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Tanaka S, Elgaabari A, Seki M, Kuwakado S, Zushi K, Miyamoto J, Sawano S, Mizunoya W, Ehara K, Watanabe N, Ogawa Y, Imakyure H, Fujimaru R, Osaki R, Shitamitsu K, Mizoguchi K, Ushijima T, Maeno T, Nakashima T, Suzuki T, Nakamura M, Anderson JE, Tatsumi R. In vitro immuno-prevention of nitration/dysfunction of myogenic stem cell activator HGF, towards developing a strategy for age-related muscle atrophy. Aging Cell 2024; 23:e14337. [PMID: 39297318 PMCID: PMC11464115 DOI: 10.1111/acel.14337] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2024] [Revised: 08/24/2024] [Accepted: 09/02/2024] [Indexed: 10/11/2024] Open
Abstract
In response to peroxynitrite (ONOO-) generation, myogenic stem satellite cell activator HGF (hepatocyte growth factor) undergoes nitration of tyrosine residues (Y198 and Y250) predominantly on fast IIa and IIx myofibers to lose its binding to the signaling receptor c-met, thereby disturbing muscle homeostasis during aging. Here we show that rat anti-HGF monoclonal antibody (mAb) 1H41C10, which was raised in-house against a synthetic peptide FTSNPEVRnitroY198EV, a site well-conserved in mammals, functions to confer resistance to nitration dysfunction on HGF. 1H41C10 was characterized by recognizing both nitrated and non-nitrated HGF with different affinities as revealed by Western blotting, indicating that the paratope of 1H41C10 may bind to the immediate vicinity of Y198. Subsequent experiments showed that 1H41C10-bound HGF resists peroxynitrite-induced nitration of Y198. A companion mAb-1H42F4 presented similar immuno-reactivity, but did not protect Y198 nitration, and thus served as the control. Importantly, 1H41C10-HGF also withstood Y250 nitration to retain c-met binding and satellite cell activation functions in culture. The Fab region of 1H41C10 exerts resistivity to Y250 nitration possibly due to its localization in the immediate vicinity to Y250, as supported by an additional set of experiments showing that the 1H41C10-Fab confers Y250-nitration resistance which the Fc segment does not. Findings highlight the in vitro preventive impact of 1H41C10 on HGF nitration-dysfunction that strongly impairs myogenic stem cell dynamics, potentially pioneering cogent strategies for counteracting or treating age-related muscle atrophy with fibrosis (including sarcopenia and frailty) and the therapeutic application of investigational HGF drugs.
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Affiliation(s)
- Sakiho Tanaka
- Department of Animal and Marine Bioresource SciencesGraduate School of Agriculture, Kyushu UniversityFukuokaJapan
| | - Alaa Elgaabari
- Department of Animal and Marine Bioresource SciencesGraduate School of Agriculture, Kyushu UniversityFukuokaJapan
- Department of Physiology, Faculty of Veterinary MedicineKafrelsheikh UniversityKafrelsheikhEgypt
| | - Miyumi Seki
- Department of Animal and Marine Bioresource SciencesGraduate School of Agriculture, Kyushu UniversityFukuokaJapan
| | - So Kuwakado
- Department of Orthopaedic Surgery, Faculty of Medical SciencesKyushu UniversityFukuokaJapan
| | - Kahona Zushi
- Department of Animal and Marine Bioresource SciencesGraduate School of Agriculture, Kyushu UniversityFukuokaJapan
| | - Junri Miyamoto
- Department of Animal and Marine Bioresource SciencesGraduate School of Agriculture, Kyushu UniversityFukuokaJapan
| | - Shoko Sawano
- Department of Food and Life Science, School of Life and Environmental ScienceAzabu UniversitySagamiharaJapan
| | - Wataru Mizunoya
- Department of Animal Science and Biotechnology, School of Veterinary MedicineAzabu UniversitySagamiharaJapan
| | - Kenshiro Ehara
- Department of Animal and Marine Bioresource SciencesGraduate School of Agriculture, Kyushu UniversityFukuokaJapan
| | - Naruha Watanabe
- Department of Animal and Marine Bioresource SciencesGraduate School of Agriculture, Kyushu UniversityFukuokaJapan
| | - Yohei Ogawa
- Department of Animal and Marine Bioresource SciencesGraduate School of Agriculture, Kyushu UniversityFukuokaJapan
| | - Hikaru Imakyure
- Department of Animal and Marine Bioresource SciencesGraduate School of Agriculture, Kyushu UniversityFukuokaJapan
| | - Reina Fujimaru
- Department of Animal and Marine Bioresource SciencesGraduate School of Agriculture, Kyushu UniversityFukuokaJapan
| | - Rika Osaki
- Department of Animal and Marine Bioresource SciencesGraduate School of Agriculture, Kyushu UniversityFukuokaJapan
| | - Kazuki Shitamitsu
- Department of Animal and Marine Bioresource SciencesGraduate School of Agriculture, Kyushu UniversityFukuokaJapan
| | - Kaoru Mizoguchi
- Department of Animal and Marine Bioresource SciencesGraduate School of Agriculture, Kyushu UniversityFukuokaJapan
| | - Tomoki Ushijima
- Department of Animal and Marine Bioresource SciencesGraduate School of Agriculture, Kyushu UniversityFukuokaJapan
| | - Takahiro Maeno
- Department of Animal and Marine Bioresource SciencesGraduate School of Agriculture, Kyushu UniversityFukuokaJapan
| | - Takashi Nakashima
- Department of Bioscience and Biotechnology, Graduate School of AgricultureKyushu UniversityFukuokaJapan
| | - Takahiro Suzuki
- Department of Animal and Marine Bioresource SciencesGraduate School of Agriculture, Kyushu UniversityFukuokaJapan
| | - Mako Nakamura
- Department of Animal and Marine Bioresource SciencesGraduate School of Agriculture, Kyushu UniversityFukuokaJapan
| | - Judy E. Anderson
- Department of Biological Sciences, Faculty of ScienceUniversity of ManitobaWinnipegManitobaCanada
| | - Ryuichi Tatsumi
- Department of Animal and Marine Bioresource SciencesGraduate School of Agriculture, Kyushu UniversityFukuokaJapan
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Chen YC, Chuang EY, Tu YK, Hsu CL, Cheng NC. Human platelet lysate-cultured adipose-derived stem cell sheets promote angiogenesis and accelerate wound healing via CCL5 modulation. Stem Cell Res Ther 2024; 15:163. [PMID: 38853252 PMCID: PMC11163789 DOI: 10.1186/s13287-024-03762-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Accepted: 05/15/2024] [Indexed: 06/11/2024] Open
Abstract
BACKGROUND A rising population faces challenges with healing-impaired cutaneous wounds, often leading to physical disabilities. Adipose-derived stem cells (ASCs), specifically in the cell sheet format, have emerged as a promising remedy for impaired wound healing. Human platelet lysate (HPL) provides an attractive alternative to fetal bovine serum (FBS) for culturing clinical-grade ASCs. However, the potential of HPL sheets in promoting wound healing has not been fully investigated. This study aimed to explore the anti-fibrotic and pro-angiogenic capabilities of HPL-cultured ASC sheets and delve into the molecular mechanism. METHODS A rat burn model was utilized to evaluate the efficacy of HPL-cultured ASC sheets in promoting wound healing. ASC sheets were fabricated with HPL, and those with FBS were included for comparison. Various analyses were conducted to assess the impact of HPL sheets on wound healing. Histological examination of wound tissues provided insights into aspects such as wound closure, collagen deposition, and overall tissue regeneration. Immunofluorescence was employed to assess the presence and distribution of transplanted ASCs after treatment. Further in vitro studies were conducted to decipher the specific factors in HPL sheets contributing to angiogenesis. RESULTS HPL-cultured ASC sheets significantly accelerated wound closure, fostering ample and organized collagen deposition in the neo-dermis. Significantly more retained ASCs were observed in wound tissues treated with HPL sheets compared to the FBS counterparts. Moreover, HPL sheets mitigated macrophage recruitment and decreased subsequent wound tissue fibrosis in vivo. Immunohistochemistry also indicated enhanced angiogenesis in the HPL sheet group. The in vitro analyses showed upregulation of C-C motif chemokine ligand 5 (CCL5) and angiogenin in HPL sheets, including both gene expression and protein secretion. Culturing endothelial cells in the conditioned media compared to media supplemented with CCL5 or angiogenin suggested a correlation between CCL5 and the pro-angiogenic effect of HPL sheets. Additionally, through neutralizing antibody experiments, we further validated the crucial role of CCL5 in HPL sheet-mediated angiogenesis in vitro. CONCLUSIONS The present study underscores CCL5 as an essential factor in the pro-angiogenic effect of HPL-cultured ASC sheets during the wound healing process. These findings highlight the potential of HPL-cultured ASC sheets as a promising therapeutic option for healing-impaired cutaneous wounds in clinical settings. Furthermore, the mechanism exploration yields valuable information for optimizing regenerative strategies with ASC products. BRIEF ACKNOWLEDGMENT This research was supported by the National Science and Technology Council, Taiwan (NSTC112-2321-B-002-018), National Taiwan University Hospital (111C-007), and E-Da Hospital-National Taiwan University Hospital Joint Research Program (111-EDN0001, 112-EDN0002).
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Affiliation(s)
- Yueh-Chen Chen
- Department of Surgery, National Taiwan University Hospital and College of Medicine, 7 Chung-Shan S. Rd, Taipei, 100, Taiwan
| | - Er-Yuan Chuang
- International Ph.D. Program in Biomedical Engineering, Graduate Institute of Biomedical Materials and Tissue Engineering, Taipei Medical University, Taipei, Taiwan
| | - Yuan-Kun Tu
- Department of Orthopedics, E-Da Hospital/I-Shou University, Kaohsiung, Taiwan
| | - Chia-Lang Hsu
- Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
| | - Nai-Chen Cheng
- Department of Surgery, National Taiwan University Hospital and College of Medicine, 7 Chung-Shan S. Rd, Taipei, 100, Taiwan.
- Research Center for Developmental Biology and Regenerative Medicine, National Taiwan University, Taipei, Taiwan.
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Elgaabari A, Imatomi N, Kido H, Nakashima T, Okuda S, Manabe Y, Sawano S, Mizunoya W, Kaneko R, Tanaka S, Maeno T, Matsuyoshi Y, Seki M, Kuwakado S, Zushi K, Daneshvar N, Nakamura M, Suzuki T, Sunagawa K, Anderson JE, Allen RE, Tatsumi R. Age-related nitration/dysfunction of myogenic stem cell activator HGF. Aging Cell 2024; 23:e14041. [PMID: 37985931 PMCID: PMC10861216 DOI: 10.1111/acel.14041] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2023] [Revised: 10/27/2023] [Accepted: 10/28/2023] [Indexed: 11/22/2023] Open
Abstract
Mechanical perturbation triggers activation of resident myogenic stem cells to enter the cell cycle through a cascade of events including hepatocyte growth factor (HGF) release from its extracellular tethering and the subsequent presentation to signaling-receptor c-met. Here, we show that with aging, extracellular HGF undergoes tyrosine-residue (Y) nitration and loses c-met binding, thereby disturbing muscle homeostasis. Biochemical studies demonstrated that nitration/dysfunction is specific to HGF among other major growth factors and is characterized by its locations at Y198 and Y250 in c-met-binding domains. Direct-immunofluorescence microscopy of lower hind limb muscles from three age groups of rat, provided direct in vivo evidence for age-related increases in nitration of ECM-bound HGF, preferentially stained for anti-nitrated Y198 and Y250-HGF mAbs (raised in-house) in fast IIa and IIx myofibers. Overall, findings highlight inhibitory impacts of HGF nitration on myogenic stem cell dynamics, pioneering a cogent discussion for better understanding age-related muscle atrophy and impaired regeneration with fibrosis (including sarcopenia and frailty).
