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Muñoz M, Rosso M. Radiotherapy Plus the Neurokinin-1 Receptor Antagonist Aprepitant: A Potent Therapeutic Strategy for the Treatment of Diffuse Intrinsic Pontine Glioma. Cancers (Basel) 2025; 17:520. [PMID: 39941886 PMCID: PMC11816061 DOI: 10.3390/cancers17030520] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2024] [Revised: 01/24/2025] [Accepted: 01/28/2025] [Indexed: 02/16/2025] Open
Abstract
Background: Diffuse intrinsic pontine glioma (DIPG) is a devastating childhood brainstem tumor. The median survival of DIPG is 16-24 months independent of the treatment received. Therefore, new therapeutic strategies against DIPG are urgently needed. Substance P (SP) peptide, through the neurokinin neurokinin-1 receptor (NK-1R), is involved in glioma progression. It induces glioma cell proliferation by activating MAPKs (p38 MAPK, ERK1/2, and JNK), c-Myc, AP-1, and NF-κB and induces antiapoptotic effects via PI3K/Akt/mTOR in glioma cells. SP favors glycogen breakdown that is essential for glycolysis. The SP/NK-1R system also regulates the migration and invasion of glioma cells, stimulates angiogenesis, and triggers inflammation which contributes to glioma progression. Moreover, all glioma cells express NK-1R, and NK-1R is essential for the viability of glioma cells and not of normal cells. In contrast, in glioma, NK-1R antagonists, such as the drug aprepitant, penetrate the brain and reach therapeutic concentrations, thereby inhibiting mitogenesis, inducing apoptosis, and inhibiting the breakdown of glycogen in glioma cells. In addition, they inhibit angiogenesis and exert antimetastatic and anti-inflammatory effects. The combination of radiotherapy with NK-1R antagonists produces radiosensitization and radioneuroprotection, reduces both peritumoral- and radiation-induced inflammation, and also provides antinausea and antivomiting effects. Objective: This review updates the involvement of the SP/NK-1R system in glioma promotion and progression and the potential clinical application of NK-1R antagonist drugs in DIPG therapy. Conclusions: NK-1R plays a crucial role in glioma progression and NK-1R antagonists such as aprepitant could be used in combination with radiotherapy as a potent therapeutic strategy for the treatment of patients with DIPG.
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Affiliation(s)
- Miguel Muñoz
- Research Laboratory on Neuropeptides, Institute of Biomedicine of Seville (IBIS), 41013 Seville, Spain;
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Jonischkies K, del Angel M, Demiray YE, Loaiza Zambrano A, Stork O. The NDR family of kinases: essential regulators of aging. Front Mol Neurosci 2024; 17:1371086. [PMID: 38803357 PMCID: PMC11129689 DOI: 10.3389/fnmol.2024.1371086] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Accepted: 04/22/2024] [Indexed: 05/29/2024] Open
Abstract
Aging is defined as a progressive decline of cognitive and physiological functions over lifetime. Since the definition of the nine hallmarks of aging in 2013 by López-Otin, numerous studies have attempted to identify the main regulators and contributors in the aging process. One interesting group of proteins whose participation has been implicated in several aging hallmarks are the nuclear DBF2-related (NDR) family of serine-threonine AGC kinases. They are one of the core components of the Hippo signaling pathway and include NDR1, NDR2, LATS1 and LATS2 in mammals, along with its highly conserved metazoan orthologs; Trc in Drosophila melanogaster, SAX-1 in Caenorhabditis elegans, CBK1, DBF20 in Saccharomyces cerevisiae and orb6 in Saccharomyces pombe. These kinases have been independently linked to the regulation of widely diverse cellular processes disrupted during aging such as the cell cycle progression, transcription, intercellular communication, nutrient homeostasis, autophagy, apoptosis, and stem cell differentiation. However, a comprehensive overview of the state-of-the-art knowledge regarding the post-translational modifications of and by NDR kinases in aging has not been conducted. In this review, we summarize the current understanding of the NDR family of kinases, focusing on their relevance to various aging hallmarks, and emphasize the growing body of evidence that suggests NDR kinases are essential regulators of aging across species.
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Affiliation(s)
- Kevin Jonischkies
- Department of Genetics and Molecular Neurobiology, Institute of Biology, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
| | - Miguel del Angel
- Department of Genetics and Molecular Neurobiology, Institute of Biology, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
| | - Yunus Emre Demiray
- Department of Genetics and Molecular Neurobiology, Institute of Biology, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
| | - Allison Loaiza Zambrano
- Department of Genetics and Molecular Neurobiology, Institute of Biology, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
| | - Oliver Stork
- Department of Genetics and Molecular Neurobiology, Institute of Biology, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
- Center for Behavioral Brain Science, Magdeburg, Germany
- Center for Intervention and Research on Adaptive and Maladaptive Brain Circuits Underlying Mental Health (C-I-R-C), Jena-Magdeburg-Halle, Germany
- German Center for Mental Health (DZPG), Jena-Magdeburg-Halle, Germany
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Kuan CH, Tai KY, Lu SC, Wu YF, Wu PS, Kwang N, Wang WH, Mai-Yi Fan S, Wang SH, Chien HF, Lai HS, Lin MH, Plikus MV, Lin SJ. Delayed Collagen Production without Myofibroblast Formation Contributes to Reduced Scarring in Adult Skin Microwounds. J Invest Dermatol 2024; 144:1124-1133.e7. [PMID: 38036291 DOI: 10.1016/j.jid.2023.10.029] [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: 07/18/2022] [Revised: 10/02/2023] [Accepted: 10/30/2023] [Indexed: 12/02/2023]
Abstract
In adult mammals, wound healing predominantly follows a fibrotic pathway, culminating in scar formation. However, cutaneous microwounds generated through fractional photothermolysis, a modality that produces a constellation of microthermal zones, exhibit a markedly different healing trajectory. Our study delineates the cellular attributes of these microthermal zones, underscoring a temporally limited, subclinical inflammatory milieu concomitant with rapid re-epithelialization within 24 hours. This wound closure is facilitated by the activation of genes associated with keratinocyte migration and differentiation. In contrast to macrothermal wounds, which predominantly heal through a robust myofibroblast-mediated collagen deposition, microthermal zones are characterized by absence of wound contraction and feature delayed collagen remodeling, initiating 5-6 weeks after injury. This distinct wound healing is characterized by a rapid re-epithelialization process and a muted inflammatory response, which collectively serve to mitigate excessive myofibroblast activation. Furthermore, we identify an initial reparative phase characterized by a heterogeneous extracellular matrix protein composition, which precedes the delayed collagen remodeling. These findings extend our understanding of cutaneous wound healing and may have significant implications for the optimization of therapeutic strategies aimed at mitigating scar formation.
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Affiliation(s)
- Chen-Hsiang Kuan
- Graduate Institute of Clinical Research, College of Medicine, National Taiwan University, Taipei, Taiwan; Division of Plastic Surgery, Department of Surgery, National Taiwan University Hospital, College of Medicine, Taipei, Taiwan; Research Center for Developmental Biology and Regenerative Medicine, National Taiwan University, Taipei, Taiwan
| | - Kang-Yu Tai
- Genome and Systems Biology Degree Program, National Taiwan University and Academia Sinica, Taipei, Taiwan
| | - Shao-Chi Lu
- Department of Biomedical Engineering, College of Medicine and College of Engineering, National Taiwan University, Taipei, Taiwan
| | - Yueh-Feng Wu
- Department of Biomedical Engineering, College of Medicine and College of Engineering, National Taiwan University, Taipei, Taiwan
| | - Pei-Shan Wu
- Department of Ophthalmology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Nellie Kwang
- Department of Developmental and Cell Biology, School of Biological Sciences, University of California, Irvine, Irvine, California, USA
| | - Wei-Hung Wang
- Department of Biomedical Engineering, College of Medicine and College of Engineering, National Taiwan University, Taipei, Taiwan
| | - Sabrina Mai-Yi Fan
- Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
| | - Shiou-Han Wang
- Department of Dermatology, National Taiwan University Hospital, College of Medicine, Taipei, Taiwan
| | - Hsiung-Fei Chien
- Division of Plastic Surgery, Department of Surgery, Taipei Medical University Hospital, Taipei, Taiwan; TMU Center for Cell Therapy and Regeneration Medicine, Taipei Medical University, Taipei, Taiwan
| | - Hong-Shiee Lai
- Department of Surgery, National Taiwan University Hospital, College of Medicine, Taipei, Taiwan; Department of Surgery, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
| | - Miao-Hsia Lin
- Graduate Institute and Department of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Maksim V Plikus
- Department of Developmental and Cell Biology, School of Biological Sciences, University of California, Irvine, Irvine, California, USA; NSF-Simons Center for Multiscale Cell Fate Research, University of California, Irvine, Irvine, California, USA; Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, California, USA
| | - Sung-Jan Lin
- Graduate Institute of Clinical Research, College of Medicine, National Taiwan University, Taipei, Taiwan; Research Center for Developmental Biology and Regenerative Medicine, National Taiwan University, Taipei, Taiwan; Department of Biomedical Engineering, College of Medicine and College of Engineering, National Taiwan University, Taipei, Taiwan; Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan; Center for Frontier Medicine, National Taiwan University Hospital, Taipei, Taiwan.
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Novis T, Takiya CM. Skin Resident Stem Cells. RESIDENT STEM CELLS AND REGENERATIVE THERAPY 2024:205-249. [DOI: 10.1016/b978-0-443-15289-4.00005-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Jassim A, Rahrmann EP, Simons BD, Gilbertson RJ. Cancers make their own luck: theories of cancer origins. Nat Rev Cancer 2023; 23:710-724. [PMID: 37488363 DOI: 10.1038/s41568-023-00602-5] [Citation(s) in RCA: 90] [Impact Index Per Article: 45.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/20/2023] [Indexed: 07/26/2023]
Abstract
Cancer has been a leading cause of death for decades. This dismal statistic has increased efforts to prevent the disease or to detect it early, when treatment is less invasive, relatively inexpensive and more likely to cure. But precisely how tissues are transformed continues to provoke controversy and debate, hindering cancer prevention and early intervention strategies. Various theories of cancer origins have emerged, including the suggestion that it is 'bad luck': the inevitable consequence of random mutations in proliferating stem cells. In this Review, we discuss the principal theories of cancer origins and the relative importance of the factors that underpin them. The body of available evidence suggests that developing and ageing tissues 'walk a tightrope', retaining adequate levels of cell plasticity to generate and maintain tissues while avoiding overstepping into transformation. Rather than viewing cancer as 'bad luck', understanding the complex choreography of cell intrinsic and extrinsic factors that characterize transformation holds promise to discover effective new ways to prevent, detect and stop cancer before it becomes incurable.
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Affiliation(s)
- Amir Jassim
- CRUK Cambridge Institute, University of Cambridge, Cambridge, UK
| | - Eric P Rahrmann
- CRUK Cambridge Institute, University of Cambridge, Cambridge, UK
| | - Ben D Simons
- Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK
- Department of Applied Mathematics and Theoretical Physics, Centre for Mathematical Sciences, University of Cambridge, Cambridge, UK
| | - Richard J Gilbertson
- CRUK Cambridge Institute, University of Cambridge, Cambridge, UK.
- Department of Oncology, University of Cambridge, Cambridge, UK.
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Liu M, Hummitzsch K, Bastian NA, Hartanti MD, Wan Q, Irving-Rodgers HF, Anderson RA, Rodgers RJ. Isolation, culture, and characterisation of bovine ovarian fetal fibroblasts and gonadal ridge epithelial-like cells and comparison to their adult counterparts. PLoS One 2022; 17:e0268467. [PMID: 35802560 PMCID: PMC9269465 DOI: 10.1371/journal.pone.0268467] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Accepted: 05/01/2022] [Indexed: 11/18/2022] Open
Abstract
During ovarian development, gonadal ridge epithelial-like (GREL) cells arise from the epithelial cells of the ventral surface of the mesonephros. They ultimately develop into follicular granulosa cells or into ovarian surface epithelial cells. Stromal fibroblasts arise from the mesonephros and penetrate the ovary. We developed methods for isolating and culturing fetal ovarian GREL cells and ovarian fibroblasts by expansion of colonies without passage. In culture, these two cell types were morphologically different. We examined the expression profile of 34 genes by qRT-PCR, of which 24 genes had previously been studied in whole fetal ovaries. Expression of nine of the 10 newly-examined genes in fetal ovaries correlated with gestational age (MUC1, PKP2, CCNE1 and CCNE2 negatively; STAR, COL4A1, GJA1, LAMB2 and HSD17B1 positively). Comparison between GREL cells and fetal fibroblasts revealed higher expression of KRT19, PKP2, OCLN, MUC1, ESR1 and LGR5 and lower expression of GJA1, FOXL2, NR2F2, FBN1, COL1A1, NR5A1, CCND2, CCNE1 and ALDH1A1. Expression of CCND2, CCNE1, CCNE2, ESR2 and TGFBR1 was higher in the fetal fibroblasts than in adult fibroblasts; FBN1 was lower. Expression of OCLN, MUC1, LAMB2, NR5A1, ESR1, ESR2, and TGFBR3 was lower in GREL cells than ovarian surface epithelial cells. Expression of KRT19, DSG2, PKP2, OCLN, MUC1, FBN1, COL1A1, COL3A1, STAR and TGFBR2 was higher and GJA1, CTNNB1, LAMB2, NR5A1, CYP11A1, HSD3B1, CYP19A1, HSD17B1, FOXL2, ESR1, ESR2, TGFBR3 and CCND2 was lower in GREL cells compared to granulosa cells. TGFβ1 altered the expression of COL1A1, COL3A1 and FBN1 in fetal fibroblasts and epidermal growth factor altered the expression of FBN1 and COL1A1. In summary, the two major somatic cell types of the developing ovary have distinct gene expression profiles. They, especially GREL cells, also differ from the cells they ultimately differentiate in to. The regulation of cell fate determination, particularly of the bi-potential GREL cells, remains to be elucidated.
