRSRQKKTT	Competitively binds heparan sulphate GAGs to inhibit its complexation with TGF-β1	^[5]
KP1	Klotho	FQGTFPDGFLWAVGSAAYQTEGGWQQHGK	Competitively binds TGFβRII to inhibit TGFβRII/RI dimerization	^[6]
C53	CNP	DLRVDTKSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC	Facilitates prolonged cGMP production, inhibits Smad3 nuclear translocation, and promotes Smad3 degradation	^[7]
M10	MET	TRPASFWETS	Interacts with Smad2 to inhibit its nuclear translocation	^[8]
H-RN	HGF	RNPRGEEGGPW	Inhibition of TGF-β2/Smad and Akt/mTOR signaling pathways	^[9]
THR123	BMP7	CYFDDSSNVLCKKYRS	BMPR1A/Smad(1/5/(8)9) pathway agonist	^[10]
THR184	BMP7	CYYDNSSSVLCKRYRS	BMPR1A/Smad(1/5/(8)9) pathway agonist	^[10]
ADP355	Adiponectin	H(dN)IP(nV)LY(dS)FA(dS)	Activates AMPK suppression of TGF-β1 induced transcription driven by Smad3-binding cis-elements	^[11]

In the extracellular space and amongst the ECM, the glycosaminoglycan (GAG) and heparan sulfate (HS) can bind TGF-β1 and -β2 to potentiate their biological activities and receptor interactions ^[12]. Poosti et al. ^[5] demonstrated that truncated proteins that contained the highly positively charged COOH-terminal region of C-X-C chemokine ligand 9 (CXCL9) could bind GAGs with high affinity. They developed a synthetic peptide mimetic of the CXCL9 COOH-terminal, CXCL9(74-103), which was capable of competing with free TGF-β1 to bind HS. The ability to interrupt TGF-β1/HS complexation was dependent on the presence of two GAG-binding domains in CXCL9(74-103). In unilateral ureteral obstruction (UUO) mouse models of renal fibrosis, CCXL9(74-103) was delivered continuously over the course of 7 days by subcutaneously implanted osmotic pumps and resulted in the inhibition of pro-fibrotic markers in the UUO kidneys, including α-SMA, vimentin, fibronectin, collagen type III, TGF-β1, and matrix metalloproteinase (MMP)-9. In addition, CXCL9(74-103) lessened inflammation, as determined by reduced expression of F4/80⁺ macrophages and the monocyte-attractant CCL2.

Upon TGF-β binding, TGF-β receptor type 2 (TGFβRII) dimerizes with TGF-β receptor type 1 (TGFβRI) on the fibroblast cell membrane, which enables TGFβRII phosphorylation of the TGFβRI kinase domain. Subsequently, phosphorylation of Smad2 and Smad3 and their oligomerization with co-Smad4 result in transcription or co-transcription factor activity in the nucleus and regulation of pro-fibrotic gene expression ^[13]. Klotho is a single-pass transmembrane co-receptor of fibroblast growth factor 23 (FGF23) that is downregulated in aging or injured kidneys. Yuan et al. ^[6] developed a synthetic Klotho-derived peptide 1 (KP1), which contains the highly homologous and conserved 30 amino acid KL1 domain of Klotho. In the presence of KP1, TGF-β1 stimulated rat renal fibroblasts failed to differentiate into myofibroblasts. The mechanism of KP1 action was determined to be the competitive blockade of TGFβRII, thereby preventing TGF-β1 binding, dimerization of TGFβRII/TGFβRI, and downstream activation and nuclear translocation of Smad2/3. Tail vein injection of KP1 into unilateral renal ischemia-reperfusion injury (IRI) and UUO mouse models of renal fibrosis reciprocallyd inhibited TGFβRII activation and expression in vivo. Renal function was protected, and fibrosis was reduced without the initiation of dysregulated blood phosphorus and calcium metabolism that has been associated with elevated serum expression of Klotho. In addition, KP1 restored endogenous expression of Klotho, reduced the presence of UUO-induced renal F4/80⁺ macrophages, and blocked the infiltration of F4/80⁺ CD3⁺ macrophages.

