|
1
|
Vanderstichele S, Vranckx JJ. Anti-fibrotic effect of adipose-derived stem cells on fibrotic scars. World J Stem Cells 2022; 14:200-213. [PMID: 35432731 PMCID: PMC8963379 DOI: 10.4252/wjsc.v14.i2.200] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 05/01/2021] [Accepted: 02/16/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Sustained injury, through radiotherapy, burns or surgical trauma, can result in fibrosis, displaying an excessive deposition of extracellular matrix (ECM), persisting inflammatory reaction, and reduced vascularization. The increasing recognition of fibrosis as a cause for disease and mortality, and increasing use of radiotherapy causing fibrosis, stresses the importance of a decent anti-fibrotic treatment.
AIM To obtain an in-depth understanding of the complex mechanisms underlying fibrosis, and more specifically, the potential mechanisms-of-action of adipose-derived stomal cells (ADSCs) in realizing their anti-fibrotic effect.
METHODS A systematic review of the literature using PubMed, Embase and Web of Science was performed by two independent reviewers.
RESULTS The injection of fat grafts into fibrotic tissue, releases ADSC into the environment. ADSCs’ capacity to directly differentiate into key cell types (e.g., ECs, fibroblasts), as well as to secrete multiple paracrine factors (e.g., hepatocyte growth factor, basis fibroblast growth factor, IL-10), allows them to alter different mechanisms underlying fibrosis in a combined approach. ADSCs favor ECM degradation by impacting the fibroblast-to-myofibroblast differentiation, favoring matrix metalloproteinases over tissue inhibitors of metalloproteinases, positively influencing collagen organization, and inhibiting the pro-fibrotic effects of transforming growth factor-β1. Furthermore, they impact elements of both the innate and adaptive immune response system, and stimulate angiogenesis on the site of injury (through secretion of pro-angiogenic cytokines like stromal cell-derived factor-1 and vascular endothelial growth factor).
CONCLUSION This review shows that understanding the complex interactions of ECM accumulation, immune response and vascularization, is vital to fibrosis treatments’ effectiveness like fat grafting. It details how ADSCs intelligently steer this complex system in an anti-fibrotic or pro-angiogenic direction, without falling into extreme dilation or stimulation of a single aspect. Detailing this combined approach, has brought fat grafting one step closer to unlocking its full potential as a non-anecdotal treatment for fibrosis.
Collapse
Affiliation(s)
| | - Jan Jeroen Vranckx
- Department of Plastic, Reconstructive Surgery, KU-Leuven University Hospitals, Leuven 3000, Belgium
| |
Collapse
|
|
2
|
Dolivo DM, Larson SA, Dominko T. Fibroblast Growth Factor 2 as an Antifibrotic: Antagonism of Myofibroblast Differentiation and Suppression of Pro-Fibrotic Gene Expression. Cytokine Growth Factor Rev 2017; 38:49-58. [PMID: 28967471 DOI: 10.1016/j.cytogfr.2017.09.003] [Citation(s) in RCA: 75] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2017] [Accepted: 09/22/2017] [Indexed: 02/08/2023]
Abstract
Fibrosis is a pathological condition that is characterized by the replacement of dead or damaged tissue with a nonfunctional, mechanically aberrant scar, and fibrotic pathologies account for nearly half of all deaths worldwide. The causes of fibrosis differ somewhat from tissue to tissue and pathology to pathology, but in general some of the cellular and molecular mechanisms remain constant regardless of the specific pathology in question. One of the common mechanisms underlying fibroses is the paradigm of the activated fibroblast, termed the "myofibroblast," a differentiated mesenchymal cell with demonstrated contractile activity and a high rate of collagen deposition. Fibroblast growth factor 2 (FGF2), one of the members of the mammalian fibroblast growth factor family, is a cytokine with demonstrated antifibrotic activity in non-human animal, human, and in vitro models. FGF2 is highly pleiotropic and its receptors are present on many different cell types throughout the body, lending a great deal of variety to the potential mechanisms of FGF2 effects on fibrosis. However, recent reports demonstrate that a substantial contribution to the antifibrotic effects of FGF2 comes from the inhibitory effects of FGF2 on connective tissue fibroblasts, activated myofibroblasts, and myofibroblast progenitors. FGF2 demonstrates effects antagonistic towards fibroblast activation and towards mesenchymal transition of potential myofibroblast-forming cells, as well as promotes a gene expression paradigm more reminiscent of regenerative healing, such as that which occurs in the fetal wound healing response, than fibrotic resolution. With a better understanding of the mechanisms by which FGF2 alters the wound healing cascade and results in a shift away from scar formation and towards functional tissue regeneration, we may be able to further address the critical need of therapy for varied fibrotic pathologies across myriad tissue types.