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Affiliation(s)
- Menghe Liu
- School of Biomedicine, Robinson Research Institute, The University of Adelaide, Adelaide, SA, Australia
| | - Katja Hummitzsch
- School of Biomedicine, Robinson Research Institute, The University of Adelaide, Adelaide, SA, Australia
| | - Nicole A. Bastian
- School of Biomedicine, Robinson Research Institute, The University of Adelaide, Adelaide, SA, Australia
| | - Monica D. Hartanti
- School of Biomedicine, Robinson Research Institute, The University of Adelaide, Adelaide, SA, Australia
- Faculty of Medicine, Universitas Trisakti, Jakarta, Indonesia
| | - Qianhui Wan
- School of Biomedicine, Robinson Research Institute, The University of Adelaide, Adelaide, SA, Australia
| | - Helen F. Irving-Rodgers
- School of Biomedicine, Robinson Research Institute, The University of Adelaide, Adelaide, SA, Australia
- School of Medical Science, Griffith University, Gold Coast Campus, QLD, Australia
| | - Richard A. Anderson
- MRC Centre for Reproductive Health, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom
| | - Raymond J. Rodgers
- School of Biomedicine, Robinson Research Institute, The University of Adelaide, Adelaide, SA, Australia
- * E-mail:
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Tran NT, Park IS, Truong MD, Park DY, Park SH, Min BH. Conditioned media derived from human fetal progenitor cells improves skin regeneration in burn wound healing. Cell Tissue Res 2022; 389:289-308. [PMID: 35624315 DOI: 10.1007/s00441-022-03638-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Accepted: 05/11/2022] [Indexed: 01/06/2023]
Abstract
Stem cells are known to have excellent regenerative ability, which is primarily facilitated by indirect paracrine factors, rather than via direct cell replacement. The regenerative process is mediated by the release of extracellular matrix molecules, cytokines, and growth factors, which are also present in the media during cultivation. Herein, we aimed to demonstrate the functionality of key factors and mechanisms in skin regeneration through the analysis of conditioned media derived from fetal stem cells. A series of processes, including 3D pellet cultures, filtration and lyophilization is developed to fabricate human fetal cartilage-derived progenitor cells-conditioned media (hFCPCs-CM) and its useful properties are compared with those of human bone marrow-derived MSCs-conditioned media (hBMSCs-CM) in terms of biochemical characterization, and in vitro studies of fibroblast behavior, macrophage polarization, and burn wound healing. The hFCPCs-CM show to be devoid of cellular components but to contain large amounts of total protein, collagen, glycosaminoglycans, and growth factors, including IGFBP-2, IGFBP-6, HGF, VEGF, TGF β3, and M-CSF, and contain a specific protein, collagen alpha-1(XIV) compare with hBMSCs-CM. The therapeutic potential of hFCPCs-CM observes to be better than that of hBMSCs-CM in the viability, proliferation, and migration of fibroblasts, and M2 macrophage polarization in vitro, and efficient acceleration of wound healing and minimization of scar formation in third-degree burn wounds in a rat model. The current study shows the potential therapeutic effect of hFCPCs and provides a rationale for using the secretome released from fetal progenitor cells to promote the regeneration of skin tissues, both quantitatively and qualitatively. The ready-to-use product of human fetal cartilage-derived progenitor cells-conditioned media (hFCPCs-CM) are fabricated via a series of techniques, including a 3D culture of hFCPCs, filtration using a 3.5 kDa cutoff dialysis membrane, and lyophilization of the CM. hFCPCs-CM contains many ECM molecules and biomolecules that improves wound healing through efficient acceleration of M2 macrophage polarization and reduction of scar formation.
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Affiliation(s)
- Ngoc-Trinh Tran
- Department of Molecular Science and Technology, Ajou University, Suwon, Korea
- Cell Therapy Center, Ajou Medical Center, Suwon, 16499, Korea
| | - In-Su Park
- Cell Therapy Center, Ajou Medical Center, Suwon, 16499, Korea
| | | | - Do-Young Park
- Department of Orthopedic Surgery, School of Medicine, Ajou University, Suwon, Korea
| | - Sang-Hyug Park
- Advanced Translational Engineering and Medical Science, Seoul, Korea.
- Department of Biomecial Engineering, Pukyong National University, Busan, 48513, Korea.
| | - Byoung-Hyun Min
- Department of Molecular Science and Technology, Ajou University, Suwon, Korea.
- Cell Therapy Center, Ajou Medical Center, Suwon, 16499, Korea.
- Department of Orthopedic Surgery, School of Medicine, Ajou University, Suwon, Korea.
- Advanced Translational Engineering and Medical Science, Seoul, Korea.
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Augmentation of Rotator Cuff Healing With Orthobiologics. J Am Acad Orthop Surg 2022; 30:e508-e516. [PMID: 34932515 PMCID: PMC8881347 DOI: 10.5435/jaaos-d-20-01011] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Accepted: 11/13/2021] [Indexed: 02/01/2023] Open
Abstract
The limited regenerative capacity of the tendon-bone enthesis after surgical repair poses a significant challenge to achieving desired clinical outcomes. Biologic augmentation of the repair site has the potential to enhance the biomechanical and histological integrity of the enthesis, leading to lower retear rates and greater patient satisfaction. Platelet-rich plasma, stem cells and bone marrow aspirate concentrate, growth factors, biodegradable or biomimetic scaffolds, and amniotic products have been investigated in preclinical and, in some cases, clinical studies aimed at augmenting tendon-bone healing. Although many of these therapies have achieved some degree of success in improving structural, histological, and clinical outcomes after surgical tendon-bone enthesis repair, none have reliably and consistently lead to clinical improvement. High-quality randomized controlled clinical studies are needed to definitively evaluate the efficacy of these biologic therapies and ultimately determine which, if any, are capable of achieving a tendon-bone repair that is structurally noninferior to the native enthesis before injury.
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Su CY, Hughes MW, Liu TY, Chuong CM, Wang HV, Yang WC. Defining Wound Healing Progression in Cetacean Skin: Characteristics of Full-Thickness Wound Healing in Fraser's Dolphins ( Lagenodelphis hosei). Animals (Basel) 2022; 12:ani12050537. [PMID: 35268108 PMCID: PMC8908859 DOI: 10.3390/ani12050537] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 02/15/2022] [Accepted: 02/18/2022] [Indexed: 01/01/2023] Open
Abstract
Simple Summary Cutaneous wound healing is a complex and tightly regulated biological process to restore physiological and anatomic function. Current knowledge of cutaneous wound healing is mostly based on studies in laboratory animals and humans. The histological and immunological features of skin, for example, cutaneous thickness, cellular components, and immune response, are not identical among animal species, and these differences may lead to substantial effects in cutaneous wound healing. In field observation, large cutaneous wounds in cetaceans could heal without medical treatments. However, little is known about the underlying mechanisms, and there is no histological study on full-thickness wound healing in cetaceans. The current study characterizes the macroscopic and histological features of large full-thickness wound healing in Fraser’s dolphins (Lagenodelphis hosei). The differences of wound healing between cetaceans and terrestrial mammals were shown from the histological aspect, including rete and dermal ridge appearance, repigmentation, and adipose tissue regeneration. Better understanding of the mechanism of full-thickness wound healing in cetaceans will shed light on veterinary and human regenerative medicine, leading to novel therapies. Abstract Cetaceans are tight-skinned mammals that exhibit an extraordinary capacity to heal deep soft tissue injuries. However, essential information of large full-thickness wound healing in cetaceans is still lacking. Here, the stages of full-thickness wound healing were characterized in Fraser’s dolphins (Lagenodelphis hosei). The skin samples were collected from normal skin and full-thickness cookiecutter shark (Isistius brasiliensis)-bite wounds of stranded carcasses. We defined five stages of wound healing according to macroscopic and histopathological examinations. Wounds in Stage 1 and 2 were characterized by intercellular and intracellular edema in the epidermal cells near the wound edge, mixed inflammatory cell infiltration, and degradation of collagen fibers. In Stage 3 wounds, melanocytes, melanin granules, rete and dermal ridges were noticed in the neo-epidermis, and the adipose tissue in adjacent blubber was replaced by cells and fibers. Wounds in Stage 4 and 5 were characterized by gradual restoration of the normal skin architecture including rete and dermal ridges, collagen bundles, and adipose tissue. These phenomena were quite different from previous studies in terrestrial tight-skinned mammals, and therefore, further in-depth research into the mechanisms of dolphin wound healing would be needed to gain new insights into veterinary and human regenerative medicine.
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Affiliation(s)
- Chen-Yi Su
- School of Veterinary Medicine, National Taiwan University, Taipei 10617, Taiwan;
| | - Michael W. Hughes
- International Center for Wound Repair and Regeneration, National Cheng Kung University, Tainan 701, Taiwan; (M.W.H.); (T.-Y.L.)
- Institute of Clinical Medicine, National Cheng Kung University, Tainan 701, Taiwan
| | - Tzu-Yu Liu
- International Center for Wound Repair and Regeneration, National Cheng Kung University, Tainan 701, Taiwan; (M.W.H.); (T.-Y.L.)
- Department of Life Sciences, National Cheng Kung University, Tainan 701, Taiwan
| | - Cheng-Ming Chuong
- Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA;
| | - Hao-Ven Wang
- Department of Life Sciences, National Cheng Kung University, Tainan 701, Taiwan
- Marine Biology and Cetacean Research Center, National Cheng Kung University, Tainan 701, Taiwan
- Correspondence: (H.-V.W.); (W.-C.Y.)
| | - Wei-Cheng Yang
- School of Veterinary Medicine, National Taiwan University, Taipei 10617, Taiwan;
- Correspondence: (H.-V.W.); (W.-C.Y.)
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Azumah R, Liu M, Hummitzsch K, Bastian NA, Hartanti MD, Irving-Rodgers HF, Anderson RA, Rodgers RJ. OUP accepted manuscript. Hum Reprod 2022; 37:1244-1254. [PMID: 35413103 PMCID: PMC9156849 DOI: 10.1093/humrep/deac049] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Revised: 01/04/2022] [Indexed: 11/25/2022] Open
Abstract
STUDY QUESTION Could changes in transforming growth factor β (TGFβ) signalling during foetal ovary development alter the expression of polycystic ovary syndrome (PCOS) candidate genes leading to a predisposition to PCOS? SUMMARY ANSWER TGFβ signalling molecules are dynamically expressed during foetal ovary development and TGFβ1 inhibits expression of the androgen receptor (AR) and 7 (INSR, C8H9orf3, RAD50, ERBB3, NEIL2, IRF1 and ZBTB16) of the 25 PCOS candidate genes in foetal ovarian fibroblasts in vitro, whilst increasing expression of the AR cofactor TGFβ-induced transcript 1 (TGFB1I1 or Hic5). WHAT IS KNOWN ALREADY The ovarian stroma arises from the mesonephros during foetal ovary development. Changes in the morphology of the ovarian stroma are cardinal features of PCOS. The ovary is more fibrous and has more tunica and cortical and subcortical stroma. It is not known why this is and when this arises. PCOS has a foetal origin and perhaps ovarian stroma development is altered during foetal life to determine the formation of a polycystic ovary later in life. PCOS also has a genetic origin with 19 loci containing 25 PCOS candidate genes. In many adult tissues, TGFβ is known to stimulate fibroblast replication and collagen deposition in stroma, though it has the opposite effect in the non-scaring foetal tissues. Our previous studies showed that TGFβ signalling molecules [TGFβs and their receptors, latent TGFβ binding proteins (LTBPs) and fibrillins, which are extracellular matrix proteins that bind LTBPs] are expressed in foetal ovaries. Also, we previously showed that TGFβ1 inhibited expression of AR and 3 PCOS candidate genes (INSR, C8H9orf3 and RAD50) and stimulated expression of TGFB1I1 in cultured foetal ovarian fibroblasts. STUDY DESIGN, SIZE, DURATION We used Bos taurus for this study as we can ethically collect foetal ovaries from across the full 9-month gestational period. Foetal ovaries (62–276 days, n = 19) from across gestation were collected from pregnant B. taurus cows for RNA-sequencing (RNA-seq) analyses. Foetal ovaries from B. taurus cows were collected (160–198 days, n = 6) for culture of ovarian fibroblasts. PARTICIPANTS/MATERIALS, SETTING, METHODS RNA-seq transcriptome profiling was performed on foetal ovaries and the data on genes involved in TGFβ signalling were extracted. Cells were dispersed from foetal ovaries and fibroblasts cultured and treated with TGFβ1. The effects of TGFβ regulation on the remaining eight PCOS candidate genes not previously studied (ERBB3, MAPRE1, FDFT1, NEIL2, ARL14EP, PLGRKT, IRF1 and ZBTB16) were examined. MAIN RESULTS AND THE ROLE OF CHANCE Many TGFβ signalling molecules are expressed in the foetal ovary, and for most, their expression levels increased accross gestation (LTBP1/2/3/4, FBN1, TGFB2/3, TGFBR2/3 and TGFB1I1), while a few decreased (FBN3, TGFBR3L, TGFBI and TGFB1) and others remained relatively constant (TGFBRAP1, TGFBR1 and FBN2). TGFβ1 significantly decreased expression of PCOS candidate genes ERBB3, NEIL2, IRF1 and ZBTB16 in cultured foetal ovarian fibroblasts. LARGE SCALE DATA The FASTQ files, normalized data and experimental information have been deposited in the Gene Expression Omnibus (GEO) accessible by accession number GSE178450. LIMITATIONS, REASONS FOR CAUTION Regulation of PCOS candidate genes by TGFβ was carried out in vitro and further studies in vivo are required. This study was carried out in bovine where foetal ovaries from across all of the 9-month gestational period were available, unlike in the human where it is not ethically possible to obtain ovaries from the second half of gestation. WIDER IMPLICATIONS OF THE FINDINGS From our current and previous results we speculate that inhibition of TGFβ signalling in the foetal ovary is likely to (i) increase androgen sensitivity by enhancing expression of AR, (ii) increase stromal activity by stimulating expression of COL1A1 and COL3A1 and (iii) increase the expression of 7 of the 25 PCOS candidate genes. Thus inhibition of TGFβ signalling could be part of the aetiology of PCOS or at least the aetiology of polycystic ovaries. STUDY FUNDING/COMPETING INTEREST(S) Funding was received from Adelaide University China Fee Scholarship (M.L.), Australian Research Training Program (R.A.) and the Faculty of Health and Medical Science Divisional Scholarship (R.A.), Adelaide Graduate Research Scholarships (R.A. and N.A.B.), Australia Awards Scholarship (M.D.H.), Robinson Research Institute Career Development Fellowship (K.H.) and Building On Ideas Grant (K.H.), National Health and Medical Research Council of Australia Centre for Research Excellence in the Evaluation, Management and Health Care Needs of Polycystic Ovary Syndrome (N.A.B., M.D.H. and R.J.R.; GTN1078444) and the Centre for Research Excellence on Women’s Health in Reproductive life (R.A., R.J.R. and K.H.; GTN1171592) and the UK Medical Research Council (R.A.A.; grant no. G1100357). The funders did not play any role in the study design, data collection and analysis, decision to publish or preparation of the manuscript. The authors of this manuscript have nothing to declare and no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
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Affiliation(s)
| | | | - Katja Hummitzsch
- Robinson Research Institute, School of Biomedicine, The University of Adelaide, Adelaide, SA, Australia
| | - Nicole A Bastian
- Robinson Research Institute, School of Biomedicine, The University of Adelaide, Adelaide, SA, Australia
| | - Monica D Hartanti
- Robinson Research Institute, School of Biomedicine, The University of Adelaide, Adelaide, SA, Australia
- Faculty of Medicine, Universitas Trisakti, Jakarta, Indonesia
| | - Helen F Irving-Rodgers
- Robinson Research Institute, School of Biomedicine, The University of Adelaide, Adelaide, SA, Australia
- School of Medical Science, Griffith University, Gold Coast Campus, Southport, QLD, Australia
| | - Richard A Anderson
- MRC Centre for Reproductive Health, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK
| | - Raymond J Rodgers
- Correspondence address. Robinson Research Institute, School of Biomedicine, The University of Adelaide, Adelaide, SA 5005, Australia. E-mail:
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11
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Ehnert S, Relja B, Schmidt-Bleek K, Fischer V, Ignatius A, Linnemann C, Rinderknecht H, Huber-Lang M, Kalbitz M, Histing T, Nussler AK. Effects of immune cells on mesenchymal stem cells during fracture healing. World J Stem Cells 2021; 13:1667-1695. [PMID: 34909117 PMCID: PMC8641016 DOI: 10.4252/wjsc.v13.i11.1667] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 03/31/2021] [Accepted: 09/03/2021] [Indexed: 02/06/2023] Open
Abstract
In vertebrates, bone is considered an osteoimmune system which encompasses functions of a locomotive organ, a mineral reservoir, a hormonal organ, a stem cell pool and a cradle for immune cells. This osteoimmune system is based on cooperatively acting bone and immune cells, cohabitating within the bone marrow. They are highly interdependent, a fact that is confounded by shared progenitors, mediators, and signaling pathways. Successful fracture healing requires the participation of all the precursors, immune and bone cells found in the osteoimmune system. Recent evidence demonstrated that changes of the immune cell composition and function may negatively influence bone healing. In this review, first the interplay between different immune cell types and osteoprogenitor cells will be elaborated more closely. The separate paragraphs focus on the specific cell types, starting with the cells of the innate immune response followed by cells of the adaptive immune response, and the complement system as mediator between them. Finally, a brief overview on the challenges of preclinical testing of immune-based therapeutic strategies to support fracture healing will be given.