C-type natriuretic peptide (CNP) induces the generation of the secondary messenger 3′,5′-cyclic guanosine monophosphate (cGMP), activation of protein kinase G-1a (PKG-1a), which in turn phosphorylates activated pSmad3 to prevent the translocation of the pSmad3/Smad4 heterodimer to the nucleus ^[14]^[15] and promotes proteasomal degradation of Smad3 ^[16]. Chen et al. ^[7] indicated that C53, a 53-amino acid intermediate form of pro-CNP, activated the particulate guanylyl cyclase B (pGC-B) receptor but elicited a more robust cGMP production response than CNP. The increased resistance of C53 against rapid degradation and catabolism by neprilysin provided sustained activity in vitro and resulted in anti-fibrotic actions in human cardiac and renal fibroblasts. M10 is a 10-amino acid peptide derived from the C-terminal cytoplasmic tail of the mesenchymal-epithelial transition factor (MET) receptor. Li et al. ^[8] demonstrated that M10 had anti-fibrotic effects during the early and late stages of silica-induced pulmonary fibrosis in mouse models. The authors then partially explored the underlying mechanisms in vitro. M10 was detected within both the cell cytoplasm and nuclei, and further investigation revealed its inhibition of Smad2 phosphorylation. M10 was suggested to have the capability to reverse silica-induced epithelial-to-mesenchymal transition (EMT) in epithelial cells and decrease TGF-β1 dependent activation of fibroblasts.

Hepatocyte growth factor splice variant NK1 (HGF/NK1) and bone morphogenetic protein 7 (BMP7) are two growth factors with demonstrated potent anti-fibrotic activities ^[17]^[18]. Huang and colleagues ^[9] employed H-RN peptide, derived from the kringle 1 domain present in HGF/NK1, to show in vitro inhibition of TGF-β2/Smad2/3-dependent induction of epithelial-mesenchymal transition (EMT) in lens epithelial cells, preventing their acquisition of myofibroblastic markers. H-RN also prevented TGF-β2/Smad-independent activation of Akt, mTOR, and p70S6K. The precise molecular mechanism of anti-fibrotic action and extent of HGF receptor MET’s role remain to be elucidated. The BMP7/Smad1/5/8 pathway competes with Smad2/3 for co-Smad4 binding, thereby interfering with pro-fibrotic gene transcription ^[19]. Salido-Medina et al. ^[10] evaluated the anti-fibrotic effects of BMP7-derived peptides, THR123 and THR184, in mouse models of transverse aortic constriction/release-induced cardiac remodeling and fibrosis. THR123 and THR184 bound BMP receptor 1A and increased phosphorylation of Smad1/5/(8)9 in the left ventricle (LV), which in turn rescued ventricular hypertrophy and dysfunction. Moreover, delayed administration of THR184 indicated its ability to prevent progressive remodeling and partially reverse LV dysfunction from pressure overload. Darmawan et al. ^[11] opted to use the adiponectin-derived peptide, ADP355, and demonstrated its antifibrotic effect on keloid fibroblasts and xenotransplanted keloid tissues. ADP355 inhibited procollagen expression and attenuated the activation of Smad3 while inducing the activation of AMP-activated protein kinase (AMPK), which has previously been described to interfere with Smad3 recruitment to gene promoters ^[20].

2. Peptides Targeting the ECM and Mechanotransduction

Mechanotransduction is required for myofibroblast maturation and terminal differentiation. Fibroblasts are mechanosensitive cells and perceive external stress forces through fibronexi and focal adhesion structures formed at the interface between the ECM, cell membrane receptors, and the cell cytoskeleton ^[21]^[22]^[23]^[24]. ECM substrate stiffness or rigidity promotes the conversion of extracellular ECM forces to intracellular signaling and contractile tension generation by the cell cytoskeleton. Elevated ECM microenvironment stiffness results in the incorporation of α-SMA into cytoplasmic β-actin stress fibers, granting myofibroblasts enhanced contractability ^[13]. Interruption of external-to-intracellular mechanotransduction signaling by preventing ECM assembly, ECM-receptor interactions, and downstream signaling associated with cytoskeletal reassembly can serve as suitable targets for peptide-based therapies (Table 2).

Table 2. Emergent peptides and corresponding amino acid sequences in relevance to ECM and mechanotransduction pathway interference.