Collapse
Affiliation(s)
- David M Dolivo
- Worcester Polytechnic Institute, Department of Biology and Biotechnology,100 Institute Road, Worcester, MA, 01609, United States
| | - Sara A Larson
- Worcester Polytechnic Institute, Department of Biology and Biotechnology,100 Institute Road, Worcester, MA, 01609, United States
| | - Tanja Dominko
- Worcester Polytechnic Institute, Department of Biology and Biotechnology,100 Institute Road, Worcester, MA, 01609, United States.
| |
Collapse
|
|
3
|
Rao VH, Rai V, Stoupa S, Agrawal DK. Blockade of Ets-1 attenuates epidermal growth factor-dependent collagen loss in human carotid plaque smooth muscle cells. Am J Physiol Heart Circ Physiol 2015; 309:H1075-86. [PMID: 26254334 DOI: 10.1152/ajpheart.00378.2015] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2015] [Accepted: 07/27/2015] [Indexed: 12/27/2022]
Abstract
Although degradation of extracellular matrix by matrix metalloproteinases (MMPs) is thought to be involved in symptomatic (S) carotid plaques in atherosclerosis, the mechanisms of MMP expression are poorly understood. Here, we demonstrate that collagen loss in vascular smooth vessel cells (VSMCs) isolated from S plaques was induced by epidermal growth factor (EGF) through the activation of p38-MAPK and JNK-MAPK pathways. Inhibitors of p38-MAPK and JNK-MAPK signaling pathways downregulated the expression of MMP-1 and MMP-9. In addition, we examined whether v-ets erythroblastosis virus E26 oncogene homologue 1 (Ets-1), an important regulator of different genes, is involved in destabilizing S plaques in patients with carotid stenosis. We demonstrate that EGF induces Ets-1 expression and decreases interstitial and basement membrane collagen in vascular smooth muscle cells (VSMCs) from patients with carotid stenosis. Increased expression of MMP-1 and -9 and decreased collagen mRNA transcripts were also found in Ets-1-overexpressed VSMCs. Transfection with both dominant-negative form of Ets-1 and small interfering RNA blocked EGF-induced MMP-1 and -9 expressions and increased the mRNA transcripts for collagen I (α1) and collagen III (α1) in S compared with asymptomatic (AS) carotid plaques. Inhibitors of p38-MAPK (SB202190) and JNK-MAPK (SP600125) signaling pathways decreased the expression of Ets-1, MMP-1, and MMP-9 and increased collagen type I and III expression in EGF-treated VSMCs. This study provides a mechanistic insight into the role of Ets-1 in the plaque destabilization in patients with carotid stenosis involving p38-MAPK and JNK signaling pathways.