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Affiliation(s)
- Sabrina Ehnert
- Siegfried Weller Research Institute at the BG Trauma Center Tübingen, Department of Trauma and Reconstructive Surgery, University of Tübingen, Tübingen 72076, Germany
| | - Borna Relja
- Experimental Radiology, Department of Radiology and Nuclear Medicine, Otto-von-Guericke University, Magdeburg 39120, Germany
| | - Katharina Schmidt-Bleek
- Julius Wolff Institute and Berlin Institute of Health Center of Regenerative Therapies, Charité - University Medicine Berlin, Berlin 13353, Germany
| | - Verena Fischer
- Institute of Orthopedic Research and Biomechanics, Ulm University Medical Center, Ulm 89091, Germany
| | - Anita Ignatius
- Institute of Orthopedic Research and Biomechanics, Ulm University Medical Center, Ulm 89091, Germany
| | - Caren Linnemann
- Siegfried Weller Research Institute at the BG Trauma Center Tübingen, Department of Trauma and Reconstructive Surgery, University of Tübingen, Tübingen 72076, Germany
| | - Helen Rinderknecht
- Siegfried Weller Research Institute at the BG Trauma Center Tübingen, Department of Trauma and Reconstructive Surgery, University of Tübingen, Tübingen 72076, Germany
| | - Markus Huber-Lang
- Institute for Clinical and Experimental Trauma-Immunology (ITI), University Hospital Ulm, Ulm 89091, Germany
| | - Miriam Kalbitz
- Department of Trauma and Orthopedic Surgery, University Hospital Erlangen Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen 91054, Germany
| | - Tina Histing
- Siegfried Weller Research Institute at the BG Trauma Center Tübingen, Department of Trauma and Reconstructive Surgery, University of Tübingen, Tübingen 72076, Germany
| | - Andreas K Nussler
- Siegfried Weller Research Institute at the BG Trauma Center Tübingen, Department of Trauma and Reconstructive Surgery, University of Tübingen, Tübingen 72076, Germany
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12
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Novel scaffold based graphene oxide doped electrospun iota carrageenan/polyvinyl alcohol for wound healing and pathogen reduction: in-vitro and in-vivo study. Sci Rep 2021; 11:20456. [PMID: 34650075 PMCID: PMC8516857 DOI: 10.1038/s41598-021-00069-0] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2021] [Accepted: 10/06/2021] [Indexed: 11/17/2022] Open
Abstract
Wound healing is a complicated multicellular process that involves several kinds of cells including macrophages, fibroblasts, endothelial cells, keratinocytes and platelets that are leading to their differentiation towards an anti-inflammatory response for producing several chemokines, cytokine and growth factors. In this study, electrospun nanofiber scaffold named (MNS) is composed of polyvinyl alcohol (PVA)/iota carrageenan (IC) and doped with partially reduced graphene oxide (prGO) that is successfully synthesized for wound healing and skin repair. The fabricated MNS was tested in case of infection and un-infection with E. coli and Staphylococcus and in both of the presence and in the absence of yeast as a natural nutritional supplement. Numerous biochemical parameters including total protein, albumin, urea and LDH, and hematological parameters were evaluated. Results revealed that the MNS was proved to be effective on most of the measured parameters and had exhibited efficient antibacterial inhibition activity. Whereas it can be used as an effective antimicrobial agent in wound healing, however, histopathological findings confirmed that the MNS caused re-epithelialization and the presence of yeast induced hair follicles growth and subsequently it may be used to hide formed head wound scar.
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13
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Otsuka T, Kan HM, Laurencin CT. Regenerative Engineering Approaches to Scar-Free Skin Regeneration. REGENERATIVE ENGINEERING AND TRANSLATIONAL MEDICINE 2021. [DOI: 10.1007/s40883-021-00229-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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14
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Basurto IM, Passipieri JA, Gardner GM, Smith KK, Amacher AR, Hansrisuk AI, Christ GJ, Caliari SR. Photoreactive hydrogel stiffness influences volumetric muscle loss repair. Tissue Eng Part A 2021; 28:312-329. [PMID: 34409861 DOI: 10.1089/ten.tea.2021.0137] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Volumetric muscle loss (VML) injuries are characterized by permanent loss of muscle mass, structure, and function. Hydrogel biomaterials provide an attractive platform for skeletal muscle tissue engineering due to the ability to easily modulate their biophysical and biochemical properties to match a range of tissue characteristics. In this work we successfully developed a mechanically tunable hyaluronic acid (HA) hydrogel system to investigate the influence of hydrogel stiffness on VML repair. HA was functionalized with photoreactive norbornene groups to create hydrogel networks that rapidly crosslink via thiol-ene click chemistry with tailored mechanics. Mechanical properties were controlled by modulating the amount of matrix metalloproteinase (MMP)-degradable peptide crosslinker to produce hydrogels with increasing elastic moduli of 1.1 ± 0.002, 3.0 ± 0.002, and 10.6 ± 0.006 kPa mimicking a relevant range of developing and mature muscle stiffnesses. Functional muscle recovery was assessed following implantation of the HA hydrogels by in situ photopolymerization into rat latissimus dorsi (LD) VML defects at 12 and 24 weeks post-injury. After 12 weeks, muscles treated with medium stiffness (3.0 kPa) hydrogels produced maximum isometric forces most similar to contralateral healthy LD muscles. This trend persisted at 24 weeks post-injury, suggestive of sustained functional recovery. Histological analysis revealed a significantly larger zone of regeneration with more de novo muscle fibers following implantation of medium stiffness hydrogels in VML-injured muscles compared to other experimental groups. Lower (low and medium) stiffness hydrogels also appeared to attenuate the chronic inflammatory response characteristic of VML injuries, displaying similar levels of macrophage infiltration and polarization to healthy muscle. Together these findings illustrate the importance of hydrogel mechanical properties in supporting functional repair of VML injuries.
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Affiliation(s)
- Ivan M Basurto
- University of Virginia, 2358, Biomedical Engineering, Charlottesville, Virginia, United States;
| | - Juliana A Passipieri
- University of Virginia, 2358, Biomedical Engineering, Orthopaedic Surgery, Charlottesville, Virginia, United States;
| | - Gregg M Gardner
- University of Virginia, 2358, Chemical Engineering, Charlottesville, Virginia, United States;
| | - Kathryn K Smith
- University of Virginia, 2358, Chemical Engineering, Charlottesville, Virginia, United States;
| | - Austin R Amacher
- University of Virginia, 2358, Biomedical Engineering, Charlottesville, Virginia, United States;
| | - Audrey I Hansrisuk
- University of Virginia, 2358, Chemistry, Charlottesville, Virginia, United States;
| | - George J Christ
- University of Virginia, 2358, Biomedical Engineering, Orthopaedic Surgery, Charlottesville, Virginia, United States;
| | - Steven R Caliari
- University of Virginia, 2358, Chemical Engineering, Biomedical Engineering, Charlottesville, Virginia, United States;
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15
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Gnyawali SC, Sinha M, El Masry MS, Wulff B, Ghatak S, Soto-Gonzalez F, Wilgus TA, Roy S, Sen CK. High resolution ultrasound imaging for repeated measure of wound tissue morphometry, biomechanics and hemodynamics under fetal, adult and diabetic conditions. PLoS One 2020; 15:e0241831. [PMID: 33227015 PMCID: PMC7682876 DOI: 10.1371/journal.pone.0241831] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Accepted: 10/21/2020] [Indexed: 02/07/2023] Open
Abstract
Non-invasive, repeated interrogation of the same wound is necessary to understand the tissue repair continuum. In this work, we sought to test the significance of non-invasive high-frequency high-resolution ultrasound technology for such interrogation. High-frequency high-resolution ultrasound imaging was employed to investigate wound healing under fetal and adult conditions. Quantitative tissue cellularity and elastic strain was obtained for visualization of unresolved inflammation using Vevo strain software. Hemodynamic properties of the blood flow in the artery supplying the wound-site were studied using color Doppler flow imaging. Non-invasive monitoring of fetal and adult wound healing provided unprecedented biomechanical and functional insight. Fetal wounds showed highly accelerated closure with transient perturbation of wound tissue cellularity. Fetal hemodynamics was unique in that sharp fall in arterial pulse pressure (APP) which was rapidly restored within 48h post-wounding. In adults, APP transiently increased post-wounding before returning to the pre-wounding levels by d10 post-wounding. The pattern of change in the elasticity of wound-edge tissue of diabetics was strikingly different. Severe strain acquired during the early inflammatory phase persisted with a slower recovery of elasticity compared to that of the non-diabetic group. Wound bed of adult diabetic mice (db/db) showed persistent hypercellularity compared to littermate controls (db/+) indicative of prolonged inflammation. Normal skin strain of db/+ and db/db were asynchronous. In db/db, severe strain acquired during the early inflammatory phase persisted with a slower recovery of elasticity compared to that of non-diabetics. This study showcases a versatile clinically relevant imaging platform suitable for real-time analyses of functional wound healing.
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Affiliation(s)
- Surya C. Gnyawali
- Department of Surgery, Davis Heart and Lung Research Institute, Center for Regenerative Medicine & Cell-Based Therapies, The Ohio State University Wexner Medical Center, Columbus, OH, United States of America
| | - Mithun Sinha
- Department of Surgery, Davis Heart and Lung Research Institute, Center for Regenerative Medicine & Cell-Based Therapies, The Ohio State University Wexner Medical Center, Columbus, OH, United States of America
- Department of Surgery, IUH Comprehensive Wound Center, Indiana Center for Regenerative Medicine and Engineering, Indiana University School of Medicine, Indianapolis, IN, United States of America
| | - Mohamed S. El Masry
- Department of Surgery, Davis Heart and Lung Research Institute, Center for Regenerative Medicine & Cell-Based Therapies, The Ohio State University Wexner Medical Center, Columbus, OH, United States of America
- Department of Surgery, IUH Comprehensive Wound Center, Indiana Center for Regenerative Medicine and Engineering, Indiana University School of Medicine, Indianapolis, IN, United States of America
- Department of Plastic and Reconstructive Surgery, Zagazig University, Zagazig, Egypt
| | - Brian Wulff
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH, United States of America
| | - Subhadip Ghatak
- Department of Surgery, Davis Heart and Lung Research Institute, Center for Regenerative Medicine & Cell-Based Therapies, The Ohio State University Wexner Medical Center, Columbus, OH, United States of America
- Department of Surgery, IUH Comprehensive Wound Center, Indiana Center for Regenerative Medicine and Engineering, Indiana University School of Medicine, Indianapolis, IN, United States of America
| | - Fidel Soto-Gonzalez
- Department of Surgery, Davis Heart and Lung Research Institute, Center for Regenerative Medicine & Cell-Based Therapies, The Ohio State University Wexner Medical Center, Columbus, OH, United States of America
| | - Traci A. Wilgus
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH, United States of America
| | - Sashwati Roy
- Department of Surgery, Davis Heart and Lung Research Institute, Center for Regenerative Medicine & Cell-Based Therapies, The Ohio State University Wexner Medical Center, Columbus, OH, United States of America
- Department of Surgery, IUH Comprehensive Wound Center, Indiana Center for Regenerative Medicine and Engineering, Indiana University School of Medicine, Indianapolis, IN, United States of America
| | - Chandan K. Sen
- Department of Surgery, Davis Heart and Lung Research Institute, Center for Regenerative Medicine & Cell-Based Therapies, The Ohio State University Wexner Medical Center, Columbus, OH, United States of America
- Department of Surgery, IUH Comprehensive Wound Center, Indiana Center for Regenerative Medicine and Engineering, Indiana University School of Medicine, Indianapolis, IN, United States of America
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16
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Stoica AE, Grumezescu AM, Hermenean AO, Andronescu E, Vasile BS. Scar-Free Healing: Current Concepts and Future Perspectives. NANOMATERIALS (BASEL, SWITZERLAND) 2020; 10:E2179. [PMID: 33142891 PMCID: PMC7693882 DOI: 10.3390/nano10112179] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Revised: 10/15/2020] [Accepted: 10/27/2020] [Indexed: 02/07/2023]
Abstract
Every year, millions of people develop scars due to skin injuries after trauma, surgery, or skin burns. From the beginning of wound healing development, scar hyperplasia, and prolonged healing time in wound healing have been severe problems. Based on the difference between adult and fetal wound healing processes, many promising therapies have been developed to decrease scar formation in skin wounds. Currently, there is no good or reliable therapy to cure or prevent scar formation. This work briefly reviews the engineering methods of scarless wound healing, focusing on regenerative biomaterials and different cytokines, growth factors, and extracellular components in regenerative wound healing to minimize skin damage cell types, and scar formation.