Peptide	Origin /Inspiration	Amino Acid Sequence	Antifibrotic Mechanism	Ref.
B7-33	H2-Relaxin	VIKLSGRELVRAQIAISGMSTWSKRSL	RXFP1 agonist; promotes MMP2 expression and inhibits TIMP1, leading to reduced collagen fiber thickness	^[25]
E4	Endostatin/COL18A1	SYCETWRTEAPSATGQASSLLGGRLLGQSAASCH HAYIVLCIENSFMT	Regulates the urokinase pathway and induces MMP-1/-3 degradation of ECM	^[26]
AF38Pep	Integrin α4/β1 (VLA-4)	VMPYISTTPAKPCTSENCGNSWYGGFKSKNENKI YFIN	Competitively binds the EDA-FN C-C’ loop to prevent recognition by integrin α4/β1 or α4/β7	^[27]^[28]
LSKL	LAP	LSKL	TSP-1 antagonist, suppresses the PI3K/Akt/mTOR pathways	^[29]

A collagen-rich ECM has increased stiffness, promotes myofibroblast differentiation, and contributes to the further excess production of collagens that contribute to the detriment of functional tissue. Thus, encouraging collagen breakdown rather than synthesis could be an effective means to reduce ECM substrate stiffness. B7-33 is a relaxin family peptide receptor 1 (RXFP1) agonist and derivative of the human gene-2 (H2)-relaxin hormone, which has been widely documented for its antifibrotic effects ^[30]. In a 2021 study by Bhuiyan et al. ^[25] on the utilization of an automated platform for collagen quantification by second-harmonic generation, the authors continuously administered B7-33 peptide to UUO mouse models via subcutaneously implanted micro-osmotic pumps over the course of 7 days. Interestingly, B7-33 treatment increased collagen fiber counts but ameliorated UUO-induced interstitial collagen fiber thickness, which prevented renal fibrosis. The changes were explained by B7-33’s induction of MMP-2 and suppression of tissue inhibitor of metalloproteinase (TIMP)-1 protein expression, suggesting a facilitation of collagen fiber breakdown. More recently, Alam et al. ^[31] demonstrated that B7-33 reciprocated the cardioprotective and antifibrotic effects of recombinant H2 relaxin hormone (RLX, Serelaxin) in mouse models of isoprenaline-induced cardiomyopathy. Treatment with B7-33 or RLX reduced the presence of myofibroblasts and the expression of TGF-β1 in the myocardium.

The endostatin neoepitope is formed in situ by the cleavage of collagen XVIII. A peptide derivative of the endostatin C-terminus, known as E4, was the subject of earlier studies showing its remarkable antifibrotic effects on dermal and pulmonary models of fibrosis ^[32]. In a recent study by Sharma et al. ^[26], the E4 mechanism of action was determined to be via binding to the urokinase-type plasminogen activator receptor (uPAR), which activated the urokinase and plasminogen pathways. Subsequently, increased MMP-1 and -3 activity resulted in an enhancement of the degradation of the collagen I-enriched ECM. Additionally, E4 promoted the production of urokinase-type plasminogen activator (uPA) and HGF while inhibiting the production of plasminogen activator inhibitor-1 (PAI-1). Furthermore, in ex vivo lung tissue cultures, E4 induced MMP-1 activity and reduced collagen I, fibronectin, and PAI-1. Indeed, previous studies also indicated the roles of uPAR in attenuating myofibroblast functions, and these included proliferation, recruitment, and the subsequent progression of renal fibrosis by regulating extracellular signal-regulated kinase (ERK) signaling and reducing the extracellular accumulation of PAI-1 ^[33], which are also well-documented downstream targets of TGF-β1 signaling ^[4]^[34]^[35].