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Affiliation(s)
- Alaa Elgaabari
- Department of Animal and Marine Bioresource Sciences, Graduate School of AgricultureKyushu UniversityFukuokaJapan
- Department of Physiology, Faculty of Veterinary MedicineKafrelsheikh UniversityKafrelsheikhEgypt
| | - Nana Imatomi
- Department of Animal and Marine Bioresource Sciences, Graduate School of AgricultureKyushu UniversityFukuokaJapan
| | - Hirochika Kido
- Department of Animal and Marine Bioresource Sciences, Graduate School of AgricultureKyushu UniversityFukuokaJapan
| | - Takashi Nakashima
- Department of Bioscience and Biotechnology, Graduate School of AgricultureKyushu UniversityFukuokaJapan
| | - Shoko Okuda
- Department of Animal and Marine Bioresource Sciences, Graduate School of AgricultureKyushu UniversityFukuokaJapan
| | - Yoshitaka Manabe
- Department of Animal and Marine Bioresource Sciences, Graduate School of AgricultureKyushu UniversityFukuokaJapan
| | - Shoko Sawano
- Department of Animal and Marine Bioresource Sciences, Graduate School of AgricultureKyushu UniversityFukuokaJapan
- Present address:
Department of Food and Life Science, School of Life and Environmental ScienceAzabu UniversitySagamiharaJapan
| | - Wataru Mizunoya
- Department of Animal and Marine Bioresource Sciences, Graduate School of AgricultureKyushu UniversityFukuokaJapan
- Present address:
Department of Animal Science and Biotechnology, School of Veterinary MedicineAzabu UniversitySagamiharaJapan
| | - Ryuki Kaneko
- Department of Animal and Marine Bioresource Sciences, Graduate School of AgricultureKyushu UniversityFukuokaJapan
| | - Sakiho Tanaka
- Department of Animal and Marine Bioresource Sciences, Graduate School of AgricultureKyushu UniversityFukuokaJapan
| | - Takahiro Maeno
- Department of Animal and Marine Bioresource Sciences, Graduate School of AgricultureKyushu UniversityFukuokaJapan
| | - Yuji Matsuyoshi
- Department of Animal and Marine Bioresource Sciences, Graduate School of AgricultureKyushu UniversityFukuokaJapan
| | - Miyumi Seki
- Department of Animal and Marine Bioresource Sciences, Graduate School of AgricultureKyushu UniversityFukuokaJapan
| | - So Kuwakado
- Department of Orthopaedic Surgery, Faculty of Medical SciencesKyushu UniversityFukuokaJapan
| | - Kahona Zushi
- Department of Animal and Marine Bioresource Sciences, Graduate School of AgricultureKyushu UniversityFukuokaJapan
| | - Nasibeh Daneshvar
- Department of Biological Sciences, Faculty of ScienceUniversity of ManitobaWinnipegManitobaCanada
| | - Mako Nakamura
- Department of Animal and Marine Bioresource Sciences, Graduate School of AgricultureKyushu UniversityFukuokaJapan
| | - Takahiro Suzuki
- Department of Animal and Marine Bioresource Sciences, Graduate School of AgricultureKyushu UniversityFukuokaJapan
| | - Kenji Sunagawa
- Department of Cardiovascular Medicine, Graduate School of MedicineKyushu UniversityFukuokaJapan
| | - Judy E. Anderson
- Department of Biological Sciences, Faculty of ScienceUniversity of ManitobaWinnipegManitobaCanada
| | - Ronald E. Allen
- The School of Animal and Comparative Biomedical SciencesUniversity of ArizonaTucsonArizonaUSA
| | - Ryuichi Tatsumi
- Department of Animal and Marine Bioresource Sciences, Graduate School of AgricultureKyushu UniversityFukuokaJapan
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Timofeeva AV, Fedorov IS, Suhova YV, Tarasova AM, Ezhova LS, Zabelina TM, Vasilchenko ON, Ivanets TY, Sukhikh GT. Diagnostic Role of Cell-Free miRNAs in Identifying Placenta Accreta Spectrum during First-Trimester Screening. Int J Mol Sci 2024; 25:871. [PMID: 38255950 PMCID: PMC10815502 DOI: 10.3390/ijms25020871] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2023] [Revised: 01/06/2024] [Accepted: 01/08/2024] [Indexed: 01/24/2024] Open
Abstract
Placenta accreta spectrum (PAS) is a severe complication of pregnancy associated with excessive invasion of cytotrophoblast cells at the sites of the endometrial-myometrial interface and the myometrium itself in cases of adherent (creta) and invasive (increta and percreta) forms, respectively. This leads to a high risk of massive blood loss, maternal hysterectomy, and preterm birth. Despite advancements in ultrasound protocols and found associations of alpha-fetoprotein, PAPP-A, hCG, PLGF, sFlt-1, IL-8, and IL-33 peripheral blood levels with PAS, there is a high need for an additional non-invasive test to improve the diagnostic accuracy and to select the real PAS from the suspected ones in the first-trimester screening. miRNA signatures of placental tissue, myometrium, and blood plasma from women with PAS in the third trimester of pregnancy, as well as miRNA profiles in exosomes from the blood serum of women in the first trimester with physiologically progressing pregnancy, complicated by PAS or pre-eclampsia, were obtained using deep sequencing. Two logistic regression models were constructed, both featuring statistically significant parameters related to the levels of miR-26a-5p, miR-17-5p, and miR-101-3p, quantified by real-time PCR in native blood serum. These models demonstrated 100% sensitivity in detecting PAS during the first pregnancy screening. These miRNAs were identified as specific markers for PAS, showing significant differences in their blood serum levels during the first trimester in the PAS group compared to those in physiological pregnancies, early- or late-onset pre-eclampsia groups. Furthermore, these miRNAs exhibited differential expression in the PAS placenta and/or myometrium in the third trimester and, according to data from the literature, control angiogenesis. Significant correlations were found between extracellular hsa-miR-101-3p and nuchal translucency thickness, hsa-miR-17-5p and uterine artery pulsatility index, and hsa-miR-26a-5p and hsa-miR-17-5p with PLGF. The developed test system for early non-invasive PAS diagnosis based on the blood serum level of extracellular miR-26a-5p, miR-17-5p, and miR-101-3p can serve as an auxiliary method for first-trimester screening of pregnant women, subject to validation with independent test samples.
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Affiliation(s)
- Angelika V. Timofeeva
- Kulakov National Medical Research Center of Obstetrics, Gynecology, and Perinatology, Ministry of Health of Russia, Ac. Oparina 4, 117997 Moscow, Russia; (I.S.F.); (Y.V.S.); (A.M.T.); (L.S.E.); (T.M.Z.); (O.N.V.); (T.Y.I.); (G.T.S.)
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Guo Y, Hu Z, Chen J, Zhang J, Fan Z, Qu Q, Miao Y. Feasibility of adipose-derived therapies for hair regeneration: Insights based on signaling interplay and clinical overview. J Am Acad Dermatol 2023; 89:784-794. [PMID: 34883154 DOI: 10.1016/j.jaad.2021.11.058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 09/13/2021] [Accepted: 11/30/2021] [Indexed: 11/22/2022]
Abstract
Dermal white adipose tissue (dWAT) is a dynamic component of the skin and closely interacts with the hair follicle. Interestingly, dWAT envelops the hair follicle during anagen and undergoes fluctuations in volume throughout the hair cycle. dWAT-derived extracellular vesicles can significantly regulate the hair cycle, and this provides a theoretical basis for utilizing adipose tissue as a feasible clinical strategy to treat hair loss. However, the amount and depth of the available literature are far from enough to fully elucidate the prominent role of dWAT in modulating the hair growth cycle. This review starts by investigating the hair cycle-coupled dWAT remodeling and the reciprocal signaling interplay underneath. Then, it summarizes the current literature and assesses the advantages and limitations of clinical research utilizing adipose-derived therapies for hair regeneration.
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Affiliation(s)
- Yilong Guo
- Department of Plastic and Aesthetic Surgery, Nanfang Hospital of Southern Medical University, Guangzhou, Guangdong Province, China
| | - Zhiqi Hu
- Department of Plastic and Aesthetic Surgery, Nanfang Hospital of Southern Medical University, Guangzhou, Guangdong Province, China
| | - Jian Chen
- Department of Plastic and Aesthetic Surgery, Nanfang Hospital of Southern Medical University, Guangzhou, Guangdong Province, China
| | - Jiarui Zhang
- Department of Plastic and Aesthetic Surgery, Nanfang Hospital of Southern Medical University, Guangzhou, Guangdong Province, China
| | - Zhexiang Fan
- Department of Plastic and Aesthetic Surgery, Nanfang Hospital of Southern Medical University, Guangzhou, Guangdong Province, China
| | - Qian Qu
- Department of Plastic and Aesthetic Surgery, Nanfang Hospital of Southern Medical University, Guangzhou, Guangdong Province, China.
| | - Yong Miao
- Department of Plastic and Aesthetic Surgery, Nanfang Hospital of Southern Medical University, Guangzhou, Guangdong Province, China.
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Chae DS, An SJ, Han S, Kim SW. Synergistic Therapeutic Potential of Dual 3D Mesenchymal Stem Cell Therapy in an Ischemic Hind Limb Mouse Model. Int J Mol Sci 2023; 24:14620. [PMID: 37834069 PMCID: PMC10572732 DOI: 10.3390/ijms241914620] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Revised: 09/15/2023] [Accepted: 09/25/2023] [Indexed: 10/15/2023] Open
Abstract
Three-dimensional (3D) culture systems have been widely used to promote the viability and metabolic activity of mesenchymal stem cells (MSCs). The aim of this study was to explore the synergistic benefits of using dual 3D MSC culture systems to promote vascular regeneration and enhance therapeutic potential. We used various experimental assays, including dual 3D cultures of human adipose MSCs (hASCs), quantitative reverse transcription polymerase chain reaction (qRT-PCR), in vitro cell migration, Matrigel tube network formation, Matrigel plug assay, therapeutic assays using an ischemic hind limb mouse model, and immunohistochemical analysis. Our qRT-PCR results revealed that fibroblast growth factor 2 (FGF-2), granulocyte chemotactic protein-2 (GCP-2), and vascular endothelial growth factor-A (VEGF-A) were highly upregulated in conventional 3D-cultured hASCs (ASC-3D) than in two-dimensional (2D)-cultured hASCs. Hepatocyte growth factor (HGF), insulin-like growth factor-1 (IGF-1), and stromal-cell-derived factor-1 (SDF-1) showed higher expression levels in cytokine-cocktail-based, 3D-cultured hASCs (ASC-3Dc). A conditioned medium (CM) mixture of dual 3D ASCs (D-3D; ASC-3D + ASC-3Dc) resulted in higher migration and Matrigel tube formation than the CM of single 3D ASCs (S-3D; ASC-3D). Matrigel plugs containing D-3D contained more red blood cells than those containing S-3D. D-3D transplantation into ischemic mouse hind limbs prevented limb loss and augmented blood perfusion when compared to S-3D transplantation. Transplanted D-3D also revealed a high capillary density and angiogenic cytokine levels and transdifferentiated into endothelial-like cells in the hind limb muscle. These findings highlight the benefits of using the dual 3D culture system to optimize stem-cell-based therapeutic strategies, thereby advancing the therapeutic strategy for ischemic vascular disease and tissue regeneration.
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Affiliation(s)
- Dong-Sik Chae
- Department of Orthopedic Surgery, College of Medicine, Catholic Kwandong University, International St. Mary’s Hospital, Incheon 22711, Republic of Korea
| | - Sang Joon An
- Department of Neurology, College of Medicine, Catholic Kwandong University, International St. Mary’s Hospital, Incheon 22711, Republic of Korea
| | - Seongho Han
- Department of Family Medicine, College of Medicine, Dong-A University, Busan 49236, Republic of Korea
| | - Sung-Whan Kim
- Department Medicine, College of Medicine, Catholic Kwandong University, Gangneung 25601, Republic of Korea
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Malektaj H, Nour S, Imani R, Siadati MH. Angiogenesis induction as a key step in cardiac tissue Regeneration: From angiogenic agents to biomaterials. Int J Pharm 2023; 643:123233. [PMID: 37460050 DOI: 10.1016/j.ijpharm.2023.123233] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2023] [Revised: 07/02/2023] [Accepted: 07/14/2023] [Indexed: 07/23/2023]
Abstract
Cardiovascular diseases are the leading cause of death worldwide. After myocardial infarction, the vascular supply of the heart is damaged or blocked, leading to the formation of scar tissue, followed by several cardiac dysfunctions or even death. In this regard, induction of angiogenesis is considered as a vital process for supplying nutrients and oxygen to the cells in cardiac tissue engineering. The current review aims to summarize different approaches of angiogenesis induction for effective cardiac tissue repair. Accordingly, a comprehensive classification of induction of pro-angiogenic signaling pathways through using engineered biomaterials, drugs, angiogenic factors, as well as combinatorial approaches is introduced as a potential platform for cardiac regeneration application. The angiogenic induction for cardiac repair can enhance patient treatment outcomes and generate economic prospects for the biomedical industry. The development and commercialization of angiogenesis methods often involves collaboration between academic institutions, research organizations, and biomedical companies.
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Affiliation(s)
- Haniyeh Malektaj
- Department of Materials and Production, Aalborg University, Fibigerstraede 16, Aalborg 9220, Denmark
| | - Shirin Nour
- Department of Biomedical Engineering, Graeme Clark Institute, The University of Melbourne, VIC 3010, Australia; Department of Chemical Engineering, The University of Melbourne, VIC 3010, Australia
| | - Rana Imani
- Department of Biomedical Engineering, Amirkabir University of Technology, Tehran, Iran.
| | - Mohammad H Siadati
- Materials Science and Engineering Faculty, K. N. Toosi University of Technology, Tehran, Iran
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Giacca M. Fulfilling the Promise of RNA Therapies for Cardiac Repair and Regeneration. Stem Cells Transl Med 2023; 12:527-535. [PMID: 37440203 PMCID: PMC10427962 DOI: 10.1093/stcltm/szad038] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2022] [Accepted: 04/07/2023] [Indexed: 07/14/2023] Open
Abstract
The progressive appreciation that multiple types of RNAs regulate virtually all aspects of tissue function and the availability of effective tools to deliver RNAs in vivo now offers unprecedented possibilities for obtaining RNA-based therapeutics. For the heart, RNA therapies can be developed that stimulate endogenous repair after cardiac damage. Applications in this area include acute cardioprotection after ischemia or cancer chemotherapy, therapeutic angiogenesis to promote new blood vessel formation, regeneration to form new cardiac mass, and editing of mutations to cure inherited cardiac disease. While the potential of RNA therapeutics for all these conditions is exciting, the field is still in its infancy. A number of roadblocks need to be overcome for RNA therapies to become effective, in particular, related to the problem of delivering RNA medicines into the cells and targeting them specifically to the heart.