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Affiliation(s)
- Alexandra Elena Stoica
- Department of Science and Engineering of Oxide Materials and Nanomaterials, Faculty of Applied Chemistry and Materials Science, University Politehnica of Bucharest, 1–7 Gheorghe Polizu Street, 011061 Bucharest, Romania; (A.E.S.); (A.M.G.); (E.A.)
- National Research Center for Micro and Nanomaterials, Faculty of Applied Chemistry and Materials Science, University Politehnica of Bucharest, 060042 Bucharest, Romania
| | - Alexandru Mihai Grumezescu
- Department of Science and Engineering of Oxide Materials and Nanomaterials, Faculty of Applied Chemistry and Materials Science, University Politehnica of Bucharest, 1–7 Gheorghe Polizu Street, 011061 Bucharest, Romania; (A.E.S.); (A.M.G.); (E.A.)
| | - Anca Oana Hermenean
- Institute of Life Sciences, Vasile Goldiş Western University of Arad, 310025 Arad, Romania;
| | - Ecaterina Andronescu
- Department of Science and Engineering of Oxide Materials and Nanomaterials, Faculty of Applied Chemistry and Materials Science, University Politehnica of Bucharest, 1–7 Gheorghe Polizu Street, 011061 Bucharest, Romania; (A.E.S.); (A.M.G.); (E.A.)
| | - Bogdan Stefan Vasile
- Department of Science and Engineering of Oxide Materials and Nanomaterials, Faculty of Applied Chemistry and Materials Science, University Politehnica of Bucharest, 1–7 Gheorghe Polizu Street, 011061 Bucharest, Romania; (A.E.S.); (A.M.G.); (E.A.)
- National Research Center for Micro and Nanomaterials, Faculty of Applied Chemistry and Materials Science, University Politehnica of Bucharest, 060042 Bucharest, Romania
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17
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Carter LE, Cook DP, Collins O, Gamwell LF, Dempster HA, Wong HW, McCloskey CW, Garson K, Vuong NH, Vanderhyden BC. COX2 is induced in the ovarian epithelium during ovulatory wound repair and promotes cell survival†. Biol Reprod 2020; 101:961-974. [PMID: 31347667 DOI: 10.1093/biolre/ioz134] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2018] [Revised: 07/02/2019] [Accepted: 07/17/2019] [Indexed: 12/18/2022] Open
Abstract
The ovarian surface epithelium (OSE) is a monolayer of cells surrounding the ovary that is ruptured during ovulation. After ovulation, the wound is repaired, however, this process is poorly understood. In epithelial tissues, wound repair is mediated by an epithelial-to-mesenchymal transition (EMT). Transforming Growth Factor Beta-1 (TGFβ1) is a cytokine commonly known to induce an EMT and is present throughout the ovarian microenvironment. We, therefore, hypothesized that TGFβ1 induces an EMT in OSE cells and activates signaling pathways important for wound repair. Treating primary cultures of mouse OSE cells with TGFβ1 induced an EMT mediated by TGFβRI signaling. The transcription factor Snail was the only EMT-associated transcription factor increased by TGFβ1 and, when overexpressed, was shown to increase OSE cell migration. A polymerase chain reaction array of TGFβ signaling targets determined Cyclooxygenase-2 (Cox2) to be most highly induced by TGFβ1. Constitutive Cox2 expression modestly increased migration and robustly enhanced cell survival, under stress conditions similar to those observed during wound repair. The increase in Snail and Cox2 expression with TGFβ1 was reproduced in human OSE cultures, suggesting these responses are conserved between mouse and human. Finally, the induction of Cox2 expression in OSE cells during ovulatory wound repair was shown in vivo, suggesting TGFβ1 increases Cox2 to promote wound repair by enhancing cell survival. These data support that TGFβ1 promotes ovulatory wound repair by induction of an EMT and activation of a COX2-mediated pro-survival pathway. Understanding ovulatory wound repair may give insight into why ovulation is the primary non-hereditary risk factor for ovarian cancer.
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Affiliation(s)
- Lauren E Carter
- Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.,Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - David P Cook
- Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.,Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Olga Collins
- Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.,Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Lisa F Gamwell
- Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.,Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Holly A Dempster
- Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.,Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Howard W Wong
- Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | - Curtis W McCloskey
- Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.,Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Ken Garson
- Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.,Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Nhung H Vuong
- Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.,Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Barbara C Vanderhyden
- Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.,Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada.,Department of Obstetrics and Gynecology, University of Ottawa/The Ottawa Hospital, Ottawa, Ontario, Canada
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18
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Tighe S, Mead OG, Lee A, Tseng SCG. Basic science review of birth tissue uses in ophthalmology. Taiwan J Ophthalmol 2020; 10:3-12. [PMID: 32309118 PMCID: PMC7158924 DOI: 10.4103/tjo.tjo_4_20] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Accepted: 01/12/2020] [Indexed: 12/31/2022] Open
Abstract
The birth tissue is predominantly comprised of amniotic membrane (AM) and umbilical cord (UC), which share the same cell origin as the fetus. These versatile biological tissues have been used to treat a wide range of conjunctival and corneal conditions since 1940. The therapeutic benefits of the birth tissue stem from its anti-inflammatory and anti-scarring properties that orchestrate regenerative healing. Although the birth tissue also contains many cytokines, growth factors, and proteins, the heavy chain 1-hyaluronic acid/pentraxin 3 (HC-HA/PTX3) matrix has been identified to be a major active tissue component responsible for AM/UC's multifactorial therapeutic actions. HC-HA/PTX3 complex is abundantly present in fresh and cryopreserved AM/UC, but not in dehydrated tissue. In this review, we discuss the tissue anatomy, the molecular mechanism of action based on HC-HA/ PTX3 to explain their therapeutic potentials, and the various forms available in ophthalmology.
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Affiliation(s)
- Sean Tighe
- R&D Department, TissueTech Inc., Miami, Florida, USA
- Department of Ophthalmology, Herbert Wertheim College of Medicine, Florida International University, Miami, Florida, USA
- Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL, USA
| | | | - Amy Lee
- R&D Department, TissueTech Inc., Miami, Florida, USA
| | - Scheffer C. G. Tseng
- R&D Department, TissueTech Inc., Miami, Florida, USA
- Ocular Surface Center and Ocular Surface Research Education Foundation, Miami, FL, USA
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19
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Abstract
Knowledge of how the joint functions as an integrated unit in health and disease requires an understanding of the stromal cells populating the joint mesenchyme, including fibroblasts, tissue-resident macrophages and endothelial cells. Knowledge of the physiological and pathological mechanisms that involve joint mesenchymal stromal cells has begun to cast new light on why joint inflammation persists. The shared embryological origins of fibroblasts and endothelial cells might shape the behaviour of these cell types in diseased adult tissues. Cells of mesenchymal origin sustain inflammation in the synovial membrane and tendons by various mechanisms, and the important contribution of newly discovered fibroblast subtypes and their associated crosstalk with endothelial cells, tissue-resident macrophages and leukocytes is beginning to emerge. Knowledge of these mechanisms should help to shape the future therapeutic landscape and emphasizes the requirement for new strategies to address the pathogenic stroma and associated crosstalk between leukocytes and cells of mesenchymal origin.
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20
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Fetal Dermal Mesenchymal Stem Cell-Derived Exosomes Accelerate Cutaneous Wound Healing by Activating Notch Signaling. Stem Cells Int 2019; 2019:2402916. [PMID: 31281370 PMCID: PMC6590601 DOI: 10.1155/2019/2402916] [Citation(s) in RCA: 82] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2019] [Revised: 05/02/2019] [Accepted: 05/14/2019] [Indexed: 12/15/2022] Open
Abstract
Fetal dermal mesenchymal stem cells (FDMSCs), isolated from fetal skin, are serving as a novel MSC candidate with great potential in regenerative medicine. More recently, the paracrine actions, especially MSC-derived exosomes, are being focused on the vital role in MSC-based cellular therapy. This study was to evaluate the therapeutic potential of exosomes secreted by FDMSCs in normal wound healing. First, the in vivo study indicated that FDMSC exosomes could accelerate wound closure in a mouse full-thickness skin wound model. Then, we investigated the role of FDMSC-derived exosomes on adult dermal fibroblast (ADFs). The results demonstrated that FDMSC exosomes could induce the proliferation, migration, and secretion of ADFs. We discovered that after treatment of exosomes, the Notch signaling pathway was activated. Then, we found that in FDMSC exosomes, the ligands of the Notch pathway were undetectable expect for Jagged 1, and the results of Jagged 1 mimic by peptide and knockdown by siRNA suggested that Jagged 1 may lead the activation of the Notch signal in ADFs. Collectively, our findings indicated that the FDMSC exosomes may promote wound healing by activating the ADF cell motility and secretion ability via the Notch signaling pathway, providing new aspects for the therapeutic strategy of FDMSC-derived exosomes for the treatment of skin wounds.
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21
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Lin C, Chiu P, Hsueh Y, Shieh S, Wu C, Wong T, Chuong C, Hughes MW. Regeneration of rete ridges in Lanyu pig (
Sus scrofa
): Insights for human skin wound healing. Exp Dermatol 2019; 28:472-479. [DOI: 10.1111/exd.13875] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2018] [Revised: 12/23/2018] [Accepted: 01/07/2019] [Indexed: 12/28/2022]
Affiliation(s)
- Chein‐Hong Lin
- International Center for Wound Repair and RegenerationNational Cheng Kung University Tainan Taiwan
- Department of Basic MedicineCollege of MedicineNational Cheng Kung University Tainan Taiwan
| | - Po‐Yuan Chiu
- International Center for Wound Repair and RegenerationNational Cheng Kung University Tainan Taiwan
- Institute of Clinical MedicineNational Cheng Kung University Hospital Tainan Taiwan
| | - Yuan‐Yu Hsueh
- International Center for Wound Repair and RegenerationNational Cheng Kung University Tainan Taiwan
- Division of Plastic and Reconstructive SurgeryDepartment of SurgeryNational Cheng Kung University Hospital Tainan Taiwan
| | - Shyh‐Jou Shieh
- International Center for Wound Repair and RegenerationNational Cheng Kung University Tainan Taiwan
- Division of Plastic and Reconstructive SurgeryDepartment of SurgeryNational Cheng Kung University Hospital Tainan Taiwan
| | - Chia‐Ching Wu
- International Center for Wound Repair and RegenerationNational Cheng Kung University Tainan Taiwan
- Department of Basic MedicineCollege of MedicineNational Cheng Kung University Tainan Taiwan
| | - Tak‐Wah Wong
- Department of DermatologyNational Cheng Kung University Hospital Tainan Taiwan
| | - Cheng‐Ming Chuong
- International Center for Wound Repair and RegenerationNational Cheng Kung University Tainan Taiwan
- Department of Basic MedicineCollege of MedicineNational Cheng Kung University Tainan Taiwan
- Institute of Clinical MedicineNational Cheng Kung University Hospital Tainan Taiwan
- Department of PathologyUniversity of Southern California Los Angeles California
| | - Michael W. Hughes
- International Center for Wound Repair and RegenerationNational Cheng Kung University Tainan Taiwan
- Institute of Clinical MedicineNational Cheng Kung University Hospital Tainan Taiwan
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22
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Royce SG, Mao W, Lim R, Kelly K, Samuel CS. iPSC- and mesenchymoangioblast-derived mesenchymal stem cells provide greater protection against experimental chronic allergic airways disease compared with a clinically used corticosteroid. FASEB J 2019; 33:6402-6411. [PMID: 30768365 DOI: 10.1096/fj.201802307r] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
The airway remodeling (AWR) associated with chronic allergic airways disease (AAD)/asthma contributes to irreversible airway obstruction. This study compared and combined the antiremodeling and other effects of induced pluripotent stem cell and mesenchymoangioblast-derived mesenchymal stem cells (MCA-MSCs) with the corticosteroid dexamethasone (Dex) in experimental chronic AAD/asthma. Female BALB/c mice subjected to 11 wk of ovalbumin (Ova)-induced chronic AAD were intranasally administered MCA-MSCs (1 × 106 cells/mouse; once weekly on wk 10 and 11), Dex (0.5 mg/ml; once daily for 2 wk), or both combined. MCA-MSC detection and changes in airway inflammation (AI), AWR, and airway hyperresponsiveness (AHR) were measured at the end of wk 11. Mice with chronic AAD had significant AI, goblet cell metaplasia, epithelial damage/thickening, aberrant TGF-β1 levels, subepithelial myofibroblast accumulation, airway/lung fibrosis, and AHR (all P < 0.001 vs. healthy controls). MCA-MSCs were detected in the lungs up to 5-7 d postadministration and demonstrated modest anti-inflammatory but striking antifibrotic effects against Ova-induced AAD, effectively decreasing AHR by 70-75% (all P < 0.05 vs. Ova alone). In comparison, Dex predominantly demonstrated anti-inflammatory effects, decreasing AHR by ∼30%. Combining MCA-MSCs with Dex provided equivalent protection to that offered by either therapy alone. MCA-MSCs reduce chronic AAD-induced AWR and AHR to a greater extent than Dex and may act as a suitable adjunct therapy to corticosteroid treatment of asthma.-Royce, S. G., Mao, W., Lim, R., Kelly, K., Samuel, C. S. iPSC- and mesenchymoangioblast-derived mesenchymal stem cells provide greater protection against experimental chronic allergic airways disease compared with a clinically used corticosteroid.