The extra domain A-containing fibronectin splice variant (EDA-FN) is detectable during tissue repair and fibrosis ^[13]. EDA-FN promotes myofibroblast differentiation by orchestrating latency-associated peptide (LAP) mitigation of TGF-β1 activation, increasing ECM stress–strain tension, and activating mechanotransduction via integrin signaling pathways. Incorporation of AF38Pep into polymeric wound dressings facilitated its controlled release into rabbit ear models of hypertrophic scarring ^[28]. AF38Pep successfully prevented myofibroblast differentiation, attenuated excessive deposition of disorganized collagen types I and III, and inhibited hypertrophic scar formation, which resulted in improved quality of dermal wound repair. Interestingly, the peptide exerted anti-proliferation activity against activated fibroblasts, myofibroblasts, and keloid fibroblasts but did not affect the proliferation rate of inactivated fibroblasts. This finding indicated a potential barrier functionality against hyperproliferative cells, offering an alternative route towards achieving regulated growth of invasive mesenchymal cell phenotypes. Xu et al. ^[29] employed the short LSKL peptide to occupy the LAP-binding site of thrombospondin-1 (TSP-1) to antagonize TSP-1-mediated activation of latent TGF-β in mechanically-induced rat tail models of hypertrophic scarring. LSKL attenuated PI3K/AKT/mTOR signaling and significantly attenuated hypertrophic scar features, such as thickened dermis and distorted collagen alignment.