Collapse
Affiliation(s)
- Velidi H Rao
- Center for Clinical and Translational Science, Creighton University School of Medicine, Omaha, Nebraska
| | - Vikrant Rai
- Center for Clinical and Translational Science, Creighton University School of Medicine, Omaha, Nebraska
| | - Samantha Stoupa
- Center for Clinical and Translational Science, Creighton University School of Medicine, Omaha, Nebraska
| | - Devendra K Agrawal
- Center for Clinical and Translational Science, Creighton University School of Medicine, Omaha, Nebraska
| |
Collapse
|
|
4
|
Abnormally differentiating keratinocytes in the epidermis of systemic sclerosis patients show enhanced secretion of CCN2 and S100A9. J Invest Dermatol 2014; 134:2693-2702. [PMID: 24933320 DOI: 10.1038/jid.2014.253] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2014] [Revised: 04/09/2014] [Accepted: 04/22/2014] [Indexed: 12/24/2022]
Abstract
Skin involvement with dermal fibrosis is a hallmark of systemic sclerosis (SSc), and keratinocytes may be critical regulators of fibroblast function through secretion of chemo-attracting agents, as well as through growth factors and cytokines influencing the phenotype and proliferation rate of fibroblasts. Epithelial-fibroblast interactions have an important role in fibrosis in general. We have characterized the SSc epidermis and asked whether SSc-injured epidermal cells release factors capable of promoting fibrosis. Our results show that the SSc epidermis is hypertrophic, and has altered expression of terminal differentiation markers involucrin, loricrin, and filaggrin. Multiplex profiling revealed that SSc epidermal explants release increased levels of CCN2 and S100A9. CCN2 induction was found to spread into the upper papillary dermis, whereas S100A9 was shown to induce fibroblast proliferation and to enhance fibroblast CCN2 expression via Toll-like receptor 4. These data suggest that the SSc epidermis provides an important source of pro-fibrotic CCN2 and proinflammatory S100A9 in SSc skin, and therefore contributes to the fibrosis and inflammation seen in the disease.
Collapse
|
|
5
|
Ham O, Lee CY, Song BW, Lee SY, Kim R, Park JH, Lee J, Seo HH, Lee CY, Chung YA, Maeng LS, Lee MY, Kim J, Hwang J, Woo DK, Chang W. Upregulation of miR-23b enhances the autologous therapeutic potential for degenerative arthritis by targeting PRKACB in synovial fluid-derived mesenchymal stem cells from patients. Mol Cells 2014; 37:449-456. [PMID: 24916040 PMCID: PMC4086338 DOI: 10.14348/molcells.2014.0023] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2014] [Revised: 05/21/2014] [Accepted: 05/22/2014] [Indexed: 01/05/2023] Open
Abstract
The use of synovial fluid-derived mesenchymal stem cells (SFMSCs) obtained from patients with degenerative arthropathy may serve as an alternative therapeutic strategy in osteoarthritis (OA) and rheumatoid arthritis (RA). For treatment of OA and RA patients, autologous transplantation of differentiated MSCs has several beneficial effects for cartilage regeneration including immunomodulatory activity. In this study, we induced chondrogenic differentiation of SFMSCs by inhibiting protein kinase A (PKA) with a small molecule and microRNA (miRNA). Chondrogenic differentiation was confirmed by PCR and immunocytochemistry using probes specific for aggrecan, the major cartilaginous proteoglycan gene. Absorbance of alcian blue stain to detect chondrogenic differentiation was increased in H-89 and/or miRNA-23btransfected cells. Furthermore, expression of matrix metalloproteinase (MMP)-9 and MMP-2 was decreased in treated cells. Therefore, differentiation of SFMSCs into chondrocytes through inhibition of PKA signaling may be a therapeutic option for OA or RA patients.