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Affiliation(s)
- Simon G Royce
- Monash Biomedicine Discovery Institute Monash University, Clayton, Victoria, Australia.,Department of Pharmacology, Monash University, Clayton, Victoria, Australia.,Central Clinical School, Monash University, Clayton, Victoria, Australia
| | - WeiYi Mao
- Monash Biomedicine Discovery Institute Monash University, Clayton, Victoria, Australia.,Department of Pharmacology, Monash University, Clayton, Victoria, Australia
| | - Rebecca Lim
- The Ritchie Centre, Hudson Institute of Medical Research and Department of Obstetrics and Gynecology, Monash University, Clayton, Victoria, Australia
| | - Kilian Kelly
- Cynata Therapeutics, Carlton, Victoria, Australia
| | - Chrishan S Samuel
- Monash Biomedicine Discovery Institute Monash University, Clayton, Victoria, Australia.,Department of Pharmacology, Monash University, Clayton, Victoria, Australia.,Department of Biochemistry and Molecular Biology, The University of Melbourne, Parkville, Victoria, Australia
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23
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Paredes J, Shiovitz DA, Andarawis-Puri N. Uncorrelated healing response of tendon and ear injuries in MRL highlight a role for the local tendon environment in driving scarless healing. Connect Tissue Res 2018; 59:472-482. [PMID: 29929396 PMCID: PMC6175637 DOI: 10.1080/03008207.2018.1485665] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
PURPOSE Tendon tears are common injuries that heal with scar formation. Interestingly, MRL/MpJ mice heal without scar in several tissues, including tendon. Most hypotheses regarding scarless healing implicate the systemic environment. However, the tissue-specificity of this regenerative response and our previous findings showing regeneration of sub-rupture tendon injuries, which lack an overt systemic response, motivate a tissue-driven hypothesis. Our objective is to investigate the potential of the local tendon environment in driving scarless healing (1) by comparing the systemic response and the healing capacity associated with ear and tendon injuries in MRL/MpJ mice, and (2) by comparing intrinsic healing properties between MRL/MpJ and normal healer C57Bl/6 tendons. METHODS We examined the systemic inflammatory and local structural environments of ear and tendon punch injuries in MRL/MpJ and C57Bl/6 mice. Systemic differences were analyzed to assess effects of different injuries on the inflammatory response. Correlations were assessed between MRL/MpJ ear and tendon injuries to compare the extent of healing between regenerative tissues. RESULTS Analysis showed similarities between the systemic environment in MRL/MpJ post ear or tendon injuries. However, comparable inflammatory responses did not translate into analogous healing between tissues, suggesting that the systemic environment is not the driver of regeneration. Supporting the regenerative role of the local environment, healing MRL/MpJ tendons exhibited improved matrix and cell alignment and a distinct composition of growth factors and Hyaluronan from C57Bl/6. CONCLUSION These findings support the tissue-driven hypothesis for MRL/MpJ tendon regeneration and motivate further investigation regarding specific roles of extracellular factors in scarless healing.
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Affiliation(s)
- Juan Paredes
- Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, USA
| | - David A. Shiovitz
- Leni and Peter W. May Department of Orthopaedics, Icahn School of Medicine, Mount Sinai, New York, NY, USA
| | - Nelly Andarawis-Puri
- Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, USA,Sibley School of Mechanical and Aerospace Engineering, Cornell University, Ithaca, NY, USA,Hospital for Special Surgery, New York, NY, USA
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24
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Comparative regenerative mechanisms across different mammalian tissues. NPJ Regen Med 2018; 3:6. [PMID: 29507774 PMCID: PMC5824955 DOI: 10.1038/s41536-018-0044-5] [Citation(s) in RCA: 145] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2017] [Revised: 01/18/2018] [Accepted: 01/23/2018] [Indexed: 02/08/2023] Open
Abstract
Stimulating regeneration of complex tissues and organs after injury to effect complete structural and functional repair, is an attractive therapeutic option that would revolutionize clinical medicine. Compared to many metazoan phyla that show extraordinary regenerative capacity, which in some instances persists throughout life, regeneration in mammalians, particularly humans, is limited or absent. Here we consider recent insights in the elucidation of molecular mechanisms of regeneration that have come from studies of tissue homeostasis and injury repair in mammalian tissues that span the spectrum from little or no self-renewal, to those showing active cell turnover throughout life. These studies highlight the diversity of factors that constrain regeneration, including immune responses, extracellular matrix composition, age, injury type, physiological adaptation, and angiogenic and neurogenic capacity. Despite these constraints, much progress has been made in elucidating key molecular mechanisms that may provide therapeutic targets for the development of future regenerative therapies, as well as previously unidentified developmental paradigms and windows-of-opportunity for improved regenerative repair.
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25
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Human Umbilical Cord Wharton Jelly-Derived Adult Mesenchymal Stem Cells, in Biohybrid Scaffolds, for Experimental Skin Regeneration. Stem Cells Int 2017; 2017:1472642. [PMID: 29456556 PMCID: PMC5804405 DOI: 10.1155/2017/1472642] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2017] [Revised: 09/12/2017] [Accepted: 10/04/2017] [Indexed: 12/29/2022] Open
Abstract
The ultimate goal for skin tissue engineering is to regenerate skin lesions to allow the full restoration of morphological and functional properties as what they were before injury. To this end, we have assembled a new prototype of a biomimetic human umbilical cord adult mesenchymal stem cell (hUCMS)/fibrin-based scaffold. We have fully characterized the proposed dermal equivalent (DE) in vitro, to assess morphological, functional, and biological properties of the encased cells. We transplanted DE subcutaneously into immunocompetent rodents, to verify its full biocompatibility. Finally, we studied DE graft effects on full-thickness wounds, in immunocompetent mice to demonstrate its capability to drive the healing process in the absence of significant scarring tissue. The excellent outcome of these in vivo studies fuels hope that this new approach, based on a biohybrid DE, may be applied to the operative treatment of skin lesions (i.e., diabetic foot ulcers and burns) in man.
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Sass PA, Dąbrowski M, Charzyńska A, Sachadyn P. Transcriptomic responses to wounding: meta-analysis of gene expression microarray data. BMC Genomics 2017; 18:850. [PMID: 29115927 PMCID: PMC5678747 DOI: 10.1186/s12864-017-4202-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2017] [Accepted: 10/08/2017] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND A vast amount of microarray data on transcriptomic response to injury has been collected so far. We designed the analysis in order to identify the genes displaying significant changes in expression after wounding in different organisms and tissues. This meta-analysis is the first study to compare gene expression profiles in response to wounding in as different tissues as heart, liver, skin, bones, and spinal cord, and species, including rat, mouse and human. RESULTS We collected available microarray transcriptomic profiles obtained from different tissue injury experiments and selected the genes showing a minimum twofold change in expression in response to wounding in prevailing number of experiments for each of five wound healing stages we distinguished: haemostasis & early inflammation, inflammation, early repair, late repair and remodelling. During the initial phases after wounding, haemostasis & early inflammation and inflammation, the transcriptomic responses showed little consistency between different tissues and experiments. For the later phases, wound repair and remodelling, we identified a number of genes displaying similar transcriptional responses in all examined tissues. As revealed by ontological analyses, activation of certain pathways was rather specific for selected phases of wound healing, such as e.g. responses to vitamin D pronounced during inflammation. Conversely, we observed induction of genes encoding inflammatory agents and extracellular matrix proteins in all wound healing phases. Further, we selected several genes differentially upregulated throughout different stages of wound response, including established factors of wound healing in addition to those previously unreported in this context such as PTPRC and AQP4. CONCLUSIONS We found that transcriptomic responses to wounding showed similar traits in a diverse selection of tissues including skin, muscles, internal organs and nervous system. Notably, we distinguished transcriptional induction of inflammatory genes not only in the initial response to wounding, but also later, during wound repair and tissue remodelling.
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Affiliation(s)
- Piotr Andrzej Sass
- Department Molecular Biotechnology and Microbiology, Gdańsk University of Technology, Gdańsk, Poland
| | - Michał Dąbrowski
- Laboratory of Bioinformatics, Neurobiology Center, Nencki Institute of Experimental Biology of Polish Academy of Sciences, Warsaw, Poland
| | - Agata Charzyńska
- Laboratory of Bioinformatics, Neurobiology Center, Nencki Institute of Experimental Biology of Polish Academy of Sciences, Warsaw, Poland
| | - Paweł Sachadyn
- Department Molecular Biotechnology and Microbiology, Gdańsk University of Technology, Gdańsk, Poland.
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27
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Yu G, Li Y, Ye L, Wang X, Zhang J, Dong Z, Jiang D. Exogenous peripheral blood mononuclear cells affect the healing process of deep‑degree burns. Mol Med Rep 2017; 16:8110-8122. [PMID: 28990101 PMCID: PMC5779898 DOI: 10.3892/mmr.2017.7672] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2016] [Accepted: 07/20/2017] [Indexed: 12/24/2022] Open
Abstract
The regenerative repair of deep-degree (second degree) burned skin remains a notable challenge in the treatment of burn injury, despite improvements being made with regards to treatment modality and the emergence of novel therapies. Fetal skin constitutes an attractive target for investigating scarless healing of burned skin. To investigate the inflammatory response during scarless healing of burned fetal skin, the present study developed a nude mouse model, which was implanted with normal human fetal skin and burned fetal skin. Subsequently, human peripheral blood mononuclear cells (PBMCs) were used to treat the nude mouse model carrying the burned fetal skin. The expression levels of matrix metalloproteinase (MMP)-9 and tissue inhibitor of metalloproteinases (TIMP)-1 were investigated during this process. In the present study, fetal skin was subcutaneously implanted into the nude mice to establish the murine model. Hematoxylin and eosin staining was used to detect alterations in the skin during the development of fetal skin and during the healing process of deep-degree burned fetal skin. The expression levels of MMP-9 and TIMP-1 were determined using immunochemical staining, and their staining intensity was evaluated by mean optical density. The results demonstrated that fetal skin subcutaneously implanted into the dorsal skin flap of nude mice developed similarly to the normal growth process in the womb. In addition, the scarless healing process was clearly observed in the mice carrying the burned fetal skin. A total of 2 weeks was required to complete scarless healing. Following treatment with PBMCs, the burned fetal skin generated inflammatory factors and enhanced the inflammatory response, which consequently resulted in a reduction in the speed of healing and in the formation of scars. Therefore, exogenous PBMCs may alter the lowered immune response environment, which is required for scarless healing, resulting in scar formation. In conclusion, the present study indicated that the involvement of inflammatory cells is important during the healing process of deep-degree burned skin, and MMP-9 and TIMP-1 may serve important roles in the process of scar formation.
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Affiliation(s)
- Guanying Yu
- Department of Burns and Plastic Surgery, The Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China
| | - Yaonan Li
- Department of Emergency, The Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China
| | - Lan Ye
- Cancer Center, The Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China
| | - Xinglei Wang
- Department of Emergency, The Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China
| | - Jixun Zhang
- Department of Burns and Plastic Surgery, The Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China
| | - Zhengxue Dong
- Department of Burns and Plastic Surgery, The Chinese People's Liberation Army 148 Hospital, Zibo, Shandong 255300, P.R. China
| | - Duyin Jiang
- Department of Burns and Plastic Surgery, The Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China
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28
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Parekh A, Hebda PA. The Contractile Phenotype of Dermal Fetal Fibroblasts in Scarless Wound Healing. CURRENT PATHOBIOLOGY REPORTS 2017; 5:271-277. [PMID: 29038745 DOI: 10.1007/s40139-017-0149-3] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
PURPOSE OF REVIEW Injured skin in the mammalian fetus can heal regeneratively due to the ability of fetal fibroblasts to effectively reorganize the extracellular matrix (ECM). This process occurs without fetal fibroblasts differentiating into highly contractile myofibroblasts which cause scarring and fibrosis in adult wounds. Here, we provide a brief review of fetal wound healing and the evidence supporting a unique contractile phenotype in fetal fibroblasts. Furthermore, we discuss the biomechanical role of the ECM in driving myofibroblast differentiation in wound healing and the implications for new clinical modalities based on the biophysical properties of fetal fibroblasts. RECENT FINDINGS We and others have found that fetal fibroblasts are refractory to the environmental stimuli necessary for myofibroblast differentiation in adult wound healing including mechanical stress. SUMMARY Understanding the biomechanical mechanisms that regulate the contractile phenotype of fetal fibroblasts may unlock new avenues for anti-scarring therapies that target myofibroblast differentiation of adult fibroblasts.
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Affiliation(s)
- Aron Parekh
- Department of Otolaryngology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.,Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA.,Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee, USA.,Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee, USA
| | - Patricia A Hebda
- Department of Plastic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.,Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.,McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
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29
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Royce SG, Rele S, Broughton BRS, Kelly K, Samuel CS. Intranasal administration of mesenchymoangioblast-derived mesenchymal stem cells abrogates airway fibrosis and airway hyperresponsiveness associated with chronic allergic airways disease. FASEB J 2017. [PMID: 28626025 DOI: 10.1096/fj.201700178r] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Structural changes known as airway remodeling (AWR) characterize chronic/severe asthma and contribute to lung dysfunction. Thus, we assessed the in vivo efficacy of induced pluripotent stem cell and mesenchymoangioblast-derived mesenchymal stem cells (MCA-MSCs) on AWR in a murine model of chronic allergic airways disease (AAD)/asthma. Female Balb/c mice were subjected to a 9-wk model of ovalbumin (Ova)-induced chronic AAD and treated intravenously or intranasally with MCA-MSCs from weeks 9 to 11. Changes in airway inflammation (AI), AWR, and airway hyperresponsiveness (AHR) were assessed. Ova-injured mice presented with AI, goblet cell metaplasia, epithelial thickening, increased airway TGF-β1 levels, subepithelial myofibroblast and collagen accumulation, total lung collagen concentration, and AHR (all P < 0.001 vs. uninjured control group). Apart from epithelial thickness, all other parameters measured were significantly, although not totally, decreased by intravenous delivery of MCA-MSCs to Ova-injured mice. In comparison, intranasal delivery of MCA-MSCs to Ova-injured mice significantly decreased all parameters measured (all P < 0.05 vs. Ova group) and, most notably, normalized aberrant airway TGF-β1 levels, airway/lung fibrosis, and AHR to values measured in uninjured animals. MCA-MSCs also increased collagen-degrading gelatinase levels. Hence, direct delivery of MCA-MSCs offers great therapeutic benefit for the AWR and AHR associated with chronic AAD.-Royce, S. G., Rele, S., Broughton, B. R. S., Kelly, K., Samuel, C. S. Intranasal administration of mesenchymoangioblast-derived mesenchymal stem cells abrogates airway fibrosis and airway hyperresponsiveness associated with chronic allergic airways disease.