References

Desmouliere, A.; Geinoz, A.; Gabbiani, F.; Gabbiani, G. Transforming growth factor-beta 1 induces alpha-smooth muscle actin expression in granulation tissue myofibroblasts and in quiescent and growing cultured fibroblasts. J. Cell Biol. 1993, 122, 103–111.
Evans, R.A.; Tian, Y.A.C.; Steadman, R.; Phillips, A.O. TGF-β1-mediated fibroblast–myofibroblast terminal differentiation—The role of smad proteins. Exp. Cell Res. 2003, 282, 90–100.
Frangogiannis, N. Transforming growth factor-beta in tissue fibrosis. J. Exp. Med. 2020, 217, e20190103.
Midgley, A.C.; Rogers, M.; Hallett, M.B.; Clayton, A.; Bowen, T.; Phillips, A.O.; Steadman, R. Transforming growth factor-beta1 (TGF-beta1)-stimulated fibroblast to myofibroblast differentiation is mediated by hyaluronan (HA)-facilitated epidermal growth factor receptor (EGFR) and CD44 co-localization in lipid rafts. J. Biol. Chem. 2013, 288, 14824–14838.
Poosti, F.; Soebadi, M.A.; Crijns, H.; De Zutter, A.; Metzemaekers, M.; Berghmans, N.; Vanheule, V.; Albersen, M.; Opdenakker, G.; Van Damme, J.; et al. Inhibition of renal fibrosis with a human CXCL9-derived glycosaminoglycan-binding peptide. Clin. Transl. Immunol. 2022, 11, e1370.
Yuan, Q.; Ren, Q.; Li, L.; Tan, H.; Lu, M.; Tian, Y.; Huang, L.; Zhao, B.; Fu, H.; Hou, F.F.; et al. A Klotho-derived peptide protects against kidney fibrosis by targeting TGF-beta signaling. Nat. Commun. 2022, 13, 438.
Chen, Y.; Zheng, Y.; Iyer, S.R.; Harders, G.E.; Pan, S.; Chen, H.H.; Ichiki, T.; Burnett, J.C., Jr.; Sangaralingham, S.J. C53: A novel particulate guanylyl cyclase B receptor activator that has sustained activity in vivo with anti-fibrotic actions in human cardiac and renal fibroblasts. J. Mol. Cell. Cardiol. 2019, 130, 140–150.
Li, Y.; Ji, X.; Yao, W.; Pan, H.; Li, P.; Liu, Y.; Yuan, J.; Xu, Q.; Ni, C. M10 peptide attenuates silica-induced pulmonary fibrosis by inhibiting Smad2 phosphorylation. Toxicol. Appl. Pharmacol. 2019, 376, 46–57.
Huang, X.; Wang, Y.; Zhang, P.; Zou, H. A HGFderived peptide suppresses EMT in human lens epithelial cells via the TGFbeta/Smad and Akt/mTOR signaling pathways. Mol. Med. Rep. 2020, 22, 551–558.
Salido-Medina, A.B.; Gil, A.; Exposito, V.; Martinez, F.; Redondo, J.M.; Hurle, M.A.; Nistal, J.F.; Garcia, R. BMP7-based peptide agonists of BMPR1A protect the left ventricle against pathological remodeling induced by pressure overload. Biomed. Pharmacother. 2022, 149, 112910.
Darmawan, C.C.; Montenegro, S.E.; Jo, G.; Kusumaningrum, N.; Lee, S.H.; Chung, J.H.; Mun, J.H. Adiponectin-Based Peptide (ADP355) Inhibits Transforming Growth Factor-beta1-Induced Fibrosis in Keloids. Int. J. Mol. Sci. 2020, 21, 2833.
Lyon, M.; Rushton, G.; Gallagher, J.T. The interaction of the transforming growth factor-betas with heparin/heparan sulfate is isoform-specific. J. Biol. Chem. 1997, 272, 18000–18006.
Tai, Y.; Woods, E.L.; Dally, J.; Kong, D.; Steadman, R.; Moseley, R.; Midgley, A.C. Myofibroblasts: Function, Formation, and Scope of Molecular Therapies for Skin Fibrosis. Biomolecules 2021, 11, 1095.
Li, P.; Oparil, S.; Novak, L.; Cao, X.; Shi, W.; Lucas, J.; Chen, Y.F. ANP signaling inhibits TGF-beta-induced Smad2 and Smad3 nuclear translocation and extracellular matrix expression in rat pulmonary arterial smooth muscle cells. J. Appl. Physiol. (1985) 2007, 102, 390–398.
Li, P.; Wang, D.; Lucas, J.; Oparil, S.; Xing, D.; Cao, X.; Novak, L.; Renfrow, M.B.; Chen, Y.F. Atrial natriuretic peptide inhibits transforming growth factor beta-induced Smad signaling and myofibroblast transformation in mouse cardiac fibroblasts. Circ. Res. 2008, 102, 185–192.
Saura, M.; Zaragoza, C.; Herranz, B.; Griera, M.; Diez-Marques, L.; Rodriguez-Puyol, D.; Rodriguez-Puyol, M. Nitric oxide regulates transforming growth factor-beta signaling in endothelial cells. Circ. Res. 2005, 97, 1115–1123.
Dally, J.; Khan, J.S.; Voisey, A.; Charalambous, C.; John, H.L.; Woods, E.L.; Steadman, R.; Moseley, R.; Midgley, A.C. Hepatocyte Growth Factor Mediates Enhanced Wound Healing Responses and Resistance to Transforming Growth Factor-beta(1)-Driven Myofibroblast Differentiation in Oral Mucosal Fibroblasts. Int. J. Mol. Sci. 2017, 18, 1843.
Midgley, A.C.; Wei, Y.; Zhu, D.; Gao, F.; Yan, H.; Khalique, A.; Luo, W.; Jiang, H.; Liu, X.; Guo, J.; et al. Multifunctional Natural Polymer Nanoparticles as Antifibrotic Gene Carriers for CKD Therapy. J. Am. Soc. Nephrol. 2020, 31, 2292–2311.