Collapse
Affiliation(s)
- Onju Ham
- Cardiovascular Research Institute, Yonsei University College of Medicine, Seoul 120-752,
Korea
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 120-752,
Korea
| | - Chang Youn Lee
- Department of Integrated Omics for Biomedical Sciences, Graduate School, Yonsei University, Seoul 120-759,
Korea
| | - Byeong-Wook Song
- Cardiovascular Research Institute, Yonsei University College of Medicine, Seoul 120-752,
Korea
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 120-752,
Korea
| | - Se-Yeon Lee
- Cardiovascular Research Institute, Yonsei University College of Medicine, Seoul 120-752,
Korea
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 120-752,
Korea
| | - Ran Kim
- Department of Biology Education, College of Education, Pusan National University, Busan 609-735,
Korea
| | - Jun-Hee Park
- Department of Integrated Omics for Biomedical Sciences, Graduate School, Yonsei University, Seoul 120-759,
Korea
| | - Jiyun Lee
- Cardiovascular Research Institute, Yonsei University College of Medicine, Seoul 120-752,
Korea
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 120-752,
Korea
| | - Hyang-Hee Seo
- Cardiovascular Research Institute, Yonsei University College of Medicine, Seoul 120-752,
Korea
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 120-752,
Korea
| | - Chae Yoon Lee
- Department of Biology Education, College of Education, Pusan National University, Busan 609-735,
Korea
| | - Yong-An Chung
- Institute of Catholic Integrative Medicine, Incheon St. Mary’s Hospital, The Catholic University of Korea College of Medicine, Incheon 403-720,
Korea
| | - Lee-So Maeng
- Institute of Catholic Integrative Medicine, Incheon St. Mary’s Hospital, The Catholic University of Korea College of Medicine, Incheon 403-720,
Korea
| | - Min Young Lee
- Department of Molecular Physiology, College of Pharmacy, Kyungpook National University, Daegu 702-701,
Korea
| | - Jongmin Kim
- Department of Life Systems, Sookmyung Women’s University, Seoul 140-742,
Korea
| | - Jihwan Hwang
- Department of Microbiology, College of Natural Science, Pusan National University, Busan 609-735,
Korea
| | - Dong Kyun Woo
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University, Jinju 660-701,
Korea
| | - Woochul Chang
- Department of Biology Education, College of Education, Pusan National University, Busan 609-735,
Korea
| |
Collapse
|
|
6
|
Arno AI, Gauglitz GG, Barret JP, Jeschke MG. New molecular medicine-based scar management strategies. Burns 2014; 40:539-51. [PMID: 24438742 DOI: 10.1016/j.burns.2013.11.010] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2013] [Revised: 10/21/2013] [Accepted: 11/18/2013] [Indexed: 02/06/2023]
Abstract
Keloids and hypertrophic scars are prevalent disabling conditions with still suboptimal treatments. Basic science and molecular-based medicine research have contributed to unravel new bench-to-bedside scar therapies and to dissect the complex signalling pathways involved. Peptides such as the transforming growth factor beta (TGF-β) superfamily, with Smads, Ski, SnoN, Fussels, endoglin, DS-Sily, Cav-1p, AZX100, thymosin-β4 and other related molecules may emerge as targets to prevent and treat keloids and hypertrophic scars. The aim of this review is to describe the basic complexity of these new molecular scar management strategies and point out new fibrosis research lines.
Collapse
Affiliation(s)
- Anna I Arno
- Ross Tilley Burn Centre and Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada; Plastic Surgery Department and Burn Unit, Vall d'Hebron University Hospital, Autonomous University of Barcelona, Barcelona, Spain
| | - Gerd G Gauglitz
- Department of Dermatology and Allergology, Ludwig Maximilians University, Munich, Germany
| | - Juan P Barret
- Plastic Surgery Department and Burn Unit, Vall d'Hebron University Hospital, Autonomous University of Barcelona, Barcelona, Spain
| | - Marc G Jeschke
- Ross Tilley Burn Centre and Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada.