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Affiliation(s)
- Mauro Giacca
- School of Cardiovascular and Metabolic Medicine & Sciences and British Heart Foundation Centre of Research Excellence, King’s College London, London, UK
- Department of Medical Sciences, University of Trieste, Italy
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Harrington J, Nixon AB, Daubert MA, Yow E, Januzzi J, Fiuzat M, Whellan DJ, O'Connor CM, Ezekowitz J, Piña IL, Adams KF, Felker GM, Karra R. Circulating Angiokines Are Associated With Reverse Remodeling and Outcomes in Chronic Heart Failure. J Card Fail 2023; 29:896-906. [PMID: 36632934 PMCID: PMC10272021 DOI: 10.1016/j.cardfail.2022.12.011] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 12/08/2022] [Accepted: 12/12/2022] [Indexed: 01/09/2023]
Abstract
BACKGROUND We sought to determine whether circulating modifiers of endothelial function are associated with cardiac structure and clinical outcomes in patients with heart failure with reduced ejection fraction (HFrEF). METHODS We measured 25 proteins related to endothelial function in 99 patients from the GUIDE-IT study. Protein levels were evaluated for association with echocardiographic parameters and the incidence of all-cause death and hospitalization for heart failure (HHF). RESULTS Higher concentrations of angiopoietin 2 (ANGPT2), vascular endothelial growth factor receptor 1 (VEGFR1) and hepatocyte growth factor (HGF) were significantly associated with worse function and larger ventricular volumes. Over time, decreases in ANGPT2 and, to a lesser extent, VEGFR1 and HGF, were associated with improvements in cardiac size and function. Individuals with higher concentrations of ANGPT2, VEGFR1 or HGF had increased risks for a composite of death and HHF in the following year (HR 2.76 (95% CI 1.73-4.40) per 2-fold change in ANGPT2; HR 1.76 (95% CI 1.11-2.79) for VEGFR1; and HR 4.04 (95% CI 2.19-7.44) for HGF). CONCLUSIONS Proteins related to endothelial function associate with cardiac size, cardiac function and clinical outcomes in patients with HFrEF. These results support the concept that endothelial function may be an important contributor to the progression to and the recovery from HFrEF.
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Affiliation(s)
- Josephine Harrington
- Department of Medicine, Duke University Medical Center, Durham, NC; Duke Clinical Research Institute, Durham, NC
| | - Andrew B Nixon
- Department of Medicine, Duke University Medical Center, Durham, NC; Duke Cancer Institute, Duke University Medical Center, Durham, NC
| | - Melissa A Daubert
- Department of Medicine, Duke University Medical Center, Durham, NC; Duke Clinical Research Institute, Durham, NC
| | - Eric Yow
- Duke Clinical Research Institute, Durham, NC
| | - James Januzzi
- Massachusetts General Hospital; Harvard Medical School, Boston, MA; Baim Institute for Clinical Research, Boston, MA
| | - Mona Fiuzat
- Duke Clinical Research Institute, Durham, NC
| | - David J Whellan
- Department of Medicine, Thomas Jefferson University, Philadelphia, PA
| | | | - Justin Ezekowitz
- Canadian VIGOUR Centre, University of Alberta, Edmonton, Alberta, Canada
| | | | - Kirkwood F Adams
- Department of Medicine, University of North Carolina, Chapel Hill, NC
| | - G Michael Felker
- Department of Medicine, Duke University Medical Center, Durham, NC; Duke Clinical Research Institute, Durham, NC
| | - Ravi Karra
- Department of Medicine, Duke University Medical Center, Durham, NC; Department of Pathology, Duke University Medical Center, Durham, NC.
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Tang H, Zhang X, Hao X, Dou H, Zou C, Zhou Y, Li B, Yue H, Wang D, Wang Y, Yang C, Fu J. Hepatocyte growth factor-modified hair follicle stem cells ameliorate cerebral ischemia/reperfusion injury in rats. Stem Cell Res Ther 2023; 14:25. [PMID: 36782269 PMCID: PMC9926795 DOI: 10.1186/s13287-023-03251-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Accepted: 08/22/2022] [Indexed: 02/15/2023] Open
Abstract
BACKGROUND Hair follicle stem cells (HFSCs) are considered as a promising cell type in the stem cell transplantation treatment of neurological diseases because of their rich sources, easy access, and the same ectoderm source as the nervous system. Hepatocyte growth factor (HGF) is a pleiotropic cytokine that shows neuroprotective function in ischemic stroke. Here we assessed the therapeutic effects of HFSCs on ischemic stroke injury and the synthetic effect of HGF along with HFSCs. METHODS Rat HFSCs were intravenously transplanted into a middle cerebral artery ischemia/reperfusion (I/R) rat model. Neurological scoring and TTC staining were performed to assess the benefits of HFSC transplantation. Inflammatory cytokines, blood-brain barrier integrity and angiogenesis within penumbra were estimated by Western blot and immunohistochemistry. The differentiation of HFSCs was detected by immunofluorescence method 2 weeks after transplantation. RESULTS HFSC transplantation could significantly inhibit the activation of microglia, improve the integrity of blood-brain barrier and reduce brain edema. Moreover, the number of surviving neurons and microvessels density in the penumbra were upregulated by HFSC transplantation, leading to better neurological score. The combination of HFSCs and HGF could significantly improve the therapeutic benefit. CONCLUSION Our results indicate for the first time that HGF modified HFSCs can reduce I/R injury and promote the neurological recovery by inhibiting inflammatory response, protecting blood-brain barrier and promoting angiogenesis.
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Affiliation(s)
- Hao Tang
- grid.412463.60000 0004 1762 6325Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, No.246 Xuefu Road, Nangang District, Harbin, 150086 Heilongjiang China
| | - Xuemei Zhang
- grid.412463.60000 0004 1762 6325Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, No.246 Xuefu Road, Nangang District, Harbin, 150086 Heilongjiang China
| | - Xiaojun Hao
- grid.412463.60000 0004 1762 6325Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, No.246 Xuefu Road, Nangang District, Harbin, 150086 Heilongjiang China
| | - Haitong Dou
- grid.412463.60000 0004 1762 6325Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, No.246 Xuefu Road, Nangang District, Harbin, 150086 Heilongjiang China
| | - Chendan Zou
- grid.410736.70000 0001 2204 9268Department of Biochemistry and Molecular Biology, Harbin Medical University, No.157 Baojian Road, Nangang District, Harbin, 150086 Heilongjiang China
| | - Yinglian Zhou
- grid.412463.60000 0004 1762 6325Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, No.246 Xuefu Road, Nangang District, Harbin, 150086 Heilongjiang China
| | - Bing Li
- grid.412463.60000 0004 1762 6325Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, No.246 Xuefu Road, Nangang District, Harbin, 150086 Heilongjiang China
| | - Hui Yue
- grid.412463.60000 0004 1762 6325Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, No.246 Xuefu Road, Nangang District, Harbin, 150086 Heilongjiang China
| | - Duo Wang
- grid.412463.60000 0004 1762 6325Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, No.246 Xuefu Road, Nangang District, Harbin, 150086 Heilongjiang China
| | - Yifei Wang
- grid.412463.60000 0004 1762 6325Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, No.246 Xuefu Road, Nangang District, Harbin, 150086 Heilongjiang China
| | - Chunxiao Yang
- Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, No.246 Xuefu Road, Nangang District, Harbin, 150086, Heilongjiang, China.
| | - Jin Fu
- Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, No.246 Xuefu Road, Nangang District, Harbin, 150086, Heilongjiang, China.
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11
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Tokarski M, Cierzniak A, Baczynska D. Role of hypoxia on microRNA-dependant regulation of HGFA - HGF - c-Met signalling pathway in human progenitor and mature endothelial cells. Int J Biochem Cell Biol 2022; 152:106310. [PMID: 36182093 DOI: 10.1016/j.biocel.2022.106310] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 09/15/2022] [Accepted: 09/25/2022] [Indexed: 10/31/2022]
Abstract
Hepatocyte growth factor (HGF) is considered to be one of the key pro-angiogenic cytokines that stimulates endothelial cells to proliferate and migrate. The activation of the precursor form of HGF is primarily undertaken by the serine protease HGFA. Research indicates that HIF-1α hypoxia stimulates the expression of HGFA, which is synthesized by a range of cells including fibroblasts, endothelium, and macrophages. To date, little is known about the potential role of epigenetic factors in the regulation of the HGFA - HGF - c-Met signalling pathway. The literature suggests that there are several microRNAs (miRNAs, miRs) directly affecting the expression of c-Met under normoxic conditions. The main objective of the research described was to explore the effect of chemically-induced hypoxia on the expression of miRNA molecules in human progenitor and mature endothelial cells, with particulate attention paid to those miRNAs that may specifically affect the HGFA - HGF - c-Met signalling pathway. This publication sheds new light on the role of miRNAs in hypoxia, as well as identifying several miRNAs directly involved in the regulation of HGFA, HGF and c-Met expression in hypoxic conditions. The results indicate that hsa-miR-335-5p, hsa-miR-425-5p and hsa-miR-101-3p are the major miRNAs that appear to play an important role in the regulation of the HGFA - HGF - c-Met signalling pathway.
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Affiliation(s)
- Miron Tokarski
- Department of Molecular Techniques, Faculty of Medicine, Wroclaw Medical University, M. Curie-Skłodowskiej 52, Wrocław 50-369, Poland.
| | - Aneta Cierzniak
- Department of Molecular Techniques, Faculty of Medicine, Wroclaw Medical University, M. Curie-Skłodowskiej 52, Wrocław 50-369, Poland
| | - Dagmara Baczynska
- Department of Molecular and Cell Biology, Faculty of Pharmacy and Laboratory Medicine, Wroclaw Medical University, Borowska 211, Wrocław 50-556, Poland
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12
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Cationic, anionic and neutral polysaccharides for skin tissue engineering and wound healing applications. Int J Biol Macromol 2021; 192:298-322. [PMID: 34634326 DOI: 10.1016/j.ijbiomac.2021.10.013] [Citation(s) in RCA: 70] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 09/25/2021] [Accepted: 10/03/2021] [Indexed: 12/17/2022]
Abstract
Today, chronic wound care and management can be regarded as a clinically critical issue. However, the limitations of current approaches for wound healing have encouraged researchers and physicians to develop more efficient alternative approaches. Advances in tissue engineering and regenerative medicine have resulted in the development of promising approaches that can accelerate wound healing and improve the skin regeneration rate and quality. The design and fabrication of scaffolds that can address the multifactorial nature of chronic wound occurrence and provide support for the healing process can be considered an important area requiring improvement. In this regard, polysaccharide-based scaffolds have distinctive properties such as biocompatibility, biodegradability, high water retention capacity and nontoxicity, making them ideal for wound healing applications. Their tunable structure and networked morphology could facilitate a number of functions, such as controlling their diffusion, maintaining wound moisture, absorbing a large amount of exudates and facilitating gas exchange. In this review, the wound healing process and the influential factors, structure and properties of carbohydrate polymers, physical and chemical crosslinking of polysaccharides, scaffold fabrication techniques, and the use of polysaccharide-based scaffolds in skin tissue engineering and wound healing applications are discussed.
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13
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Wan Mohd Tajuddin WNB, Abas F, Othman I, Naidu R. Molecular Mechanisms of Antiproliferative and Apoptosis Activity by 1,5-Bis(4-Hydroxy-3-Methoxyphenyl)1,4-Pentadiene-3-one (MS13) on Human Non-Small Cell Lung Cancer Cells. Int J Mol Sci 2021; 22:ijms22147424. [PMID: 34299042 PMCID: PMC8307969 DOI: 10.3390/ijms22147424] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 06/30/2021] [Accepted: 07/04/2021] [Indexed: 01/12/2023] Open
Abstract
Diarylpentanoid (DAP), an analog that was structurally modified from a naturally occurring curcumin, has shown to enhance anticancer efficacy compared to its parent compound in various cancers. This study aims to determine the cytotoxicity, antiproliferative, and apoptotic activity of diarylpentanoid MS13 on two subtypes of non-small cell lung cancer (NSCLC) cells: squamous cell carcinoma (NCI-H520) and adenocarcinoma (NCI-H23). Gene expression analysis was performed using Nanostring PanCancer Pathways Panel to determine significant signaling pathways and targeted genes in these treated cells. Cytotoxicity screening revealed that MS13 exhibited greater inhibitory effect in NCI-H520 and NCI-H23 cells compared to curcumin. MS13 induced anti-proliferative activity in both cells in a dose- and time-dependent manner. Morphological analysis revealed that a significant number of MS13-treated cells exhibited apoptosis. A significant increase in caspase-3 activity and decrease in Bcl-2 protein concentration was noted in both MS13-treated cells in a time- and dose-dependent manner. A total of 77 and 47 differential expressed genes (DEGs) were regulated in MS13 treated-NCI-H520 and NCI-H23 cells, respectively. Among the DEGs, 22 were mutually expressed in both NCI-H520 and NCI-H23 cells in response to MS13 treatment. The top DEGs modulated by MS13 in NCI-H520—DUSP4, CDKN1A, GADD45G, NGFR, and EPHA2—and NCI-H23 cells—HGF, MET, COL5A2, MCM7, and GNG4—were highly associated with PI3K, cell cycle-apoptosis, and MAPK signaling pathways. In conclusion, MS13 may induce antiproliferation and apoptosis activity in squamous cell carcinoma and adenocarcinoma of NSCLC cells by modulating DEGs associated with PI3K-AKT, cell cycle-apoptosis, and MAPK pathways. Therefore, our present findings could provide an insight into the anticancer activity of MS13 and merits further investigation as a potential anticancer agent for NSCLC cancer therapy.
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Affiliation(s)
- Wan Nur Baitty Wan Mohd Tajuddin
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway 47500, Selangor Darul Ehsan, Malaysia; (W.N.B.W.M.T.); (I.O.)
| | - Faridah Abas
- Laboratory of Natural Products, Faculty of Science, Universiti Putra Malaysia, UPM, Serdang 43400, Malaysia;
- Department of Food Science, Faculty of Food Science and Technology, Universiti Putra Malaysia, UPM, Serdang 43400, Malaysia
| | - Iekhsan Othman
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway 47500, Selangor Darul Ehsan, Malaysia; (W.N.B.W.M.T.); (I.O.)