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Affiliation(s)
- Simon G Royce
- Fibrosis Laboratory, Monash University, Clayton, Victoria, Australia; .,Department of Medicine, Central Clinical School, Monash University, Prahran, Victoria, Australia; and
| | - Siddharth Rele
- Fibrosis Laboratory, Monash University, Clayton, Victoria, Australia
| | - Brad R S Broughton
- Cardiovascular and Pulmonary Pharmacology Group, Cardiovascular Disease Program, Biomedicine Discovery Institute and Department of Pharmacology, Monash University, Clayton, Victoria, Australia
| | - Kilian Kelly
- Cynata Therapeutics, Armadale, Victoria, Australia
| | - Chrishan S Samuel
- Fibrosis Laboratory, Monash University, Clayton, Victoria, Australia;
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30
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Heil N, Bravo K, Montoya A, Robledo S, Osorio E. Wound healing activity of Ullucus tuberosus , an Andean tuber crop. Asian Pac J Trop Biomed 2017. [DOI: 10.1016/j.apjtb.2017.05.007] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
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31
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Jung M, Ma Y, Iyer RP, DeLeon-Pennell KY, Yabluchanskiy A, Garrett MR, Lindsey ML. IL-10 improves cardiac remodeling after myocardial infarction by stimulating M2 macrophage polarization and fibroblast activation. Basic Res Cardiol 2017; 112:33. [PMID: 28439731 DOI: 10.1007/s00395-017-0622-5] [Citation(s) in RCA: 320] [Impact Index Per Article: 40.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2017] [Accepted: 04/13/2017] [Indexed: 01/26/2023]
Abstract
Inflammation resolution is important for scar formation following myocardial infarction (MI) and requires the coordinated actions of macrophages and fibroblasts. In this study, we hypothesized that exogenous interleukin-10 (IL-10), an anti-inflammatory cytokine, promotes post-MI repair through actions on these cardiac cell types. To test this hypothesis, C57BL/6J mice (male, 3- to 6-month old, n = 24/group) were treated with saline or IL-10 (50 μg/kg/day) by osmotic mini-pump infusion starting at day (d) 1 post-MI and sacrificed at d7 post-MI. IL-10 infusion doubled plasma IL-10 concentrations by d7 post-MI. Despite similar infarct areas and mortality rates, IL-10 treatment significantly decreased LV dilation (1.6-fold for end-systolic volume and 1.4-fold for end-diastolic volume) and improved ejection fraction 1.8-fold (both p < 0.05). IL-10 treatment attenuated inflammation at d7 post-MI, evidenced by decreased numbers of Mac-3-positive macrophages in the infarct (p < 0.05). LV macrophages isolated from d7 post-MI mice treated with IL-10 showed significantly elevated gene expression of M2 markers (Arg1, Ym1, and Tgfb1; all p < 0.05). We further performed RNA-seq analysis on post-MI cardiac macrophages and identified 410 significantly different genes (155 increased, 225 decreased by IL-10 treatment). By functional network analysis grouping, the majority of genes (133 out of 410) were part of the cellular assembly and repair functional group. Of these, hyaluronidase 3 (Hyal3) was the most important feature identified by p value. IL-10 treatment decreased Hyal3 by 28%, which reduced hyaluronan degradation and limited collagen deposition (all p < 0.05). In addition, in vivo IL-10 treatment increased fibroblast activation (proliferation, migration, and collagen production), an effect that was both directly and indirectly influenced by macrophage M2 polarization. Combined, our results indicate that in vivo infusion of IL-10 post-MI improves the LV microenvironment to dampen inflammation and facilitate cardiac wound healing.
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Affiliation(s)
- Mira Jung
- Department of Physiology and Biophysics, Mississippi Center for Heart Research, University of Mississippi Medical Center, 2500 North State St., Jackson, MS, 39216-4505, USA
| | - Yonggang Ma
- Department of Physiology and Biophysics, Mississippi Center for Heart Research, University of Mississippi Medical Center, 2500 North State St., Jackson, MS, 39216-4505, USA
| | - Rugmani Padmanabhan Iyer
- Department of Physiology and Biophysics, Mississippi Center for Heart Research, University of Mississippi Medical Center, 2500 North State St., Jackson, MS, 39216-4505, USA
| | - Kristine Y DeLeon-Pennell
- Department of Physiology and Biophysics, Mississippi Center for Heart Research, University of Mississippi Medical Center, 2500 North State St., Jackson, MS, 39216-4505, USA.,Research Service, G.V. (Sonny) Montgomery Veterans Affairs Medical Center, Jackson, MS, USA
| | - Andriy Yabluchanskiy
- Donald W. Reynolds Department of Geriatric Medicine, Reynolds Oklahoma Center on Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | | | - Merry L Lindsey
- Department of Physiology and Biophysics, Mississippi Center for Heart Research, University of Mississippi Medical Center, 2500 North State St., Jackson, MS, 39216-4505, USA. .,Research Service, G.V. (Sonny) Montgomery Veterans Affairs Medical Center, Jackson, MS, USA.
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32
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Cantaruti TA, Costa RA, de Souza KS, Vaz NM, Carvalho CR. Indirect effects of immunological tolerance to a regular dietary protein reduce cutaneous scar formation. Immunology 2017; 151:314-323. [PMID: 28295241 DOI: 10.1111/imm.12732] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2016] [Revised: 02/15/2017] [Accepted: 03/06/2017] [Indexed: 12/20/2022] Open
Abstract
Oral tolerance refers to the specific inhibition of immune responsiveness to T-cell-dependent antigens contacted through the oral route before parenteral immunization. Oral tolerance to one protein does not inhibit immune responses to other unrelated proteins, but parenteral injection of tolerated antigens plus adjuvant into tolerant, but not normal, mice inhibits immune responses to antigens injected concomitantly or soon thereafter. The inhibitory effect triggered by parenteral injection of tolerated proteins is known as bystander suppression or indirect effects of oral tolerance. Intraperitoneal injection of ovalbumin (OVA) plus alum adjuvant in OVA-tolerant mice soon before skin injury inhibits inflammation and improves cutaneous wound healing. However, as OVA is not a regular component of mouse chow, we tested whether indirect effects could be triggered by zein, the main protein of corn that is regularly present in mouse chow. We show that intraperitoneal injection of a single dose (10 μg) of zein plus alum adjuvant soon before skin injury in mice reduces leucocyte infiltration but increase the number of T cells and the expression of resistin-like molecule-α (a marker of alternatively activated macrophages) in the wound bed, increases the expression of transforming growth factor-β3 in the newly formed epidermis and reduces cutaneous scar formation. These results suggest that indirect effects of oral tolerance triggered by parenteral injection of regular dietary components may be further explored as one alternative way to promote scarless wound healing.
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Affiliation(s)
| | | | - Kênia Soares de Souza
- Departamento de Morfologia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Nelson Monteiro Vaz
- Departamento de Bioquímica e Imunologia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Cláudia Rocha Carvalho
- Departamento de Morfologia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
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33
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Lesions requiring wound management in a central tertiary neonatal intensive care unit. World J Pediatr 2017; 13:165-172. [PMID: 27878785 DOI: 10.1007/s12519-016-0070-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2015] [Accepted: 06/22/2015] [Indexed: 01/29/2023]
Abstract
BACKGROUND Most of the skin disorders that occur in neonatal intensive care units are due in part to the immaturity and vulnerability of the neonatal skin. Various iatrogenic diagnostic and therapeutic procedures are also conducive to iatrogenic damage. This study was to review the neonates admitted to our neonatal intensive care unit who needed wound management, and to assess the most common skin injuries and wounds, and their aetiology. METHODS Data were extracted from medical records of neonates who needed wound management in our Neonatal Intensive Care Unit between January 31, 2012 and January 31, 2013. Information about gestational age, sex, birth weight, area of involvement, wound aetiology, and therapy were collected. RESULTS Among the 211 neonates observed, wound management was required in 10 cases of diaper dermatitis, 7 epidermal stripping, 6 extravasation injuries, 5 pressure ulcers, 1 surgical wound and infection, 1 thermal burn, and 5 other lesions. CONCLUSIONS International guidelines in neonatal wound care practice are not available, and further research concerns are clearly needed. Dressings and antiseptic agents should be chosen with great care for application to neonates, with particular attention to the prevention of adverse events in this sensitive population. Team work among dermatologists, neonatologists and nurses is crucial for the successful treatment of neonates.
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Abstract
Purpose: To review the recent data about eyelid morphogenesis, and outline a timeline for eyelid development from the very early stages during embryonic life till final maturation of the eyelid late in fetal life. Methods: The authors extensively review major studies detailing human embryologic and fetal eyelid morphogenesis. These studies span almost a century and include some more recent cadaver studies. Numerous studies in the murine model have helped to better understand the molecular signals that govern eyelid embryogenesis. The authors summarize the current findings in molecular biology, and highlight the most significant studies in mice regarding the multiple and interacting signaling pathways involved in regulating normal eyelid morphogenesis. Results: Eyelid morphogenesis involves a succession of subtle yet strictly regulated morphogenetic episodes of tissue folding, proliferation, contraction, and even migration, which may occur simultaneously or in succession. Conclusions: Understanding the extraordinary process of building eyelid tissue in embryonic life, and deciphering its underlying signaling machinery has far reaching clinical implications beyond understanding the developmental abnormalities involving the eyelids, and may pave the way for achieving scar-reducing therapies in adult mammalian wounds, or control the spread of malignancies. The authors describe in detail the recent advances in the knowledge of embryological and fetal development of the eyelids, and briefly outline the molecular basis of eyelid morphogenesis.
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35
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Zhou H, You C, Wang X, Jin R, Wu P, Li Q, Han C. The progress and challenges for dermal regeneration in tissue engineering. J Biomed Mater Res A 2017; 105:1208-1218. [PMID: 28063210 DOI: 10.1002/jbm.a.35996] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2016] [Revised: 12/30/2016] [Accepted: 01/03/2017] [Indexed: 01/17/2023]
Affiliation(s)
- Hanlei Zhou
- Department of Burns; 2nd Affiliated Hospital of Zhejiang University, College of Medicine; Hangzhou 310009 China
| | - Chuangang You
- Department of Burns; 2nd Affiliated Hospital of Zhejiang University, College of Medicine; Hangzhou 310009 China
| | - Xingang Wang
- Department of Burns; 2nd Affiliated Hospital of Zhejiang University, College of Medicine; Hangzhou 310009 China
| | - Ronghua Jin
- Department of Burns; 2nd Affiliated Hospital of Zhejiang University, College of Medicine; Hangzhou 310009 China
| | - Pan Wu
- Department of Burns; 2nd Affiliated Hospital of Zhejiang University, College of Medicine; Hangzhou 310009 China
| | - Qiong Li
- Department of Burns; 2nd Affiliated Hospital of Zhejiang University, College of Medicine; Hangzhou 310009 China
| | - Chunmao Han
- Department of Burns; 2nd Affiliated Hospital of Zhejiang University, College of Medicine; Hangzhou 310009 China
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36
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Milyavsky M, Dickie R. Methylene Blue Assay for Estimation of Regenerative Re-Epithelialization In Vivo. MICROSCOPY AND MICROANALYSIS : THE OFFICIAL JOURNAL OF MICROSCOPY SOCIETY OF AMERICA, MICROBEAM ANALYSIS SOCIETY, MICROSCOPICAL SOCIETY OF CANADA 2017; 23:113-121. [PMID: 28228166 DOI: 10.1017/s1431927617000101] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/06/2023]
Abstract
The rapidity with which epithelial cells cover a wound surface helps determine whether scarring or scar-less healing results. As methylene blue is a vital dye that is absorbed by damaged tissue but not undamaged epidermis, it can be used to assess wound closure. We sought to develop a quantitative methylene blue exclusion assay to estimate the timeframe for re-epithelialization in regenerating appendages in zebrafish and axolotls, two classic model systems of regeneration. Following application of methylene blue to the amputation plane and extensive washing, the regenerating tail was imaged in vivo until staining was no longer visible. The percent area of the amputation plane positive for methylene blue, representing the area of the amputation plane not yet re-epithelialized, was measured for each time point. The loss of methylene blue occurred rapidly, within ~2.5 h in larval and juvenile axolotls and <1 h in adult zebrafish, consistent with high rates of re-epithelialization in these models of regeneration. The assay allows simple, rapid estimation of the time course for regenerative re-epithelialization without affecting subsequent regenerative ability. This technique will permit comparison of re-epithelialization across different strains and stages, as well as under the influence of various pharmacological inhibitors that affect regeneration.