| |
Collapse
|
|
7
|
Frost J, Ramsay M, Mia R, Moosa L, Musenge E, Tikly M. Differential gene expression of MMP-1, TIMP-1 and HGF in clinically involved and uninvolved skin in South Africans with SSc. Rheumatology (Oxford) 2012; 51:1049-52. [DOI: 10.1093/rheumatology/ker367] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
|
|
8
|
Chabaud S, Corriveau MP, Grodzicky T, Senécal JL, Chartier S, Raymond Y, Moulin VJ. Decreased secretion of MMP by non-lesional late-stage scleroderma fibroblasts after selection via activation of the apoptotic fas-pathway. J Cell Physiol 2011; 226:1907-14. [DOI: 10.1002/jcp.22520] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
|
|
9
|
Bauman KA, Wettlaufer SH, Okunishi K, Vannella KM, Stoolman JS, Huang SK, Courey AJ, White ES, Hogaboam CM, Simon RH, Toews GB, Sisson TH, Moore BB, Peters-Golden M. The antifibrotic effects of plasminogen activation occur via prostaglandin E2 synthesis in humans and mice. J Clin Invest 2010; 120:1950-60. [PMID: 20501949 DOI: 10.1172/jci38369] [Citation(s) in RCA: 119] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2010] [Accepted: 03/17/2010] [Indexed: 02/06/2023] Open
Abstract
Plasminogen activation to plasmin protects from lung fibrosis, but the mechanism underlying this antifibrotic effect remains unclear. We found that mice lacking plasminogen activation inhibitor-1 (PAI-1), which are protected from bleomycin-induced pulmonary fibrosis, exhibit lung overproduction of the antifibrotic lipid mediator prostaglandin E2 (PGE2). Plasminogen activation upregulated PGE2 synthesis in alveolar epithelial cells, lung fibroblasts, and lung fibrocytes from saline- and bleomycin-treated mice, as well as in normal fetal and adult primary human lung fibroblasts. This response was exaggerated in cells from Pai1-/- mice. Although enhanced PGE2 formation required the generation of plasmin, it was independent of proteinase-activated receptor 1 (PAR-1) and instead reflected proteolytic activation and release of HGF with subsequent induction of COX-2. That the HGF/COX-2/PGE2 axis mediates in vivo protection from fibrosis in Pai1-/- mice was demonstrated by experiments showing that a selective inhibitor of the HGF receptor c-Met increased lung collagen to WT levels while reducing COX-2 protein and PGE2 levels. Of clinical interest, fibroblasts from patients with idiopathic pulmonary fibrosis were found to be defective in their ability to induce COX-2 and, therefore, unable to upregulate PGE2 synthesis in response to plasmin or HGF. These studies demonstrate crosstalk between plasminogen activation and PGE2 generation in the lung and provide a mechanism for the well-known antifibrotic actions of the fibrinolytic pathway.
Collapse
Affiliation(s)
- Kristy A Bauman
- Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
10
|
Park HJ, Cho DH, Kim HJ, Lee JY, Cho BK, Bang SI, Song SY, Yamasaki K, Di Nardo A, Gallo RL. Collagen synthesis is suppressed in dermal fibroblasts by the human antimicrobial peptide LL-37. J Invest Dermatol 2008; 129:843-50. [PMID: 18923445 DOI: 10.1038/jid.2008.320] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
LL-37 is a human cathelicidin antimicrobial peptide that is released in the skin after injury and acts to defend against infection and modulate the local cellular immune response. We observed in human dermal keloids that fibrosis was inversely related to the expression of cathelicidin and sought to determine how LL-37 influenced expression of types I and III collagen genes in dermal fibroblasts. At nano-molar concentrations, LL-37 inhibited baseline and transforming growth factor-beta-induced collagen expression. At these concentrations, LL-37 also induced phosphorylation of extracellular signal-regulated kinase (ERK) within 30 minutes. Activation of ERK, and the activation of a G-protein-dependent pathway, was essential for inhibition of collagen expression as pertussis toxin or an inhibitor of ERK blocked the inhibitory effects of LL-37. c-Jun N-terminal kinase and p38 mitogen-activated protein kinase inhibitors did not alter the effects of cathelicidin. Silencing of the Ets-1 reversed inhibitory effects of LL-37. Taken together, these findings show that LL-37 can directly act on dermal fibroblasts and may have antifibrotic action during the wound repair process.
Collapse
Affiliation(s)
- Hyun Jeong Park
- Department of Dermatology, St Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | | | | | | | | | | | | | | | | | | |
Collapse
|