- Global Asia in the 21s Century Platform, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway 47500, Selangor Darul Ehsan, Malaysia
| | - Rakesh Naidu
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway 47500, Selangor Darul Ehsan, Malaysia; (W.N.B.W.M.T.); (I.O.)
- Global Asia in the 21s Century Platform, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway 47500, Selangor Darul Ehsan, Malaysia
- Correspondence: ; Tel.: +60-3-5514-63-45
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14
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Klotz DM, Link T, Goeckenjan M, Wimberger P, Kuhlmann JD. The levels of soluble cMET ectodomain in the blood of patients with ovarian cancer are an independent prognostic biomarker. Mol Oncol 2021; 15:2491-2503. [PMID: 33690968 PMCID: PMC8410524 DOI: 10.1002/1878-0261.12939] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Revised: 02/16/2021] [Accepted: 03/08/2021] [Indexed: 12/21/2022] Open
Abstract
The tyrosine kinase mesenchymal–epithelial transition (cMET) is typically overexpressed in up to 75% of patients with ovarian cancer, and cMET overexpression has been associated with poor prognosis. The proteolytic release of the soluble cMET (sMET) ectodomain by metalloproteases, a process called ectodomain shedding, reflects the malignant potential of tumour cells. sMET can be detected in the human circulation and has been proposed as biomarker in several cancers. However, the clinical relevance of sMET in ovarian cancer as blood‐based biomarker is unknown and was therefore investigated in this study. sMET levels were determined by enzyme‐linked immunosorbent assay in a set of 432 serum samples from 85 healthy controls and 86 patients with ovarian cancer (87% FIGO III/IV). Samples were collected at primary diagnosis, at four longitudinal follow‐up time points during the course of treatment and at disease recurrence. Although there was no significant difference between median sMET levels at primary diagnosis of ovarian cancer vs. healthy controls, increased sMET levels at primary diagnosis were an independent predictor of shorter PFS (HR = 0.354, 95% CI: 0.130–0.968, P = 0.043) and shorter OS (HR = 0.217, 95% CI: 0.064–0.734, P = 0.014). In the follow‐up samples, sMET levels were prognostically most informative after the first three cycles of chemotherapy, with high sMET levels being an independent predictor of shorter PFS (HR = 0.245, 95% CI: 0.100–0.602, P = 0.002). This is the first study to suggest that sMET levels in the blood can be used as an independent prognostic biomarker for ovarian cancer. Patients at high risk of recurrence and with poor prognosis, as identified based on sMET levels in the blood, could potentially benefit from cMET‐directed therapies or other targeted regimes, such as PARP inhibitors or immunotherapy.
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Affiliation(s)
- Daniel Martin Klotz
- Department of Gynecology and Obstetrics, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany.,National Center for Tumour Diseases (NCT), Dresden, Germany.,German Cancer Research Center (DKFZ), Heidelberg, Germany.,Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany.,Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Germany.,German Cancer Consortium (DKTK), Dresden, Germany
| | - Theresa Link
- Department of Gynecology and Obstetrics, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany.,National Center for Tumour Diseases (NCT), Dresden, Germany.,German Cancer Research Center (DKFZ), Heidelberg, Germany.,Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany.,Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Germany.,German Cancer Consortium (DKTK), Dresden, Germany
| | - Maren Goeckenjan
- Department of Gynecology and Obstetrics, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany.,National Center for Tumour Diseases (NCT), Dresden, Germany.,German Cancer Research Center (DKFZ), Heidelberg, Germany.,Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany.,Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Germany.,German Cancer Consortium (DKTK), Dresden, Germany
| | - Pauline Wimberger
- Department of Gynecology and Obstetrics, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany.,National Center for Tumour Diseases (NCT), Dresden, Germany.,German Cancer Research Center (DKFZ), Heidelberg, Germany.,Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany.,Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Germany.,German Cancer Consortium (DKTK), Dresden, Germany
| | - Jan Dominik Kuhlmann
- Department of Gynecology and Obstetrics, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany.,National Center for Tumour Diseases (NCT), Dresden, Germany.,German Cancer Research Center (DKFZ), Heidelberg, Germany.,Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany.,Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Germany.,German Cancer Consortium (DKTK), Dresden, Germany
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15
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Efficacy of nonviral gene transfer of human hepatocyte growth factor (HGF) against ischemic-reperfusion nerve injury in rats. PLoS One 2020; 15:e0237156. [PMID: 32780756 PMCID: PMC7418984 DOI: 10.1371/journal.pone.0237156] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Accepted: 07/21/2020] [Indexed: 01/20/2023] Open
Abstract
Ischemic neuropathy is common in subjects with critical limb ischemia, frequently causing chronic neuropathic pain. However, neuropathic pain caused by ischemia is hard to control despite the restoration of an adequate blood flow. Here, we used a rat model of ischemic-reperfusion nerve injury (IRI) to investigate possible effects of hepatocyte growth factor (HGF) against ischemic neuropathy. Hemagglutinating virus of Japan (HVJ) liposomes containing plasmids encoded with HGF was delivered into the peripheral nervous system by retrograde axonal transport following its repeated injections into the tibialis anterior muscle in the right hindlimb. First HGF gene transfer was done immediately after IRI, and repeated at 1, 2 and 3 weeks later. Rats with IRI exhibited pronounced mechanical allodynia and thermal hyperalgesia, decreased blood flow and skin temperature, and lowered thresholds of plantar stimuli in the hind paw. These were all significantly improved by HGF gene transfer, as also were sciatic nerve conduction velocity and muscle action potential amplitudes. Histologically, HGF gene transfer resulted in a significant increase of endoneurial microvessels in sciatic and tibial nerves and promoted nerve regeneration which were confirmed by morphometric analysis. Neovascularization was observed in the contralateral side of peripheral nerves as well. In addition, IRI elevated mRNA levels of P2X3 and P2Y1 receptors, and transient receptor potential vanilloid receptor subtype 1 (TRPV1) in sciatic nerves, dorsal root ganglia and spinal cord, and these elevated levels were inhibited by HGF gene transfer. In conclusion, HGF gene transfer is a potent candidate for treatment of acute ischemic neuropathy caused by reperfusion injury, because of robust angiogenesis and enhanced nerve regeneration.
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16
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Han SW, Vergani CA, Reis PEO. Is gene therapy for limb ischemia a reality? J Vasc Bras 2020; 19:e20190059. [PMID: 34178054 PMCID: PMC8202161 DOI: 10.1590/1677-5449.190059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Accepted: 12/15/2019] [Indexed: 11/21/2022] Open
Abstract
The concept of angiogenic therapy emerged in the early 1990s. The method employs genes that encode growth factors to promote formation of new vessels and remodeling of collateral vessels. Since the procedure involved in this therapy usually only consists of local injections of vectors, the process is minimally invasive, quick, and simple to perform. However, since the first clinical evidence of the effects of gene therapy with vascular endothelial growth factor (VEGF) was observed in patients with peripheral artery disease, to date only two angiogenic therapy drugs have been approved, one in Russia and another in Japan, which seem a very small number, in view of the large volume of investment made in pre-clinical and clinical studies. After all, can we conclude that angiogenic therapy is a reality?
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Affiliation(s)
- Sang Won Han
- Universidade Federal de São Paulo – UNIFESP,
Departamento de Biofísica, Escola Paulista de Medicina, São Paulo, SP,
Brasil.
- Universidade Federal de São Paulo – UNIFESP,
Centro Interdisciplinar de Terapia Gênica – CINTERGEN, São Paulo, SP,
Brasil.
| | - Carlos Alberto Vergani
- Universidade Federal de São Paulo – UNIFESP,
Centro Interdisciplinar de Terapia Gênica – CINTERGEN, São Paulo, SP,
Brasil.
| | - Paulo Eduardo Ocke Reis
- Universidade Federal Fluminense – UFF,
Departamento de Cirurgia Geral e Especializada, Rio de Janeiro, RJ,
Brasil.
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17
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Allogeneic Adipose-Derived Mesenchymal Stem Cell Transplantation Enhances the Expression of Angiogenic Factors in a Mouse Acute Hindlimb Ischemic Model. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1083:1-17. [PMID: 28687961 DOI: 10.1007/5584_2017_63] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Cell migration and molecular mechanisms during healing of damaged vascular or muscle tissues are emerging fields of interest worldwide. The study herein focuses on evaluating the role of allogenic adipose-derived mesenchymal stem cells (ADMSCs) in restoring damaged tissues. Using a hindlimb ischemic mouse model, ADMSC-mediated induction of cell migration and gene expression related to myocyte regeneration and angiogenesis were evaluated. ADMSCs were labeled with GFP (ADMSC-GFP). The proximal end of the femoral blood vessel of mice (over 6 months of age) are ligated at two positions then cut between the two ties. Hindlimb ischemic mice were randomly divided into two groups: Group I (n = 30) which was injected with PBS (100 μL) and Group II (n = 30) which was transplanted with ADMSC-GFP (106 cells/100 μL PBS) at the rectus femoris muscle. The migration of ADMSC-GFP in hindlimb was analyzed by UV-Vis system. The expression of genes related to angiogenesis and muscle tissue repair was quantified by real-time RT-PCR. The results showed that ADMSCs existed in the grafted hindlimb for 7 days. Grafted cells migrated to other damaged areas such as thigh and heel. In both groups the ischemic hindlimb showed an increased expression of several angiogenic genes, including Flt-1, Flk-1, and Ang-2. In particular, the expression of Ang-2 and myogenic-related gene MyoD was significantly increased in the ADMSC-treated group compared to the PBS-treated (control) group; the expression increased at day 28 compared to day 3. The other factors, such as VE-Cadherin, HGF, CD31, Myf5, and TGF-β, were also more highly expressed in the ADMSC-treated group than in the control group. Thus, grafted ADMSCs were able to migrate to other areas in the injured hindlimb, persist for approximately 7 days, and have a significantly positive impact on stimulating expression of myogenic- and angiogenesis-related genes.
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18
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Abstract
Recent breakthroughs in our understanding of the molecular pathophysiology of retinal vascular disease have allowed us to specifically target pathological angiogenesis while minimizing damage to the neurosensory retina. This is perhaps best exemplified by the development of therapies targeting the potent angiogenic growth factor and vascular permeability mediator, vascular endothelial growth factor (VEGF). Anti-VEGF therapies, initially introduced for the treatment of choroidal neovascularization in patients with age-related macular degeneration, have also had a dramatic impact on the management of retinal vascular disease and are currently an indispensable component for the treatment of macular edema in patients with diabetic eye disease and retinal vein occlusions. Emerging evidence supports expanding the use of therapies targeting VEGF for the treatment of retinal neovascularization in patients with diabetic retinopathy and retinopathy of prematurity. However, VEGF is among a growing list of angiogenic and vascular hyperpermeability factors that promote retinal vascular disease. Many of these mediators are expressed in response to stabilization of a single family of transcription factors, the hypoxia-inducible factors (HIFs), that regulate the expression of these angiogenic stimulators. Here we review the basic principles driving pathological angiogenesis and discuss the current state of retinal anti-angiogenic pharmacotherapy as well as future directions.
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Affiliation(s)
- Yannis M Paulus
- Kellogg Eye Center, University of Michigan School of Medicine, 1000 Wall Street, Ann Arbor, MI, 48105, USA
| | - Akrit Sodhi
- Wilmer Eye Institute, Johns Hopkins University School of Medicine, 400 N. Broadway St., Smith Building, 4039, Baltimore, MD, 21287, USA.
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19
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Ghanaatgar-Kasbi S, Khorrami S, Avan A, Aledavoud SA, Ferns GA. Targeting the C-MET/HGF Signaling Pathway in Pancreatic Ductal Adenocarcinoma. Curr Pharm Des 2019; 24:4619-4625. [PMID: 30636579 DOI: 10.2174/1381612825666190110145855] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Revised: 12/24/2018] [Accepted: 12/31/2018] [Indexed: 02/06/2023]
Abstract
The c-mesenchymal-epithelial transition factor (c-MET) is involved in the tumorigenesis of various
cancers. HGF/Met inhibitors are now attracting considerable interest due to their anti-tumor activity in multiple
malignancies such as pancreatic cancer. It is likely that within the next few years, HGF/Met inhibitors will become
a crucial component for cancer management. In this review, we summarize the role of HGF/Met pathway in
the pathogenesis of pancreatic cancer, with particular emphasize on HGF/Met inhibitors in the clinical setting,
including Cabozantinib (XL184, BMS-907351), Crizotinib (PF-02341066), MK-2461, Merestinib (LY2801653),
Tivantinib (ARQ197), SU11274, Onartuzumab (MetMab), Emibetuzumab (LY2875358), Ficlatuzumab (AV-
299), Rilotumumab (AMG 102), and NK4 in pancreatic cancer.