Meng, X.M.; Chung, A.C.; Lan, H.Y. Role of the TGF-beta/BMP-7/Smad pathways in renal diseases. Clin. Sci. 2013, 124, 243–254.
Mishra, R.; Cool, B.L.; Laderoute, K.R.; Foretz, M.; Viollet, B.; Simonson, M.S. AMP-activated protein kinase inhibits transforming growth factor-beta-induced Smad3-dependent transcription and myofibroblast transdifferentiation. J. Biol. Chem. 2008, 283, 10461–10469.
Bochaton-Piallat, M.L.; Gabbiani, G.; Hinz, B. The myofibroblast in wound healing and fibrosis: Answered and unanswered questions. F1000Res 2016, 5, F1000.
Goffin, J.M.; Pittet, P.; Csucs, G.; Lussi, J.W.; Meister, J.J.; Hinz, B. Focal adhesion size controls tension-dependent recruitment of alpha-smooth muscle actin to stress fibers. J. Cell Biol. 2006, 172, 259–268.
Hinz, B. Masters and servants of the force: The role of matrix adhesions in myofibroblast force perception and transmission. Eur. J. Cell Biol. 2006, 85, 175–181.
Tomasek, J.J.; Gabbiani, G.; Hinz, B.; Chaponnier, C.; Brown, R.A. Myofibroblasts and mechano-regulation of connective tissue remodelling. Nat. Rev. Mol. Cell Biol. 2002, 3, 349–363.
Bhuiyan, S.; Shen, M.; Chelvaretnam, S.; Tan, A.Y.; Ho, G.; Hossain, M.A.; Widdop, R.E.; Samuel, C.S. Assessment of renal fibrosis and anti-fibrotic agents using a novel diagnostic and stain-free second-harmonic generation platform. FASEB J. 2021, 35, e21595.
Sharma, S.; Watanabe, T.; Nishimoto, T.; Takihara, T.; Mlakar, L.; Nguyen, X.X.; Sanderson, M.; Su, Y.; Chambers, R.A.; Feghali-Bostwick, C. E4 engages uPAR and enolase-1 and activates urokinase to exert antifibrotic effects. JCI Insight 2021, 6, e144935.
Zhang, L.; Yan, H.; Tai, Y.; Xue, Y.; Wei, Y.; Wang, K.; Zhao, Q.; Wang, S.; Kong, D.; Midgley, A.C. Design and Evaluation of a Polypeptide that Mimics the Integrin Binding Site for EDA Fibronectin to Block Profibrotic Cell Activity. Int. J. Mol. Sci. 2021, 22, 1575.
Zhang, L.; Tai, Y.; Liu, X.; Liu, Y.; Dong, Y.; Liu, Y.; Yang, C.; Kong, D.; Qi, C.; Wang, S.; et al. Natural polymeric and peptide-loaded composite wound dressings for scar prevention. Appl. Mater. Today 2021, 25, 101186.
Xu, X.; Khoong, Y.M.; Gu, S.; Huang, X.; Ren, J.Y.; Gu, Y.H.; Li, H.; Gao, Y.; Wang, Z.; Zan, T. Investigating the potential of LSKL peptide as a novel hypertrophic scar treatment. Biomed. Pharmacother. 2020, 124, 109824.
Samuel, C.S.; Royce, S.G.; Hewitson, T.D.; Denton, K.M.; Cooney, T.E.; Bennett, R.G. Anti-fibrotic actions of relaxin. Br. J. Pharmacol. 2017, 174, 962–976.
Alam, F.; Gaspari, T.A.; Kemp-Harper, B.K.; Low, E.; Aw, A.; Ferens, D.; Spizzo, I.; Jefferis, A.M.; Praveen, P.; Widdop, R.E.; et al. The single-chain relaxin mimetic, B7-33, maintains the cardioprotective effects of relaxin and more rapidly reduces left ventricular fibrosis compared to perindopril in an experimental model of cardiomyopathy. Biomed. Pharmacother. 2023, 160, 114370.
Yamaguchi, Y.; Takihara, T.; Chambers, R.A.; Veraldi, K.L.; Larregina, A.T.; Feghali-Bostwick, C.A. A peptide derived from endostatin ameliorates organ fibrosis. Sci. Transl. Med. 2012, 4, 136ra171.
Zhang, G.; Cai, X.; Lopez-Guisa, J.M.; Collins, S.J.; Eddy, A.A. Mitogenic signaling of urokinase receptor-deficient kidney fibroblasts: Actions of an alternative urokinase receptor and LDL receptor-related protein. J. Am. Soc. Nephrol. 2004, 15, 2090–2102.
Alenchery, R.G.; Ajalik, R.E.; Jerreld, K.; Midekksa, F.; Zhong, S.; Alkatib, B.; Awad, H.A. PAI-1 mediates TGF-beta1-induced myofibroblast activation in tenocytes via mTOR signaling. J. Orthop. Res. 2023.
Omori, K.; Hattori, N.; Senoo, T.; Takayama, Y.; Masuda, T.; Nakashima, T.; Iwamoto, H.; Fujitaka, K.; Hamada, H.; Kohno, N. Inhibition of Plasminogen Activator Inhibitor-1 Attenuates Transforming Growth Factor-beta-Dependent Epithelial Mesenchymal Transition and Differentiation of Fibroblasts to Myofibroblasts. PLoS ONE 2016, 11, e0148969.

© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.

Upload a video for this entry

Information

Subjects: Biochemistry & Molecular Biology

Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :

Zhen Liu

Xinyan Zhang

Yanrong Wang

Yifan Tai

Xiaolin Yao

Adam C. Midgley

View Times: 454

Update Date: 11 Aug 2023

Table of Contents

Video Upload Options

Confirm

1. Peptides Targeting the TGF-β Pathway

2. Peptides Targeting the ECM and Mechanotransduction

References