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Affiliation(s)
- Maresha Milyavsky
- Department of Biological Sciences,Towson University,Towson, MD 21252,USA
| | - Renee Dickie
- Department of Biological Sciences,Towson University,Towson, MD 21252,USA
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37
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Sang J, Li X, Shao Y, Li Z, Fu J. Controlled Tubular Unit Formation from Collagen Film for Modular Tissue Engineering. ACS Biomater Sci Eng 2016; 3:2860-2868. [DOI: 10.1021/acsbiomaterials.6b00468] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Affiliation(s)
- Jianming Sang
- Department of Mechanical Engineering, University of Michigan, 2350 Hayward Street, Ann
Arbor, Michigan 48109, United States
| | - Xiang Li
- Department of Mechanical Engineering, University of Michigan, 2350 Hayward Street, Ann
Arbor, Michigan 48109, United States
| | - Yue Shao
- Department of Mechanical Engineering, University of Michigan, 2350 Hayward Street, Ann
Arbor, Michigan 48109, United States
| | - Zida Li
- Department of Mechanical Engineering, University of Michigan, 2350 Hayward Street, Ann
Arbor, Michigan 48109, United States
| | - Jianping Fu
- Department of Mechanical Engineering, University of Michigan, 2350 Hayward Street, Ann
Arbor, Michigan 48109, United States
- Michigan Center for Integrative Research
in Critical Care, University of Michigan, 2800 Plymouth Road, Ann Arbor, Michigan 48109, United States
- Department
of Biomedical Engineering, University of Michigan, 2200 Bonisteel
Boulevard, Ann Arbor, Michigan 48109, United States
- Department of Cell and Developmental Biology, University of Michigan, 109 Zina Pitcher Place, Ann Arbor, Michigan 48109, United States
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38
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Zheng Z, Zhang X, Dang C, Beanes S, Chang GX, Chen Y, Li CS, Lee KS, Ting K, Soo C. Fibromodulin Is Essential for Fetal-Type Scarless Cutaneous Wound Healing. THE AMERICAN JOURNAL OF PATHOLOGY 2016; 186:2824-2832. [PMID: 27665369 DOI: 10.1016/j.ajpath.2016.07.023] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/29/2016] [Revised: 07/11/2016] [Accepted: 07/22/2016] [Indexed: 12/21/2022]
Abstract
In contrast to adult and late-gestation fetal skin wounds, which heal with scar, early-gestation fetal skin wounds display a remarkable capacity to heal scarlessly. Although the underlying mechanism of this transition from fetal-type scarless healing to adult-type healing with scar has been actively investigated for decades, in utero restoration of scarless healing in late-gestation fetal wounds has not been reported. In this study, using loss- and gain-of-function rodent fetal wound models, we identified that fibromodulin (Fm) is essential for fetal-type scarless wound healing. In particular, we found that loss of Fm can eliminate the ability of early-gestation fetal rodents to heal without scar. Meanwhile, administration of fibromodulin protein (FM) alone was capable of restoring scarless healing in late-gestation rat fetal wounds, which naturally heal with scar, as characterized by dermal appendage restoration and organized collagen architectures that were virtually indistinguishable from those in age-matched unwounded skin. High Fm levels correlated with decreased transforming growth factor (TGF)-β1 expression and scarless repair, while low Fm levels correlated with increased TGF-β1 expression and scar formation. This study represents the first successful in utero attempt to induce scarless repair in late-gestation fetal wounds by using a single protein, Fm, and highlights the crucial role that the FM-TGF-β1 nexus plays in fetal-type scarless skin repair.
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Affiliation(s)
- Zhong Zheng
- Dental and Craniofacial Research Institute and Section of Orthodontics, School of Dentistry, University of California, Los Angeles, Los Angeles, California; UCLA Division of Plastic and Reconstructive Surgery, the Department of Orthopaedic Surgery, and the Orthopaedic Hospital Research Center, University of California, Los Angeles, Los Angeles, California
| | - Xinli Zhang
- Dental and Craniofacial Research Institute and Section of Orthodontics, School of Dentistry, University of California, Los Angeles, Los Angeles, California
| | - Catherine Dang
- Saul & Joyce Brandman Breast Center, Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California
| | | | - Grace X Chang
- Department of Surgery, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California
| | - Yao Chen
- Dental and Craniofacial Research Institute and Section of Orthodontics, School of Dentistry, University of California, Los Angeles, Los Angeles, California
| | - Chen-Shuang Li
- Dental and Craniofacial Research Institute and Section of Orthodontics, School of Dentistry, University of California, Los Angeles, Los Angeles, California
| | - Kevin S Lee
- Dental and Craniofacial Research Institute and Section of Orthodontics, School of Dentistry, University of California, Los Angeles, Los Angeles, California
| | - Kang Ting
- Dental and Craniofacial Research Institute and Section of Orthodontics, School of Dentistry, University of California, Los Angeles, Los Angeles, California; UCLA Division of Plastic and Reconstructive Surgery, the Department of Orthopaedic Surgery, and the Orthopaedic Hospital Research Center, University of California, Los Angeles, Los Angeles, California; Department of Bioengineering, School of Engineering, University of California, Los Angeles, Los Angeles, California.
| | - Chia Soo
- UCLA Division of Plastic and Reconstructive Surgery, the Department of Orthopaedic Surgery, and the Orthopaedic Hospital Research Center, University of California, Los Angeles, Los Angeles, California.
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Podolak-Popinigis J, Ronowicz A, Dmochowska M, Jakubiak A, Sachadyn P. The methylome and transcriptome of fetal skin: implications for scarless healing. Epigenomics 2016; 8:1331-1345. [PMID: 27510554 DOI: 10.2217/epi-2016-0068] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
AIM Fetal skin is known to heal without scarring. In mice, the phenomenon is observed until the 16-17 day of gestation - the day of transition from scarless to normal healing. The study aims to identify key methylome and transcriptome changes following the transition. MATERIALS & METHODS Methylome and transcriptome profiles were analyzed in murine dorsal skin using microarray approach. RESULTS & CONCLUSION The genes associated with inflammatory response and hyaluronate degradation showed increased DNA methylation before the transition, while those involved in embryonic morphogenesis, neuron differentiation and synapse functions did so after. A number of the methylome alterations were retained until adulthood and correlated with gene expression, while the functional associations imply that scarless healing depends on epigenetic regulation.
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Affiliation(s)
- Justyna Podolak-Popinigis
- Department of Molecular Biotechnology & Microbiology, Gdańsk University of Technology, Gdańsk, Poland.,Department of Biology & Pharmaceutical Botany, Medical University of Gdańsk, Gdańsk, Poland.,Tri-City Academic Laboratory Animal Centre - Research & Services Centre, Medical University of Gdańsk, Gdańsk, Poland
| | - Anna Ronowicz
- Department of Molecular Biotechnology & Microbiology, Gdańsk University of Technology, Gdańsk, Poland.,Department of Biology & Pharmaceutical Botany, Medical University of Gdańsk, Gdańsk, Poland.,Tri-City Academic Laboratory Animal Centre - Research & Services Centre, Medical University of Gdańsk, Gdańsk, Poland
| | - Monika Dmochowska
- Department of Molecular Biotechnology & Microbiology, Gdańsk University of Technology, Gdańsk, Poland.,Department of Biology & Pharmaceutical Botany, Medical University of Gdańsk, Gdańsk, Poland.,Tri-City Academic Laboratory Animal Centre - Research & Services Centre, Medical University of Gdańsk, Gdańsk, Poland
| | - Agnieszka Jakubiak
- Department of Molecular Biotechnology & Microbiology, Gdańsk University of Technology, Gdańsk, Poland.,Department of Biology & Pharmaceutical Botany, Medical University of Gdańsk, Gdańsk, Poland.,Tri-City Academic Laboratory Animal Centre - Research & Services Centre, Medical University of Gdańsk, Gdańsk, Poland
| | - Paweł Sachadyn
- Department of Molecular Biotechnology & Microbiology, Gdańsk University of Technology, Gdańsk, Poland.,Department of Biology & Pharmaceutical Botany, Medical University of Gdańsk, Gdańsk, Poland.,Tri-City Academic Laboratory Animal Centre - Research & Services Centre, Medical University of Gdańsk, Gdańsk, Poland
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40
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Godwin JW, Pinto AR, Rosenthal NA. Chasing the recipe for a pro-regenerative immune system. Semin Cell Dev Biol 2016; 61:71-79. [PMID: 27521522 DOI: 10.1016/j.semcdb.2016.08.008] [Citation(s) in RCA: 90] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2016] [Revised: 08/08/2016] [Accepted: 08/09/2016] [Indexed: 02/07/2023]
Abstract
Identification of the key ingredients and essential processes required to achieve perfect tissue regeneration in humans has so far remained elusive. Injury in vertebrates induces an obligatory wound response that will precede or overlap any regeneration specific program or scarring outcome. This process shapes the cellular and molecular landscape of the tissue, influencing the success of endogenous repair pathways or for potential clinical intervention. The involvement of immune cells is also required for aspects of development extending beyond the initial inflammatory phase of wounding. It has now become clear from amphibian, fish and mammalian models of tissue injury that the type of immune response and the profile of immune cells attending the site of injury can act as the gatekeepers that determine wound repair quality. The heterogeneity among innate and adaptive immune cell populations, along with the developmental origin of these cells, form key ingredients affecting the potential for downstream repair and the suppression of fibrosis. Cell-to-cell interactions between immune cells, such as macrophages and T cells, with stem cells and mesenchymal cells are critically important for shaping this process and these exchanges, are in turn influenced by the type of injury, tissue location and developmental stage of the organism. Developmentally, mouse cardiac regeneration is restricted to early stages of postnatal life where the balance of innate to adaptive immune cells may be poised towards regeneration. In the injured adult mouse liver, specific macrophage subsets improve repair while other bone marrow derived cells can exacerbate injury. Other studies using genetically diverse mice have shown enhanced regeneration in certain strains, restricted to specific tissues. This enhanced repair is linked with expression of genes such as Insulin-like Growth Factor- 1 (IGF-1) and activin (Act 1), that both play important roles in shaping the immune system. Immune cells are now appreciated to have powerful influences on critical cell types required for regeneration success. The winning recipe for tissue regeneration is likely to be found ultimately by identifying the genetic elements and specific cell populations that limit or allow intrinsic potential. This will be essential for developing therapeutic strategies for tissue regeneration in humans.
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Affiliation(s)
- James W Godwin
- The Jackson Laboratory, Bar Harbor, ME, 04609, USA; MDI Biological Laboratory, Salisbury Cove, ME 04672, USA; Australian Regenerative Medicine Institute, Monash University, Victoria, 3800, Australia.
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41
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Pritchard MT, McCracken JM. Identifying Novel Targets for Treatment of Liver Fibrosis: What Can We Learn from Injured Tissues which Heal Without a Scar? Curr Drug Targets 2016; 16:1332-46. [PMID: 26302807 DOI: 10.2174/1389450116666150825111439] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2015] [Accepted: 08/08/2015] [Indexed: 02/07/2023]
Abstract
The liver is unique in that it is able to regenerate. This regeneration occurs without formation of a scar in the case of non-iterative hepatic injury. However, when the liver is exposed to chronic liver injury, the purely regenerative process fails and excessive extracellular matrix proteins are deposited in place of normal liver parenchyma. While much has been discovered in the past three decades, insights into fibrotic mechanisms have not yet lead to effective therapies; liver transplant remains the only cure for advanced liver disease. In an effort to broaden the collection of possible therapeutic targets, this review will compare and contrast the liver wound healing response to that found in two types of wound healing: scarless wound healing of fetal skin and oral mucosa and scar-forming wound healing found in adult skin. This review will examine wound healing in the liver and the skin in relation to the role of humoral and cellular factors, as well as the extracellular matrix, in this process. While several therapeutic targets are similar between fibrotic liver and adult skin wound healing, others are unique and represent novel areas for hepatic anti-fibrotic research. In particular, investigations into the role of hyaluronan in liver fibrosis and fibrosis resolution are warranted.
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Affiliation(s)
- Michele T Pritchard
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66161, USA.
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42
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Yagi LH, Watanuki LM, Isaac C, Gemperli R, Nakamura YM, Ladeira PRS. Human fetal wound healing: a review of molecular and cellular aspects. EUROPEAN JOURNAL OF PLASTIC SURGERY 2016. [DOI: 10.1007/s00238-016-1201-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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43
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Zelen CM, Orgill DP, Serena T, Galiano R, Carter MJ, DiDomenico LA, Keller J, Kaufman J, Li WW. A prospective, randomised, controlled, multicentre clinical trial examining healing rates, safety and cost to closure of an acellular reticular allogenic human dermis versus standard of care in the treatment of chronic diabetic foot ulcers. Int Wound J 2016; 14:307-315. [PMID: 27073000 PMCID: PMC7949710 DOI: 10.1111/iwj.12600] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2016] [Accepted: 03/10/2016] [Indexed: 02/06/2023] Open
Abstract
Acellular dermal matrices can successfully heal wounds. This study's goal was to compare clinical outcomes of a novel, open‐structure human reticular acellular dermis matrix (HR‐ADM) to facilitate wound closure in non‐healing diabetic foot ulcers (DFUs) versus DFUs treated with standard of care (SOC). Following a 2‐week screening period in which DFUs were treated with offloading and moist wound care, patients were randomised to either SOC alone or HR‐ADM plus SOC applied weekly for up to 12 weeks. At 6 weeks, the primary outcome time, 65% of the HR‐ADM‐treated DFUs healed (13/20) compared with 5% (1/20) of DFUs that received SOC alone. At 12 weeks, the proportions of DFUs healed were 80% and 20%, respectively. Mean time to heal within 12 weeks was 40 days for the HR‐ADM group compared with 77 days for the SOC group. There was no incidence of increased adverse or serious adverse events between groups or any adverse events related to the graft. Mean and median graft costs to closure per healed wound in the HR‐ADM group were $1475 and $963, respectively. Weekly application of HR‐ADM is an effective intervention for promoting closure of non‐healing DFUs.
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Affiliation(s)
- Charles M Zelen
- Department of Medical Education, Professional Education and Research Institute, Roanoke, VA, USA
| | - Dennis P Orgill
- Department of Plastic Surgery, Brigham and Women's Hospital, Boston, MA, USA
| | | | - Robert Galiano
- Division of Plastic Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
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44
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Tseng SCG. HC-HA/PTX3 Purified From Amniotic Membrane as Novel Regenerative Matrix: Insight Into Relationship Between Inflammation and Regeneration. Invest Ophthalmol Vis Sci 2016; 57:ORSFh1-8. [PMID: 27116665 PMCID: PMC4855828 DOI: 10.1167/iovs.15-17637] [Citation(s) in RCA: 98] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2015] [Accepted: 08/03/2015] [Indexed: 12/22/2022] Open
Abstract
PURPOSE Human limbal palisade of Vogt is an ideal model for studying and practicing regenerative medicine due to their accessibility. Nonresolving inflammation is a common manifestation of limbal stem cell deficiency, which is the major cause of corneal blindness, and presents as a threat to the success of transplanted limbal epithelial stem cells. Clinical studies have shown that the efficacy of transplantation of limbal epithelial stem cells can be augmented by transplantation of cryopreserved human amniotic membrane (AM), which exerts anti-inflammatory, antiscarring, and antiangiogenic action to promote wound healing. METHODS Review of published data to determine the molecular action mechanism explaining how AM exerts the aforementioned therapeutic actions. RESULTS From the water-soluble extract of cryopreserved AM, we have biochemically purified one novel matrix component termed heavy chain (HC)-hyaluronan (HA)/pentraxin 3 (PTX3) as the key relevant tissue characteristic responsible for the aforementioned AM's efficacy. Heavy chain-HA is a complex formed by a covalent linkage between HA and HC1 of inter-α-trypsin inhibitor (IαI) by tumor necrosis factor-stimulated gene-6 (TSG-6). This complex may then be tightly associated with PTX3 to form HC-HA/PTX3 complex. Besides exerting an anti-inflammatory, antiscarring, and antiangiogenic effects, HC-HA/PTX3 complex also uniquely maintains limbal niche cells to support the quiescence of limbal epithelial stem cells. CONCLUSIONS We envision that HC-HA/PTX3 purified from AM can be used as a unique substrate to refine ex vivo expansion of limbal epithelial stem cells by maintaining stem cell quiescence, self-renewal and fate decision. Furthermore, it can also be deployed as a platform to launch new therapeutics in regenerative medicine by mitigating nonresolving inflammation and reinforcing the well-being of stem cell niche.