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Affiliation(s)
- Sadaf Ghanaatgar-Kasbi
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Shadi Khorrami
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amir Avan
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed A. Aledavoud
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Gordon A. Ferns
- Brighton & Sussex Medical School, Division of Medical Education, Falmer, Brighton, Sussex BN1 9PH, United Kingdom
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20
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Application of Hepatocyte Growth Factor for Acute Spinal Cord Injury: The Road from Basic Studies to Human Treatment. Int J Mol Sci 2019; 20:ijms20051054. [PMID: 30823442 PMCID: PMC6429374 DOI: 10.3390/ijms20051054] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2019] [Revised: 02/22/2019] [Accepted: 02/24/2019] [Indexed: 11/25/2022] Open
Abstract
Hepatocyte growth factor (HGF) was first identified as a potent mitogen for mature hepatocytes, and has also gained attention as a strong neurotrophic factor in the central nervous system. We found that during the acute phase of spinal cord injury (SCI) in rats, c-Met, the specific receptor for HGF, increases sharply, while the endogenous HGF up-regulation is relatively weak. Introducing exogenous HGF into the spinal cord by injecting an HGF-expressing viral vector significantly increased the neuron and oligodendrocyte survival, angiogenesis, and axonal regeneration, to reduce the area of damage and to promote functional recovery in rats after SCI. Other recent studies in rodents have shown that exogenously administered HGF during the acute phase of SCI reduces astrocyte activation to decrease glial scar formation, and exerts anti-inflammatory effects to reduce leukocyte infiltration. We also reported that the intrathecal infusion of recombinant human HGF (intrathecal rhHGF) improves neurological hand function after cervical contusive SCI in the common marmoset, a non-human primate. Based on these collective results, we conducted a phase I/II clinical trial of intrathecal rhHGF for patients with acute cervical SCI who showed a modified Frankel grade of A/B1/B2 72 h after injury onset, from June 2014 to May 2018.
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21
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Enriched Environment Elicits Proangiogenic Mechanisms After Focal Cerebral Ischemia. Transl Stroke Res 2018; 10:150-159. [PMID: 29700717 DOI: 10.1007/s12975-018-0629-8] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2017] [Revised: 03/01/2018] [Accepted: 03/29/2018] [Indexed: 01/10/2023]
Abstract
Brain has limited capacity for spontaneous recovery of lost function after stroke. Exposure to enriched environment (EE) can facilitate functional recovery, but mechanisms underlying this effect are poorly understood. Here, we used a middle cerebral artery occlusion (MCAO) model to investigate the impact of EE on angiogenesis in the post-ischemic brain in adult male Sprague Dawley rats, and examined whether blood-borne factors may contribute. Compared with standard cage (SC), exposure to EE was associated with greater improvement in neurological function, higher peri-infarct vascular density, and higher chronic post-ischemic cerebral blood flow assessed by laser speckle imaging. The effect persisted for at least 28 days. EE also enhanced the expression of hepatocyte growth factor in the peri-ischemic cortex when measured 15 days after MCAO. Interestingly, serum from rats exposed to EE after MCAO showed elevated levels of hepatocyte growth factor, and plasma or serum from rats exposed to EE after MCAO enhanced the survival and proliferation of cultured endothelial cells, in vitro, when compared with control plasma or serum from SC group after MCAO. Together, our data suggest that exposure to EE promotes angiogenesis in the ischemic brain that may in part be mediated by blood-borne factors.
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Madonna R, Cevik C, Nasser M, De Caterina R. Hepatocyte growth factor: Molecular biomarker and player in cardioprotection and cardiovascular regeneration. Thromb Haemost 2017; 107:656-61. [DOI: 10.1160/th11-10-0711] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2011] [Accepted: 01/03/2012] [Indexed: 11/05/2022]
Abstract
SummaryThe liver possesses impressive regenerative capacities. Grafts of embryonic liver explants and liver explant-conditioned media have been shown to enhance the mitotic activity of hepatocytes. Hepatocyte growth factor (HGF), also named scatter factor (SF), has been identified as a primary candidate in promoting and regulating liver regeneration. Although initially thought to be a liver-specific mitogen, HGF was later reported to have mitogenic, motogenic, morphogenic, and anti-apoptotic activities in various cell types. By promoting angiogenesis and inhibiting apoptosis, endogenous HGF may play an important role in cardioprotection as well as in the regeneration of endothelial cells and cardiomyocytes after myocardial infarction. Since serum concentration of HGF increases in the early phase of myocardial infarction and in heart failure, HGF may also play a key role as a prognostic and diagnostic biomarker of cardiovascular disease. Here we discuss the role of HGF as a biomarker and mediator in cardioprotection and cardiovascular regeneration.
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Improvement of Flap Necrosis in a Rat Random Skin Flap Model by In Vivo Electroporation-Mediated HGF Gene Transfer. Plast Reconstr Surg 2017; 139:1116e-1127e. [PMID: 28445365 DOI: 10.1097/prs.0000000000003259] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Despite great understanding of underlying mechanisms for flap necrosis and advances in surgical techniques, flap necrosis remains a critical issue. In the present study, the authors investigated the efficacy of electroporation-mediated hepatocyte growth factor (HGF) gene delivery to random dorsal skin flaps (McFarlane) to accelerate wound healing and reduce flap necrosis. METHODS Fifteen male Wistar rats (290 to 320 g) were divided randomly into three groups. Group a, the control group (n = 5), underwent surgery and received no gene transfer. Group b received electroporation-mediated HGF gene delivery 24 hours after surgery as a treatment. Group c received electroporation-mediated HGF gene delivery 24 hours before surgery as prophylaxis (n = 5). Planimetry, laser Doppler imaging, and immunohistochemistry were used to assess the efficacy of HGF gene therapy among the groups. RESULTS Electroporation-mediated HGF gene delivery significantly decreased flap necrosis percentage compared with the control group in prophylactic and treatment groups (p = 0.0317 and p = 0.0079, respectively) and significantly increased cutaneous perfusion compared with the control group (p = 0.0317 and p = 0.0159, respectively). Moreover, Spearman rank correlation showed a significant negative correlation between flap necrosis percentage and laser index (p = 0.0213 and r = -0.5964, respectively). Furthermore, significantly higher mean CD31 vessel density was detected in treatment and prophylactic groups (p = 0.0079 and p = 0.0159, respectively). In addition, quantitative image analysis revealed significantly higher HGF protein expression in groups b and c (p = 0.0079 and p = 0.0079, respectively). CONCLUSION These findings suggested in vivo electroporation-mediated HGF gene delivery enhanced viability and vascularity of the ischemic skin flap.
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Chae YK, Arya A, Chiec L, Shah H, Rosenberg A, Patel S, Raparia K, Choi J, Wainwright DA, Villaflor V, Cristofanilli M, Giles F. Challenges and future of biomarker tests in the era of precision oncology: Can we rely on immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH) to select the optimal patients for matched therapy? Oncotarget 2017; 8:100863-100898. [PMID: 29246028 PMCID: PMC5725070 DOI: 10.18632/oncotarget.19809] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2016] [Accepted: 04/11/2017] [Indexed: 12/22/2022] Open
Abstract
Molecular techniques have improved our understanding of the pathogenesis of cancer development. These techniques have also fueled the rational development of targeted drugs for patient populations stratified by their genetic characteristics. These novel methods have changed the classic paradigm of diagnostic pathology; among them are IHC, FISH, polymerase chain reaction (PCR) and microarray technology. IHC and FISH detection methods for human epidermal growth factor receptor-2 (HER2), epidermal growth factor receptor (EGFR) and programmed death ligand-1 (PD-L1) were recently approved by the Food and Drug Administration (FDA) as routine clinical practice for cancer patients. Here, we discuss general challenges related to the predictive power of these molecular biomarkers for targeted therapy in cancer medicine. We will also discuss the prospects of utilizing new biomarkers for fibroblast growth factor receptor (FGFR) and hepatocyte growth factor receptor (cMET/MET) targeted therapies for developing new and robust predictive biomarkers in oncology.
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Affiliation(s)
- Young Kwang Chae
- Developmental Therapeutics Program of the Division of Hematology Oncology, Chicago, IL, USA.,Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA.,Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Ayush Arya
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA
| | - Lauren Chiec
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA
| | - Hiral Shah
- Developmental Therapeutics Program of the Division of Hematology Oncology, Chicago, IL, USA
| | - Ari Rosenberg
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA
| | - Sandip Patel
- University of California San Diego, San Diego, CA, USA
| | - Kirtee Raparia
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA.,Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Jaehyuk Choi
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA.,Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Derek A Wainwright
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA.,Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Victoria Villaflor
- Developmental Therapeutics Program of the Division of Hematology Oncology, Chicago, IL, USA.,Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA.,Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Massimo Cristofanilli
- Developmental Therapeutics Program of the Division of Hematology Oncology, Chicago, IL, USA.,Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA.,Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Francis Giles
- Developmental Therapeutics Program of the Division of Hematology Oncology, Chicago, IL, USA.,Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA.,Northwestern University Feinberg School of Medicine, Chicago, IL, USA
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Targeting the hepatocyte growth factor/Met pathway in cancer. Biochem Soc Trans 2017; 45:855-870. [PMID: 28673936 DOI: 10.1042/bst20160132] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2017] [Revised: 05/23/2017] [Accepted: 05/30/2017] [Indexed: 02/07/2023]
Abstract
Hepatocyte growth factor (HGF)-induced activation of its cell surface receptor, the Met tyrosine kinase, drives mitogenesis, motogenesis and morphogenesis in a wide spectrum of target cell types and embryologic, developmental and homeostatic contexts. Typical paracrine HGF/Met signaling is regulated by HGF activation at target cell surfaces, HGF binding-induced receptor activation, internalization and degradation. Despite these controls, HGF/Met signaling contributes to oncogenesis, tumor angiogenesis and invasiveness, and tumor metastasis in many types of cancer, leading to the rapid growth of pathway-targeted anticancer drug development programs. We review here HGF and Met structure and function, basic properties of HGF/Met pathway antagonists now in clinical development, and recent clinical trial results. Presently, the main challenges facing the effective use of HGF/Met-targeted antagonists for cancer treatment include optimal patient selection, diagnostic and pharmacodynamic biomarker development, and the identification and testing of effective therapy combinations. The wealth of basic information, analytical reagents and model systems available regarding normal and oncogenic HGF/Met signaling will continue to be invaluable in meeting these challenges and moving expeditiously toward more effective cancer treatment.
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Pérez-Calvo JI, Morales-Rull JL, Gimeno-Orna JA, Lasierra-Díaz P, Josa-Laorden C, Puente-Lanzarote JJ, Bettencourt P, Pascual-Figal DA. Usefulness of the Hepatocyte Growth Factor as a Predictor of Mortality in Patients Hospitalized With Acute Heart Failure Regardless of Ejection Fraction. Am J Cardiol 2016; 118:543-9. [PMID: 27338207 DOI: 10.1016/j.amjcard.2016.05.048] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2015] [Revised: 05/09/2016] [Accepted: 05/09/2016] [Indexed: 11/16/2022]
Abstract
Hepatocyte growth factor (HGF) plays a role in the improvement of cardiac function and remodeling. Their serum levels are strongly related with mortality in chronic systolic heart failure (HF). The aim of this study was to study prognostic value of HGF in acute HF, interaction with ejection fraction, renal function, and natriuretic peptides. We included 373 patients (age 76 ± 10 years, left ventricular ejection fraction [LVEF] 46 ± 14%, 48% men) consecutively admitted for acute HF. Blood samples were obtained at admission. All patients were followed up until death or close of study (>1 year, median 371 days). HGF concentrations were determined using a commercial enzyme-linked immunosorbent assay (human HGF immunoassay). The predictive power of HGF was estimated by Cox regression with calculation of Harrell C-statistic. HGF had a median of 1,942 pg/ml (interquartile rank 1,354). According to HGF quartiles, mortality rates (per 1,000 patients/year) were 98, 183, 375, and 393, respectively (p <0.001). In Cox regression analysis, HGF (hazard ratio1SD = 1.5, 95% confidence interval 1.1 to 2.1, p = 0.002) and N-terminal pro b-type natriuretic peptide (NT-proBNP; hazard ratio1SD = 1.8, 95% confidence interval 1.2 to 2.6, p = 0.002) were independent predictors of mortality. Interaction between HGF and LVEF, origin, and renal function was nonsignificant. The addition of HGF improved the predictive ability of the models (C-statistic 0.768 vs 0.741, p = 0.016). HGF showed a complementary value over NT-proBNP (p = 0.001): mortality rate was 490 with both above the median versus 72 with both below. In conclusion, in patients with acute HF, serum HGF concentrations are elevated and identify patients at higher risk of mortality, regardless of LVEF, ischemic origin, or renal function. HGF had independent and additive information over NT-proBNP.
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Affiliation(s)
- Juan-Ignacio Pérez-Calvo
- Servicio de Medicina Interna, Facultad de Medicina, Instituto de Investigación Sanitaria de Aragón, Hospital Clínico Universitario "Lozano Blesa", Zaragoza, Spain.
| | - José-Luis Morales-Rull
- Servicio de Medicina Interna, Hospital Universitario "Arnau de Villanova", Lleida, Spain
| | - José-Antonio Gimeno-Orna
- Servicio de Endocrinología y Metabolismo, Hospital Clínico Universitario "Lozano Blesa", Zaragoza, Spain
| | - Pilar Lasierra-Díaz
- Laboratorio de Inmunología, Hospital Clínico Universitario "Lozano Blesa", Zaragoza, Spain
| | - Claudia Josa-Laorden
- Servicio de Medicina Interna, Facultad de Medicina, Instituto de Investigación Sanitaria de Aragón, Hospital Clínico Universitario "Lozano Blesa", Zaragoza, Spain
| | | | - Paulo Bettencourt
- Serviço de Medicina Interna, Hospital CUF-Porto, Faculdade Medicina Porto, Portugal
| | - Domingo A Pascual-Figal
- Servicio de Cardiología, Hospital Universitario "Virgen de la Arrixaca", Facultad de Medicina, Murcia, Spain
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Shali H, Ahmadi M, Kafil HS, Dorosti A, Yousefi M. IGF1R and c-met as therapeutic targets for colorectal cancer. Biomed Pharmacother 2016; 82:528-36. [DOI: 10.1016/j.biopha.2016.05.034] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2016] [Revised: 05/01/2016] [Accepted: 05/02/2016] [Indexed: 12/15/2022] Open
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Bhattacharjee M, Balakrishnan L, Renuse S, Advani J, Goel R, Sathe G, Keshava Prasad TS, Nair B, Jois R, Shankar S, Pandey A. Synovial fluid proteome in rheumatoid arthritis. Clin Proteomics 2016; 13:12. [PMID: 27274716 PMCID: PMC4893419 DOI: 10.1186/s12014-016-9113-1] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2016] [Accepted: 04/26/2016] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Rheumatoid arthritis (RA) is a chronic autoinflammatory disorder that affects small joints. Despite intense efforts, there are currently no definitive markers for early diagnosis of RA and for monitoring the progression of this disease, though some of the markers like anti CCP antibodies and anti vimentin antibodies are promising. We sought to catalogue the proteins present in the synovial fluid of patients with RA. It was done with the aim of identifying newer biomarkers, if any, that might prove promising in future. METHODS To enrich the low abundance proteins, we undertook two approaches-multiple affinity removal system (MARS14) to deplete some of the most abundant proteins and lectin affinity chromatography for enrichment of glycoproteins. The peptides were analyzed by LC-MS/MS on a high resolution Fourier transform mass spectrometer. RESULTS This effort was the first total profiling of the synovial fluid proteome in RA that led to identification of 956 proteins. From the list, we identified a number of functionally significant proteins including vascular cell adhesion molecule-1, S100 proteins, AXL receptor protein tyrosine kinase, macrophage colony stimulating factor (M-CSF), programmed cell death ligand 2 (PDCD1LG2), TNF receptor 2, (TNFRSF1B) and many novel proteins including hyaluronan-binding protein 2, semaphorin 4A (SEMA4D) and osteoclast stimulating factor 1. Overall, our findings illustrate the complex and dynamic nature of RA in which multiple pathways seems to be participating actively. CONCLUSIONS The use of high resolution mass spectrometry thus, enabled identification of proteins which might be critical to the progression of RA.
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Affiliation(s)
- Mitali Bhattacharjee
- />Institute of Bioinformatics, International Technology Park, Bangalore, 560066 India
- />Amrita School of Biotechnology, Amrita University, Kollam, 690525 India
| | - Lavanya Balakrishnan
- />Institute of Bioinformatics, International Technology Park, Bangalore, 560066 India
- />Department of Biotechnology, Kuvempu University, Shankaraghatta, 577451 India
| | - Santosh Renuse
- />Institute of Bioinformatics, International Technology Park, Bangalore, 560066 India
- />Amrita School of Biotechnology, Amrita University, Kollam, 690525 India
| | - Jayshree Advani
- />Institute of Bioinformatics, International Technology Park, Bangalore, 560066 India
- />Manipal University, Madhav Nagar, Manipal, 576104 India
| | - Renu Goel
- />Institute of Bioinformatics, International Technology Park, Bangalore, 560066 India
- />Department of Biotechnology, Kuvempu University, Shankaraghatta, 577451 India
| | - Gajanan Sathe
- />Institute of Bioinformatics, International Technology Park, Bangalore, 560066 India
- />Manipal University, Madhav Nagar, Manipal, 576104 India
| | - T. S. Keshava Prasad
- />Institute of Bioinformatics, International Technology Park, Bangalore, 560066 India
- />Amrita School of Biotechnology, Amrita University, Kollam, 690525 India
| | - Bipin Nair
- />Amrita School of Biotechnology, Amrita University, Kollam, 690525 India
| | - Ramesh Jois
- />Department of Rheumatology, Fortis Hospital, Bangalore, 560066 India
| | - Subramanian Shankar
- />Department of Rheumatology, Medical Division, Command Hospital (Air Force), Bangalore, 560007 India
| | - Akhilesh Pandey
- />McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, 733 N. Broadway, BRB 527, Baltimore, MD 21205 USA
- />Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205 USA
- />Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205 USA
- />Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205 USA
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Stoddart MJ, Bara J, Alini M. Cells and secretome--towards endogenous cell re-activation for cartilage repair. Adv Drug Deliv Rev 2015; 84:135-45. [PMID: 25174306 DOI: 10.1016/j.addr.2014.08.007] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2014] [Revised: 06/26/2014] [Accepted: 08/20/2014] [Indexed: 01/01/2023]
Abstract
Regenerative medicine approaches to cartilage tissue repair have mainly been concerned with the implantation of a scaffold material containing monolayer expanded cells into the defect, with the aim to differentiate the cells into chondrocytes. While this may be a valid approach, the secretome of the implanted cells and its effects on the endogenous resident cells, is gaining in interest. This review aims to summarize the knowledge on the secretome of mesenchymal stem cells, including knowledge from other tissues, in order to indicate how these mechanisms may be of value in repairing articular cartilage defects. Potential therapies and their effects on the repair of articular cartilage defects will be discussed, with a focus on the transition from classical cell therapy to the implantation of cell free matrices releasing specific cytokines.
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Abstract
Hyaluronan (HA) is a non-sulfated glycosaminoglycan distributed throughout the extracellular matrix that plays a major role in cell adhesion, migration, and proliferation. CD44, a multifunctional cell surface glycoprotein, is a receptor for HA. In addition, CD44 is known to interact with other receptors and ligands, and to mediate a number of cellular functions as well as disease progression. Studies have shown that binding of HA to CD44 in cancer cells activates survival pathways resulting in cancer cell survival. This effect can be blocked by anti-CD44 monoclonal antibodies. A6 is a capped, eight l-amino acid peptide (Ac-KPSSPPEE-NH2) derived from the biologically active connecting peptide domain of the serine protease, human urokinase plasminogen activator (uPA). A6 neither binds to the uPA receptor (uPAR) nor interferes with uPA/uPAR binding. A6 binds to CD44 resulting in the inhibition of migration, invasion, and metastasis of tumor cells, and the modulation of CD44-mediated cell signaling. A6 has been shown to have no dose-limiting toxicity in animal studies. A6 has demonstrated efficacy and an excellent safety profile in Phase 1a, 1b, and 2 clinical trials. In animal models, A6 has also exhibited promising results for the treatment of diabetic retinopathy and wet age-related macular degeneration through the reduction of retinal vascular permeability and inhibition of choroidal neovascularization, respectively. Recently, A6 has been shown to be directly cytotoxic for B-lymphocytes obtained from patients with chronic lymphocytic leukemia expressing the kinase, ZAP-70. This review will discuss the activity of A6, A6 modulation of HA and CD44, and a novel strategy for therapeutic intervention in disease.
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31
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Kameyama H, Udagawa O, Hoshi T, Toukairin Y, Arai T, Nogami M. The mRNA expressions and immunohistochemistry of factors involved in angiogenesis and lymphangiogenesis in the early stage of rat skin incision wounds. Leg Med (Tokyo) 2015; 17:255-60. [PMID: 25794881 DOI: 10.1016/j.legalmed.2015.02.007] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2014] [Revised: 02/24/2015] [Accepted: 02/25/2015] [Indexed: 10/23/2022]
Abstract
Wound healing evaluation is important in forensic pathology, in which angiogenesis plays an important role. We have already shown that vascular endothelial growth factor A (VEGF) is produced in the rat skin incision wounds by neutrophils, endothelial cells, and fibroblasts. In this study, we assessed the changes in the mRNA expressions of various factors possibly involved in angiogenesis including angiopoietin (ANGPT) 1 and 2, cadherin 5 (CDH5), granulocyte-macrophage colony stimulating factor (CSF2/GM-CSF), granulocyte colony stimulating factor (CSF3/G-CSF), chemokine (C-X-C motif) ligand 2 (CXCL2), chemokine (C-X-C motif) ligand12 (CXCL12/SDF1), endothelin 1 (ET1), fibroblast growth factor 1 (FGF 1), hepatocyte growth factor (HGF), hypoxia inducible factor 1 alpha (HIF1a), leptin, matrix metallopepitidase 9 (MMP9), serpine/plasminogen activator inhibitor1 (PAI1), platelet-derived growth factor-A (PDGF-A), transforming growth factor alpha and beta 1 (TGFa and b1), tenomodulin (TNMD), and troponin I type 2 (TNNI2) in the early stage of the rat skin incision wounds by real time RT-PCR. Factors reported to be involved in lymphangiogenesis such as fibroblast growth factor 2 (FGF 2), c-fos induced growth factor (FIGF/VEGF-D), forkhead box C2 (FOXC2), and prospero homeobox 1 (PROX1) were also studied. One and 3 days after the dorsal skin incisions, wounds on male Sprague-Dawley rats showed the statistically significant increases in the mRNA expressions for CXCL2, CSF3, MMP9, PAI1, and CSF2, whereas TGFa, TNNI2, FGF1, TNMD, leptin, and CXCL12 showed the statistically significant decreases. Interestingly, lymphgangiogenic factors FOXC2, PROX1, and FGF2 also showed the statistically significant decreases. In situ hybridization and immunohistochemistry showed the mRNA and protein positivity in endothelial cells, fibroblasts, and some leukocytes at the bottom of the wound tissue for PAI1, CSF3, and MMP9, 1 day after the skin incisions. Our novel findings show the possible involvement of several factors involved in angiogenesis and lymphangiogenesis in the early stage of wound healing process, which may be useful for forensic wound evaluations.
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Affiliation(s)
- Hiroshi Kameyama
- Criminal Investigation Laboratory, Saitama Prefectural Police Headquarters, 3-15-1, Takasago, Urawa-ku, Saitama City, Saitama 330-8533, Japan; Department of Legal Medicine, Teikyo University School of Medicine, 2-11-1, Kaga, Itabashi-ku, Tokyo 173-8605, Japan
| | - Orie Udagawa
- Department of Legal Medicine, Teikyo University School of Medicine, 2-11-1, Kaga, Itabashi-ku, Tokyo 173-8605, Japan
| | - Tomoaki Hoshi
- Department of Legal Medicine, Teikyo University School of Medicine, 2-11-1, Kaga, Itabashi-ku, Tokyo 173-8605, Japan
| | - Yoko Toukairin
- Department of Legal Medicine, Teikyo University School of Medicine, 2-11-1, Kaga, Itabashi-ku, Tokyo 173-8605, Japan
| | - Tomomi Arai
- Department of Legal Medicine, Teikyo University School of Medicine, 2-11-1, Kaga, Itabashi-ku, Tokyo 173-8605, Japan
| | - Makoto Nogami
- Department of Legal Medicine, Teikyo University School of Medicine, 2-11-1, Kaga, Itabashi-ku, Tokyo 173-8605, Japan.
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Zeng W, Ju R, Mao M. Therapeutic potential of hepatocyte growth factor against cerebral ischemia (Review). Exp Ther Med 2014; 9:283-288. [PMID: 25574187 PMCID: PMC4280917 DOI: 10.3892/etm.2014.2133] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2014] [Accepted: 11/24/2014] [Indexed: 12/31/2022] Open
Abstract
The effective treatment for cerebral ischemia has not yet been established. Hepatocyte growth factor (HGF) is a potent pleiotropic cytokine that is involved in cell and tissue regeneration, including in the central nervous system. Studies have demonstrated that an exogenous administration of HGF protects brain tissue from ischemic damage. In response to binding to the receptor c-Met, HGF activates the downstream signaling pathways (including the phosphatidylinositol 3-kinase/Akt, Ras/MAPK and signal transducer and activator of transcription pathways) which leads to various cellular responses involved in angiogenesis, glial scar formation, anti-apoptosis and neurogenesis. The purpose of this review is to summarize the present understanding of the therapeutic potential of HGF in cerebral ischemia.
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Affiliation(s)
- Wen Zeng
- Department of Neonatology, Chengdu Women's and Children's Central Hospital, Chengdu, Sichuan 610031, P.R. China
| | - Rong Ju
- Department of Neonatology, Chengdu Women's and Children's Central Hospital, Chengdu, Sichuan 610031, P.R. China
| | - Meng Mao
- Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China ; Key Laboratory of Obstetric & Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, Chengdu, Sichuan 610041, P.R. China
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Konya H, Miuchi M, Satani K, Matsutani S, Tsunoda T, Yano Y, Katsuno T, Hamaguchi T, Miyagawa JI, Namba M. Hepatocyte growth factor, a biomarker of macroangiopathy in diabetes mellitus. World J Diabetes 2014; 5:678-688. [PMID: 25317245 PMCID: PMC4138591 DOI: 10.4239/wjd.v5.i5.678] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2013] [Revised: 03/01/2014] [Accepted: 06/03/2014] [Indexed: 02/05/2023] Open
Abstract
Atherosclerotic involvements are an essential causal element of prospect in diabetes mellitus (DM), with carotid atherosclerosis (CA) being a common risk-factor for prospective crisis of coronary artery diseases (CAD) and/or cerebral infarction (CI) in DM subjects. From another point of view, several reports have supplied augmenting proof that hepatocyte growth factor (HGF) has a physiopathological part in DM involvements. HGF has been a mesenchymal-derived polyphenic factor which modulates development, motion, and morphosis of diverse cells, and has been regarded as a humor intermediator of epithelial-mesenchymal interplays. The serum concentrations of HGF have been elevated in subjects with CAD and CI, especially during the acute phase of both disturbances. In our study with 89 type 2 DM patients, the association between serum concentrations of HGF and risk-factors for macrovascular complications inclusive of CA were examined. The average of serum HGF levels in the subjects was more elevated than the reference interval. The serum HGF concentrations associated positively with both intimal-media thickness (IMT) (r = 0.24, P = 0.0248) and plaque score (r = 0.27, P = 0.0126), indicating a relationship between the elevated HGF concentrations and advancement of CA involvements. Multivariate statistical analysis accentuated that serum concentrations of HGF would be associated independently with IMT (standardized = 0.28, P = 0.0499). The review indicates what is presently known regarding serum HGF might be a new and meaningful biomarker of macroangiopathy in DM subjects.
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Wira CR, Fahey JV, Rodriguez-Garcia M, Shen Z, Patel MV. Regulation of mucosal immunity in the female reproductive tract: the role of sex hormones in immune protection against sexually transmitted pathogens. Am J Reprod Immunol 2014; 72:236-58. [PMID: 24734774 PMCID: PMC4351777 DOI: 10.1111/aji.12252] [Citation(s) in RCA: 77] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2014] [Accepted: 03/15/2014] [Indexed: 01/01/2023] Open
Abstract
The immune system in the female reproductive tract (FRT) does not mount an attack against human immunodeficiency virus (HIV) or other sexually transmitted infections (STI) with a single endogenously produced microbicide or with a single arm of the immune system. Instead, the body deploys dozens of innate antimicrobials to the secretions of the FRT. Working together, these antimicrobials along with mucosal antibodies attack viral, bacterial, and fungal targets. Within the FRT, the unique challenges of protection against sexually transmitted pathogens coupled with the need to sustain the development of an allogeneic fetus, has evolved in such a way that sex hormones precisely regulate immune function to accomplish both tasks. The studies presented in this review demonstrate that estradiol (E2 ) and progesterone secreted during the menstrual cycle act both directly and indirectly on epithelial cells, fibroblasts and immune cells in the reproductive tract to modify immune function in a way that is unique to specific sites throughout the FRT. As presented in this review, studies from our laboratory and others demonstrate that the innate and adaptive immune systems are under hormonal control, that protection varies with the stage of the menstrual cycle and as such, is dampened during the secretory stage of the cycle to optimize conditions for fertilization and pregnancy. In doing so, a window of STI vulnerability is created during which potential pathogens including HIV enter the reproductive tract to infect host targets.
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Affiliation(s)
- Charles R Wira
- Department of Physiology and Neurobiology, Geisel School of Medicine at Dartmouth, One Medical Center Drive, Lebanon, NH, USA
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35
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Hepatocyte growth factor/Met signaling in cancer. Mol Oncol 2013. [DOI: 10.1017/cbo9781139046947.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022] Open
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36
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Influence of oxidative stress on the level of genes expression TGFB1 and HGF in rat liver upon long-term gastric hypochlorhydria and administration of multiprobiotic Symbiter. UKRAINIAN BIOCHEMICAL JOURNAL 2013. [DOI: 10.15407/ubj85.05.114] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
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Pérez-Vargas JCS, Biondani P, Maggi C, Gariboldi M, Gloghini A, Inno A, Volpi CC, Gualeni AV, di Bartolomeo M, de Braud F, Castano A, Bossi I, Pietrantonio F. Role of cMET in the development and progression of colorectal cancer. Int J Mol Sci 2013; 14:18056-77. [PMID: 24005867 PMCID: PMC3794769 DOI: 10.3390/ijms140918056] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2013] [Revised: 08/13/2013] [Accepted: 08/27/2013] [Indexed: 12/15/2022] Open
Abstract
Mesenchymal-epithelial transition (MET) is a member of a distinct subfamily of heterodimeric receptor tyrosine kinase receptors that specifically binds the hepatocyte growth factor (HGF). Binding to HGF leads to receptor dimerization/multimerization and phosphorylation, resulting in its catalytic activation. MET activation drives the malignant progression of several tumor types, including colorectal cancer (CRC), by promoting signaling cascades that mainly result in alterations of cell motility, survival, and proliferation. MET is aberrantly activated in many human cancers through various mechanisms, including point mutations, gene amplification, transcriptional up-regulation, or ligand autocrine loops. MET promotes cell scattering, invasion, and protection from apoptosis, thereby acting as an adjuvant pro-metastatic gene for many tumor types. In CRC, MET expression confers more aggressiveness and worse clinical prognosis. With all of this rationale, inhibitors that target the HGF/MET axis with different types of response have been developed. HGF and MET are new promising targets to understand the pathogenesis of CRC and for the development of new, targeted therapies.
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Affiliation(s)
| | - Pamela Biondani
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, 1-20133 Milan, Italy; E-Mails: (P.B.); (C.M.); (M.B.); (F.B.); (A.C.); (I.B.)
| | - Claudia Maggi
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, 1-20133 Milan, Italy; E-Mails: (P.B.); (C.M.); (M.B.); (F.B.); (A.C.); (I.B.)
| | - Manuela Gariboldi
- Experimental Oncology and Molecular Medicine Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, 1-20133 Milan, Italy; E-Mail:
- FIRC Institute of Molecolar Oncology Foundation (IFOM), 1-20133 Milan, Italy
| | - Annunziata Gloghini
- Pathology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, 1-20133 Milan, Italy; E-Mails: (A.G.); (C.C.V.); (A.V.G.)
| | - Alessandro Inno
- Medical Oncology, Sacro Cuore-Don Calabria Hospital, 37024 Negrar (Verona), Italy; E-Mail:
| | - Chiara Costanza Volpi
- Pathology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, 1-20133 Milan, Italy; E-Mails: (A.G.); (C.C.V.); (A.V.G.)
| | - Ambra Vittoria Gualeni
- Pathology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, 1-20133 Milan, Italy; E-Mails: (A.G.); (C.C.V.); (A.V.G.)
| | - Maria di Bartolomeo
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, 1-20133 Milan, Italy; E-Mails: (P.B.); (C.M.); (M.B.); (F.B.); (A.C.); (I.B.)
| | - Filippo de Braud
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, 1-20133 Milan, Italy; E-Mails: (P.B.); (C.M.); (M.B.); (F.B.); (A.C.); (I.B.)
| | - Alessandra Castano
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, 1-20133 Milan, Italy; E-Mails: (P.B.); (C.M.); (M.B.); (F.B.); (A.C.); (I.B.)
| | - Ilaria Bossi
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, 1-20133 Milan, Italy; E-Mails: (P.B.); (C.M.); (M.B.); (F.B.); (A.C.); (I.B.)
| | - Filippo Pietrantonio
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, 1-20133 Milan, Italy; E-Mails: (P.B.); (C.M.); (M.B.); (F.B.); (A.C.); (I.B.)
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Jin Q, Sun L, Li S, Yang X, Lu Y, Li Y. Number and function impairment of resident C-Kit+ cardiac stem cells in mice with renal dysfunction caused by 5/6 nephrectomy. Ren Fail 2013; 35:1136-41. [PMID: 23879535 DOI: 10.3109/0886022x.2013.815108] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Cardiac stem cell (CSC) dysfunction exists in various kinds of cardiovascular diseases, and may be responsible for the insufficient regeneration of cardiac myocytes and coronary vessels. However, whether chronic renal failure (CRF) affected CSC is unknown. METHOD CRF was induced in adult male mice by 5/6 nephrectomy. The mice were killed at 12 weeks after operation. C-kit+ CSC numbers was evaluated by flow cytometer. Apoptosis and DNA damage of C-kit+ CSC in the control and CRF mice was analyzed by immunohistochemistry. In the in vitro study, normal medium, and medium with uremic rat serum were used for the CSC culture. RESULTS CSC counts attenuated significantly in the chronic renal failure model, whereas apoptosis cells and 8-OHdG-positive cells significantly increased. CSC derived form 5/6 nephrectomy mice showed an impaired anti-oxidant potential. In the cultured cells, CSCs subjected to uremic rat serum showed a higher frequency of TUNEL stain-positive and 8-OHdG-positive cells. The uremia rat serum reduced the expression of hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF) in CSC. CONCLUSIONS The current study elucidated that CSC number and function disorders existed in mice with chronic renal insufficiency. Apoptosis, oxidative stress and reduced angiogenic factors secretion caused by uremic toxins in serum are contributors to CSC dysfunction.
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Affiliation(s)
- Qiu Jin
- Kidney Disease Center, The First Affiliated Hospital, Medical College of Zhejiang University, Hangzhou, Zhejiang, PR China
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Kuehl AR, Abshagen K, Eipel C, Laschke MW, Menger MD, Laue M, Vollmar B. External inosculation as a feature of revascularization occurs after free transplantation of murine liver grafts. Am J Transplant 2013; 13:286-98. [PMID: 23205733 DOI: 10.1111/j.1600-6143.2012.04336.x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2012] [Revised: 10/02/2012] [Accepted: 10/09/2012] [Indexed: 01/25/2023]
Abstract
The induction of angiogenesis is essential for successful engraftment of freely transplanted cells or cellular composites. How to augment angiogenesis to ensure an appropriate viability of the grafts is still under investigation. This study evaluated the proangiogenic capability of different syngeneic free liver transplants and elucidated the origin of the newly formed vascular network via use of an eGFP(+) /eGFP(-) (enhanced green fluorescent protein) cross-over design. Using intravital fluorescence microscopy, we found that neonatal and resected murine liver transplants implanted into dorsal skinfold chambers display a significantly enhanced vascularization compared to regular adult transplants. Immunohistochemically, less tissue hypoxia, apoptosis and macrophage infiltration was observed in the neonatal and resected transplants, which is in line with improved vascularization of those grafts. Additionally, electron microscopy revealed morphological hallmarks of liver cells. eGFP(+) liver transplants implanted on eGFP(-) recipients displayed vascular sprouting from the grafts themselves and connection to the recipients` microvasculature, which also undergoes transient proangiogenic response. This process is described as external inosculation, with microvessels exhibiting a chimeric nature of the endothelial lining. These data collectively show that proliferative stimulation is taking effect on angiogenic properties of free transplants and might provide a novel tool for modulating the revascularization of free grafts.
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Affiliation(s)
- A-R Kuehl
- Institute for Experimental Surgery, University of Rostock, Rostock, Germany
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40
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Stewart N, Chade AR. Renoprotective effects of hepatocyte growth factor in the stenotic kidney. Am J Physiol Renal Physiol 2012; 304:F625-33. [PMID: 23269649 DOI: 10.1152/ajprenal.00504.2012] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Renal microvascular (MV) damage and loss contribute to the progression of renal injury in renal artery stenosis (RAS). Hepatocyte growth factor (HGF) is a powerful angiogenic and antifibrotic cytokine that we showed to be decreased in the stenotic kidney. We hypothesized that renal HGF therapy will improve renal function mainly by protecting the renal microcirculation. Unilateral RAS was induced in 15 pigs. Six weeks later, single-kidney RBF and GFR were quantified in vivo using multidetector computed tomography (CT). Then, intrarenal rh-HGF or vehicle was randomly administered into the stenotic kidney (RAS, n = 8; RAS+HGF, n = 7). Pigs were observed for 4 additional weeks before CT studies were repeated. Renal MV density was quantified by 3D micro-CT ex vivo and histology, and expression of angiogenic and inflammatory factors, apoptosis, and fibrosis was determined. HGF therapy improved RBF and GFR compared with vehicle-treated pigs. This was accompanied by improved renal expression of angiogenic cytokines (VEGF, p-Akt) and tissue-healing promoters (SDF-1, CXCR4, MMP-9), reduced MV remodeling, apoptosis, and fibrosis, and attenuated renal inflammation. However, HGF therapy did not improve renal MV density, which was similarly reduced in RAS and RAS+HGF compared with controls. Using a clinically relevant animal model of RAS, we showed novel therapeutic effects of a targeted renal intervention. Our results show distinct actions on the existing renal microcirculation and promising renoprotective effects of HGF therapy in RAS. Furthermore, these effects imply plasticity of the stenotic kidney to recuperate its function and underscore the importance of MV integrity in the progression of renal injury in RAS.
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Affiliation(s)
- Nicholas Stewart
- Department of Physiology and Biophysics, Center for Excellence in Cardiovascular-Renal Research, University of Mississippi Medical Center, Jackson, MS 39216, USA
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41
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Long X, Li Y, Qi Y, Xu J, Wang Z, Zhang X, Zhang D, Zhang L, Huang J. XAF1 contributes to dengue virus-induced apoptosis in vascular endothelial cells. FASEB J 2012. [PMID: 23207547 DOI: 10.1096/fj.12-213967] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
The mechanism of vascular leakage in severe dengue infection remains unclear. Here, we used primary human umbilical vein endothelial cells (HUVECs) and the EA.hy926 cell line to study the molecular events that occur after dengue virus serotype 2 (DENV2) infection. DENV2-induced apoptosis was confirmed using nuclear staining, TUNEL assay, and electron microscopy. A genome-wide transcriptome analysis was performed using a microarray of DENV2-infected HUVECs. Notably, interferon-inducible genes were differentially expressed after DENV2 infection. Prominent among these genes was the X chromosome-linked inhibitor of apoptosis protein (XIAP)-associated factor 1 (XAF1; up-regulated 1.2-fold in the microarray analysis and ∼8-fold by qRT-PCR after DENV2 infection). XAF1 protein levels were up-regulated after DENV2 infection in both HUVECs and EA.hy926 cells. Evidence indicated interaction between XAF1 and XIAP during DENV2 infection based on their cellular localization, as observed by confocal microscopy and the coimmunoprecipitation of XIAP with an anti-XAF1 antibody. Next, recombinant EA.hy926 cell lines in which XAF1 was either knocked down or overexpressed were constructed. The expression levels of the apoptosis-related genes caspase 3, caspase 8, caspase 9, and poly-(ADP-ribose) polymerase (PARP) were down-regulated in the XAF1 knockdown (24-48 h postinfection) but were up-regulated in XAF1 overexpressing cells (36 h postinfection). This is the first study of the role of XAF1 in promoting apoptosis in vascular endothelial cells after DENV2 infection.
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Affiliation(s)
- Xigui Long
- Institute of Immunology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China
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Salimath AS, Phelps EA, Boopathy AV, Che PL, Brown M, García AJ, Davis ME. Dual delivery of hepatocyte and vascular endothelial growth factors via a protease-degradable hydrogel improves cardiac function in rats. PLoS One 2012; 7:e50980. [PMID: 23226440 PMCID: PMC3511447 DOI: 10.1371/journal.pone.0050980] [Citation(s) in RCA: 79] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2012] [Accepted: 10/31/2012] [Indexed: 11/30/2022] Open
Abstract
Acute myocardial infarction (MI) caused by ischemia and reperfusion (IR) is the most common cause of cardiac dysfunction due to local cell death and a temporally regulated inflammatory response. Current therapeutics are limited by delivery vehicles that do not address spatial and temporal aspects of healing. The aim of this study was to engineer biotherapeutic delivery materials to harness endogenous cell repair to enhance myocardial repair and function. We have previously engineered poly(ethylene glycol) (PEG)-based hydrogels to present cell adhesive motifs and deliver VEGF to promote vascularization in vivo. In the current study, bioactive hydrogels with a protease-degradable crosslinker were loaded with hepatocyte and vascular endothelial growth factors (HGF and VEGF, respectively) and delivered to the infarcted myocardium of rats. Release of both growth factors was accelerated in the presence of collagenase due to hydrogel degradation. When delivered to the border zones following ischemia-reperfusion injury, there was no acute effect on cardiac function as measured by echocardiography. Over time there was a significant increase in angiogenesis, stem cell recruitment, and a decrease in fibrosis in the dual growth factor delivery group that was significant compared with single growth factor therapy. This led to an improvement in chronic function as measured by both invasive hemodynamics and echocardiography. These data demonstrate that dual growth factor release of HGF and VEGF from a bioactive hydrogel has the capacity to significantly improve cardiac remodeling and function following IR injury.
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Affiliation(s)
- Apoorva S. Salimath
- Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia, United States of America
- George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, Georgia, United States of America
| | - Edward A. Phelps
- Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia, United States of America
- George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, Georgia, United States of America
| | - Archana V. Boopathy
- Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia, United States of America
- Wallace H. Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, Georgia, United States of America
- Division of Cardiology, Emory University School of Medicine, Atlanta, Georgia, United States of America
| | - Pao-lin Che
- Wallace H. Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, Georgia, United States of America
- Division of Cardiology, Emory University School of Medicine, Atlanta, Georgia, United States of America
| | - Milton Brown
- Wallace H. Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, Georgia, United States of America
- Division of Cardiology, Emory University School of Medicine, Atlanta, Georgia, United States of America
| | - Andrés J. García
- Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia, United States of America
- George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, Georgia, United States of America
| | - Michael E. Davis
- Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia, United States of America
- Wallace H. Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, Georgia, United States of America
- Division of Cardiology, Emory University School of Medicine, Atlanta, Georgia, United States of America
- * E-mail:
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Kim JS, Hwang HY, Cho KR, Park EA, Lee W, Paeng JC, Lee DS, Kim HK, Sohn DW, Kim KB. Intramyocardial transfer of hepatocyte growth factor as an adjunct to CABG: phase I clinical study. Gene Ther 2012; 20:717-22. [PMID: 23151518 DOI: 10.1038/gt.2012.87] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2012] [Revised: 08/31/2012] [Accepted: 10/08/2012] [Indexed: 11/09/2022]
Abstract
The purpose of this phase I clinical trial was to evaluate the safety, tolerability and potential efficacy of VM202, naked DNA expressing two isoforms of hepatocyte growth factor, as an adjunct therapy to coronary artery bypass grafting (CABG) in patients with ischemic heart disease (IHD). Nine patients were assigned to receive increasing doses (0.5 to 2.0 mg) of VM202 injected into the right coronary artery (RCA) territory following completion of CABG for the left coronary artery territory. Patients were evaluated for safety and tolerability, and changes in myocardial functions were monitored via echocardiography, cardiac magnetic resonance imaging and myocardial single photon emission computed tomography throughout 6-month follow-up period. No serious complication related to VM202 was observed throughout the 6-month follow-up period. Global myocardial functions (wall motion score index, P=0.0084; stress perfusion, P=0.0002) improved during the follow-up period. In the RCA region, there was an increase in the stress perfusion (baseline vs 3-month, P=0.024; baseline vs 6-month, P=0.024) and also in the wall thickness of the diastolic and systolic phases. Intramyocardial injection of VM202 can be safely used in IHD patients with the tolerable dose of 2.0 mg. In addition, VM202 might appear to have improved regional myocardial perfusion and wall thickness in the injected region.
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Affiliation(s)
- J S Kim
- Seoul National University Bundang Hospital, Gyeonggi, Korea
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Pardue EL, Ibrahim S, Ramamurthi A. Role of hyaluronan in angiogenesis and its utility to angiogenic tissue engineering. Organogenesis 2012; 4:203-14. [PMID: 19337400 DOI: 10.4161/org.4.4.6926] [Citation(s) in RCA: 122] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2008] [Accepted: 09/08/2008] [Indexed: 01/30/2023] Open
Abstract
Angiogenesis represents the outgrowth of new blood vessels from existing ones, a physiologic process that is vital to supply nourishment to newly forming tissues during development and tissue remodeling and repair (wound healing). Regulation of angiogenesis in the healthy body occurs through a fine balance of angiogenesis-stimulating factors and angiogenesis inhibitors. When this balance is disturbed, excessive or deficient angiogenesis can result and contribute to development of a wide variety of pathological conditions. The therapeutic stimulation or suppression of angiogenesis could be the key to abrogating these diseases. In recent years, tissue engineering has emerged as a promising technology for regenerating tissues or organs that are diseased beyond repair. Among the critical challenges that deter the practical realization of the vision of regenerating functional tissues for clinical implantation, is how tissues of finite size can be regenerated and maintained viable in the long-term. Since the diffusion of nutrients and essential gases to cells, and removal of metabolic wastes is typically limited to a depth of 150-250 microm from a capillary (3-10 cells thick), tissue constructs must mandatorily permit in-growth of a blood capillary network to nourish and sustain the viability of cells within. The purpose of this article is to provide an overview of the role and significance of hyaluronan (HA), a glycosaminoglycan (GAG) component of connective tissues, in physiologic and pathological angiogenesis, its applicability as a therapeutic to stimulate or suppress angiogenesis in situ within necrotic tissues in vivo, and the factors determining its potential utility as a pro-angiogenic stimulus that will enable tissue engineering of neo-vascularized and functional tissue constructs for clinical use.
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Affiliation(s)
- Erin L Pardue
- Clemson University; Medical University of South Carolina Bioengineering Program; Charleston, South Carolina USA
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Abstract
INTRODUCTION Under normal conditions, hepatocyte growth factor (HGF)-induced activation of its cell surface receptor, the Met tyrosine kinase (TK), is tightly regulated by paracrine ligand delivery, ligand activation at the target cell surface, and ligand-activated receptor internalization and degradation. Despite these controls, HGF/Met signaling contributes to oncogenesis and tumor progression in several cancers and promotes aggressive cellular invasiveness that is strongly linked to tumor metastasis. AREA COVERED The prevalence of HGF/Met pathway activation in human malignancies has driven rapid growth in cancer drug development programs. The authors review Met structure and function, the basic properties of HGF/Met pathway antagonists now in preclinical and clinical development, as well as the latest clinical trial results. EXPERT OPINION Clinical trials with HGF/Met pathway antagonists show that as a class these agents are well tolerated. Although widespread efficacy was not seen in several completed Phase II studies, promising results have been reported in lung, gastric, prostate and papillary renal cancer patients treated with these agents. The main challenges facing the effective use of HGF/Met-targeted antagonists for cancer treatment are optimal patient selection, diagnostic and pharmacodynamic biomarker development, and the identification and testing of optimal therapy combinations. The wealth of basic information, analytical reagents, and model systems available concerning HGF/Met oncogenic signaling will continue to be invaluable in meeting these challenges and moving expeditiously toward more effective disease control.
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Affiliation(s)
- Fabiola Cecchi
- National Cancer Institute, National Institutes of Health, Center for Cancer Research, Urologic Oncology Branch, 10 Center Drive MSC 1107, Bethesda, MD 20892-1107, USA.
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Enhanced cardioprotective effects by coexpression of two isoforms of hepatocyte growth factor from naked plasmid DNA in a rat ischemic heart disease model. J Gene Med 2011; 13:549-55. [DOI: 10.1002/jgm.1603] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022] Open
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47
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Long-term effects of hepatocyte growth factor gene therapy in rat myocardial infarct model. Gene Ther 2011; 19:836-43. [DOI: 10.1038/gt.2011.128] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Cecchi F, Rabe DC, Bottaro DP. The Hepatocyte Growth Factor Receptor: Structure, Function and Pharmacological Targeting in Cancer. ACTA ACUST UNITED AC 2011; 6:146-151. [PMID: 25197268 DOI: 10.2174/157436211795659955] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Under normal conditions, hepatocyte growth factor (HGF)-induced activation of its cell surface receptor, the Met tyrosine kinase (TK), is tightly regulated by paracrine ligand delivery, ligand activation at the target cell surface, and ligand activated receptor internalization and degradation. Despite these controls, HGF/Met signaling contributes to oncogenesis and tumor progression in several cancers and promotes aggressive cellular invasiveness that is strongly linked to tumor metastasis. The prevalence of HGF/Met pathway activation in human malignancies has driven rapid growth in cancer drug development programs. Pathway inhibitors can be divided broadly into biologicals and low molecular weight synthetic TK inhibitors; of these, the latter now outnumber all other inhibitor types. We review here Met structure and function, the basic properties of HGF/Met pathway antagonists now in preclinical and clinical development, as well as the latest clinical trial results. The main challenges facing the effective use of HGF/Met-targeted antagonists for cancer treatment include optimal patient selection, diagnostic and pharmacodynamic biomarker development, and the identification and testing of optimal therapy combinations. The wealth of basic information, analytical reagents and model systems available concerning HGF/Met oncogenic signaling will continue to be invaluable in meeting these challenges and moving expeditiously toward more effective disease control.
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Affiliation(s)
- Fabiola Cecchi
- Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
| | - Daniel C Rabe
- Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
| | - Donald P Bottaro
- Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
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Madonna R, Rokosh G, De Caterina R, Bolli R. Hepatocyte growth factor/Met gene transfer in cardiac stem cells--potential for cardiac repair. Basic Res Cardiol 2010; 105:443-52. [PMID: 20393738 DOI: 10.1007/s00395-010-0102-7] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2009] [Revised: 03/24/2010] [Accepted: 03/31/2010] [Indexed: 01/17/2023]
Abstract
The adult heart has been recently recognized as a self-renewing organ that contains a pool of committed resident cardiac stem cells (CSCs) and cardiac progenitor cells (CPCs). These adult CSCs and CPCs can be induced by cytokines and growth factors to migrate, differentiate, and proliferate in situ and potentially replace lost cardiomyocytes. Ligand-receptor systems, such as the tyrosine kinase receptor mesenchymal-epithelial transition factor (Met) and its ligand hepatocyte growth factor (HGF), are potential candidates for boosting migration, engraftment and commitment of CSCs. Here, we discuss the possible application of HGF/Met gene therapy to enhance the ability of CSCs to promote myocardial regeneration.
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Affiliation(s)
- Rosalinda Madonna
- Institute of Molecular Cardiology, University of Louisville, Louisville, KY, USA.
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Pyun WB, Hahn W, Kim DS, Yoo WS, Lee SD, Won JH, Rho BS, Park ZY, Kim JM, Kim S. Naked DNA expressing two isoforms of hepatocyte growth factor induces collateral artery augmentation in a rabbit model of limb ischemia. Gene Ther 2010; 17:1442-52. [PMID: 20668482 DOI: 10.1038/gt.2010.101] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Hepatocyte growth factor (HGF) has been shown to induce angiogenesis in vivo and has potential as a candidate gene for 'therapeutic angiogenesis'. In vivo, two isoforms of HGF, HGF₇₂₃ and HGF₇₂₈, consisting of 723 and 728 amino acids, are generated through alternative splicing between exons 4 and 5, but the biological effects of their coexpression have not yet been elucidated. In this study, we generated a series of genomic-complementary DNA (cDNA) hybrids of the HGF gene by inserting various truncated intron 4 into the junction of exons 4 and 5 of HGF cDNA and analyzed the biological activities of these hybrid constructs. We showed that: (1) the hybrid called HGF-X7, which contained 1502 base pairs of intron 4, could drive a higher level of HGF expression than other hybrid constructs and cDNAs of each isoform alone; (2) the pCK vector was most efficient for the gene expression of HGF-X7; (3) coexpression of both isoforms of HGF could more efficiently induce the migration of human umbilical vein endothelial cell (HUVEC) and of the mouse myoblast cell line C₂C₁₂ myoblasts than a single isoform of HGF and human vascular endothelial growth factor (VEGF)₁₆₅ at a given concentration; (4) intramuscular administration of pCK-HGF-X7 resulted in transient and localized HGF expression in the injected muscle without an increase in the HGF protein levels in other tissues including serum; and (5) intramuscular injection of pCK-HGF-X7 could more efficiently increase the number of angiographically recognizable collateral vessels, as well as improve an intra-arterial Doppler wire-measured blood flow in the rabbit model of hindlimb ischemia when compared with the identical vector encoding VEGF₁₆₅ gene. These results showed that transfer of the genomic-cDNA hybrid of the HGF gene could be used as a potential therapeutic approach to human vascular diseases.
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Affiliation(s)
- W-B Pyun
- Department of Cardiology, Medical College of Ewha Womans University, Mokdong Hospital, Seoul, Korea
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