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Affiliation(s)
- Scheffer C. G. Tseng
- The R&D Department of TissueTech Inc., Ocular Surface Center, and Ocular Surface Research and Education Foundation, Miami, Florida, United States
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45
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Leung TH, Snyder ER, Liu Y, Wang J, Kim SK. A cellular, molecular, and pharmacological basis for appendage regeneration in mice. Genes Dev 2016; 29:2097-107. [PMID: 26494786 PMCID: PMC4617975 DOI: 10.1101/gad.267724.115] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Regenerative medicine aims to restore normal tissue architecture and function. However, the basis of tissue regeneration in mammalian solid organs remains undefined. Remarkably, mice lacking p21 fully regenerate injured ears without discernable scarring. Here we show that, in wild-type mice following tissue injury, stromal-derived factor-1 (Sdf1) is up-regulated in the wound epidermis and recruits Cxcr4-expressing leukocytes to the injury site. In p21-deficient mice, Sdf1 up-regulation and the subsequent recruitment of Cxcr4-expressing leukocytes are significantly diminished, thereby permitting scarless appendage regeneration. Lineage tracing demonstrates that this regeneration derives from fate-restricted progenitor cells. Pharmacological or genetic disruption of Sdf1-Cxcr4 signaling enhances tissue repair, including full reconstitution of tissue architecture and all cell types. Our findings identify signaling and cellular mechanisms underlying appendage regeneration in mice and suggest new therapeutic approaches for regenerative medicine.
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Affiliation(s)
- Thomas H Leung
- Department of Developmental Biology, Stanford University School of Medicine, Stanford, California 94305, USA; Department of Dermatology, Stanford University School of Medicine, Stanford, California 94305, USA
| | - Emily R Snyder
- Department of Developmental Biology, Stanford University School of Medicine, Stanford, California 94305, USA
| | - Yinghua Liu
- Department of Developmental Biology, Stanford University School of Medicine, Stanford, California 94305, USA
| | - Jing Wang
- Department of Developmental Biology, Stanford University School of Medicine, Stanford, California 94305, USA
| | - Seung K Kim
- Department of Developmental Biology, Stanford University School of Medicine, Stanford, California 94305, USA; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California 94305, USA; Department of Medicine, Oncology Division, Stanford University School of Medicine, Stanford, California 94305, USA
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46
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Tseng SCG, He H, Zhang S, Chen SY. Niche Regulation of Limbal Epithelial Stem Cells: Relationship between Inflammation and Regeneration. Ocul Surf 2016; 14:100-12. [PMID: 26769483 DOI: 10.1016/j.jtos.2015.12.002] [Citation(s) in RCA: 68] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2015] [Revised: 12/17/2015] [Accepted: 12/24/2015] [Indexed: 02/07/2023]
Abstract
Human limbal palisades of Vogt are the ideal site for studying and practicing regenerative medicine due to their accessibility. Nonresolving inflammation in limbal stroma is common manifestation of limbal stem cell (SC) deficiency and presents as a threat to the success of transplanted limbal epithelial SCs. This pathologic process can be overcome by transplantation of cryopreserved human amniotic membrane (AM), which exerts anti-inflammatory, antiscarring and anti-angiogenic action to promote wound healing. To determine how AM might exert anti-inflammation and promote regeneration, we have purified a novel matrix, HC-HA/PTX3, responsible for the efficacy of AM efficacy. HC-HA complex is covalently formed by hyaluronan (HA) and heavy chain 1 (HC1) of inter-α-trypsin inhibitor by the catalytic action of tumor necrosis factor-stimulated gene-6 (TSG-6) and are tightly associated with pentraxin 3 (PTX3) to form HC-HA/PTX3. In vitro reconstitution of the limbal niche can be established by reunion between limbal epithelial progenitors and limbal niche cells on different substrates. In 3-dimensional Matrigel, clonal expansion indicative of SC renewal is correlated with activation of canonical Wnt signaling and suppression of canonical bone morphogenetic protein (BMP) signaling. In contrast, SC quiescence can be achieved in HC-HA/PTX3 by activation of canonical BMP signaling and non-canonical planar cell polarity (PCP) Wnt signaling, but suppression of canonical Wnt signaling. HC-HA/PTX3 is a novel matrix mitigating nonresolving inflammation and restoring SC quiescence in the niche for various applications in regenerative medicine.
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Affiliation(s)
- Scheffer C G Tseng
- R&D Department, TissueTech, Inc., Ocular Surface Center, and Ocular Surface Research and Education Foundation, Miami, Florida, USA.
| | - Hua He
- R&D Department, TissueTech, Inc., Ocular Surface Center, and Ocular Surface Research and Education Foundation, Miami, Florida, USA
| | - Suzhen Zhang
- R&D Department, TissueTech, Inc., Ocular Surface Center, and Ocular Surface Research and Education Foundation, Miami, Florida, USA
| | - Szu-Yu Chen
- R&D Department, TissueTech, Inc., Ocular Surface Center, and Ocular Surface Research and Education Foundation, Miami, Florida, USA
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47
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Gould LJ. Topical Collagen-Based Biomaterials for Chronic Wounds: Rationale and Clinical Application. Adv Wound Care (New Rochelle) 2016; 5:19-31. [PMID: 26858912 DOI: 10.1089/wound.2014.0595] [Citation(s) in RCA: 65] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Significance: The extracellular matrix (ECM) is known to be deficient in chronic wounds. Collagen is the major protein in the ECM. Many claims are made while extolling the virtues of collagen-based biomaterials in promoting cell growth and modulating matrix metalloproteinases. This review will explore the rationale for using topical collagen or ECM as an interface for healing. Recent Advances: Rapid improvements in electrospinning and nanotechnology have resulted in the creation of third-generation biomaterials that mimic the native ECM, stimulate cellular and genetic responses in the target tissue, and provide a platform for controlled release of bioactive molecules and live cells. Although the major focus is currently on development of artificial tissues and organ regeneration, better understanding of the mechanisms that stimulate wound healing can be applied to specific deficits in the chronic wound. Critical Issues: When choosing between the various advanced wound-care products and dressings, the clinician is challenged to select the most appropriate material at the right time. Understanding how the ECM components promote tissue regeneration and modulate the wound microenvironment will facilitate those choices. Laboratory discoveries of biomolecular and cellular strategies that promote skin regeneration rather than repair should be demonstrated to translate to deficits in the chronic wound. Future Directions: Cost-effective production of materials that utilize non-mammalian sources of collagen or ECM components combined with synthetic scaffolding will provide an optimal structure for cellular ingrowth and modulation of the chronic wound microenvironment to facilitate healing. These bioengineered materials will be customizable to provide time-released delivery of bioactive molecules or drugs based on the degradation rate of the scaffold or specific signals from the wound.
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Affiliation(s)
- Lisa J. Gould
- Wound Recovery and Hyperbaric Medicine Center, Kent Hospital, Warwick, Rhode Island
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48
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Han X, Liu H, Chen M, Gong L, Pang H, Deng X, Jin Y. Acellular dermal matrix from one-day-old mouse skin on adult scarless cutaneous wound repair by second harmonic generation microscopic imaging. RSC Adv 2016. [DOI: 10.1039/c6ra11179c] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
The impacts of two types of acellular dermal matrix (ADM), ADM-1D and ADM-20W (ADM from 1-day-old and 20-week-old mouse skin), are evaluated on collagen density, orientation and the stiffness of new born dermis in adult cutaneous wound healing.
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Affiliation(s)
- Xue Han
- MOE Key Laboratory of Laser Life Science
- College of Biophotonics
- South China Normal University
- Guangzhou
- China
| | - Hanping Liu
- MOE Key Laboratory of Laser Life Science
- College of Biophotonics
- South China Normal University
- Guangzhou
- China
| | - Maosheng Chen
- MOE Key Laboratory of Laser Life Science
- College of Biophotonics
- South China Normal University
- Guangzhou
- China
| | - Li Gong
- Instrumental Analysis and Research Center
- Sun Yat-Sen University
- Guangzhou
- China
| | - Hongwen Pang
- Guangzhou Institutes of Biomedicine and Health
- Chinese Academy of Sciences
- Guangzhou
- China
| | - Xiaoyuan Deng
- MOE Key Laboratory of Laser Life Science
- College of Biophotonics
- South China Normal University
- Guangzhou
- China
| | - Ying Jin
- MOE Key Laboratory of Laser Life Science
- College of Biophotonics
- South China Normal University
- Guangzhou
- China
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49
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Schmidt JG, Andersen EW, Ersbøll BK, Nielsen ME. Muscle wound healing in rainbow trout (Oncorhynchus mykiss). FISH & SHELLFISH IMMUNOLOGY 2016; 48:273-284. [PMID: 26702558 DOI: 10.1016/j.fsi.2015.12.010] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/15/2013] [Revised: 11/30/2015] [Accepted: 12/10/2015] [Indexed: 06/05/2023]
Abstract
We followed the progression of healing of deep excisional biopsy punch wounds over the course of 365 days in rainbow trout (Oncorhynchus mykiss) by monitoring visual wound healing and gene expression in the healing muscle at regular intervals (1, 3, 7, 14, 38 and 100 days post-wounding). In addition, we performed muscle texture analysis one year after wound infliction. The selected genes have all previously been investigated in relation to vertebrate wound healing, but only few specifically in fish. The selected genes were interleukin (IL)-1β, IL-6, transforming growth factor (TGF)-β1 and -β3, matrix metalloproteinase (MMP) -9 and -13, inducible nitric oxide synthase (iNOS), fibronectin (FN), tenascin-C (TN-C), prolyl 4-hydroxylase α1-chain (P4Hα1), lysyl oxidase (LOX), collagen type I α1-chain (ColIα1), CD41 and CD163. Wound healing progressed slowly in the presented study, which is at least partially due to the low temperature of about 8.5 °C during the first 100 days. The inflammation phase lasted more than 14 days, and the genes relating to production and remodeling of new extracellular matrix (ECM) exhibited a delayed but prolonged upregulation starting 1-2 weeks post-wounding and lasting until at least 100 days post-wounding. The gene expression patterns and histology reveal limited capacity for muscle regeneration in rainbow trout, and muscle texture analyses one year after wound infliction confirm that wounds heal with fibrosis. At 100 dpw epidermis had fully regenerated, and dermis partially regenerated. Scales had not regenerated even after one year. CD163 is a marker of "wound healing"-type M2c macrophages in mammals. M2 macrophage markers are as yet poorly described in fish. The pattern of CD163 expression in the present study is consistent with the expected timing of presence of M2c macrophages in the wound. CD163 may thus potentially prove a valuable marker of M2 macrophages - or a subset hereof - in fish. We subjected a group of fish to bathing in an immunomodulatory β-glucan product during wound healing, but found this to have very limited effect on wound healing in contrast to a previously published study on common carp.
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Affiliation(s)
- J G Schmidt
- Laboratory of Aquatic Pathobiology, Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Stigbøjlen 7, DK-1970 Frederiksberg, Denmark.
| | - E W Andersen
- Technical University of Denmark, Department of Applied Mathematics and Computer Science, Statistics and Data Analysis, Matematiktorvet, Building 324, DK-2800 Kgs. Lyngby, Denmark
| | - B K Ersbøll
- Technical University of Denmark, Department of Applied Mathematics and Computer Science, Statistics and Data Analysis, Matematiktorvet, Building 324, DK-2800 Kgs. Lyngby, Denmark
| | - M E Nielsen
- Leo Pharma A/S, Industriparken 55, DK-2750 Ballerup, Denmark
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Brant JO, Lopez MC, Baker HV, Barbazuk WB, Maden M. A Comparative Analysis of Gene Expression Profiles during Skin Regeneration in Mus and Acomys. PLoS One 2015; 10:e0142931. [PMID: 26606282 PMCID: PMC4659537 DOI: 10.1371/journal.pone.0142931] [Citation(s) in RCA: 63] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2015] [Accepted: 10/28/2015] [Indexed: 12/29/2022] Open
Abstract
The African spiny mouse (Acomys spp.) can heal full thickness excisional skin wounds in a scar-free manner with regeneration of all dermal components including hair and associated structures. Comparing Acomys scar-free healing from Mus scarring identifies gene expression differences that discriminate these processes. We have performed an extensive comparison of gene expression profiles in response to 8mm full-thickness excisional wounds at days 3, 5, 7 and 14 post-wounding between Acomys and Mus to characterize differences in wound healing, and identify mechanisms involved in scar-free healing. We also identify similarities with scar-free healing observed in fetal wounds. While wounding in Mus elicits a strong inflammatory response, wounding in Acomys produces a moderated immune response and little to no increase in expression for most cytokines and chemokines assayed. We also identified differences in the ECM profiles of the Acomys wounds, which appear to have a collagen profile more similar to fetal wounds, with larger increases in expression of collagen types III and V. In contrast, Mus wounds have very high levels of collagen XII. This data suggests that an overall lack of induction of cytokines and chemokines, coupled with an ECM profile more similar to fetal wounds, may underlie scar-free wound healing in Acomys skin. These data identify candidate genes for further testing in order to elucidate the causal mechanisms of scar-free healing.
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Affiliation(s)
- Jason Orr Brant
- Department of Biology, University of Florida, Gainesville, Florida, United States of America
- UF Genetics Institute, University of Florida, Gainesville, Florida, United States of America
- * E-mail:
| | - Maria-Cecilia Lopez
- UF Genetics Institute, University of Florida, Gainesville, Florida, United States of America
- Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida, United States of America
| | - Henry V. Baker
- UF Genetics Institute, University of Florida, Gainesville, Florida, United States of America
- Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida, United States of America
| | - W. Brad Barbazuk
- Department of Biology, University of Florida, Gainesville, Florida, United States of America
- UF Genetics Institute, University of Florida, Gainesville, Florida, United States of America
| | - Malcolm Maden
- Department of Biology, University of Florida, Gainesville, Florida, United States of America
- UF Genetics Institute, University of Florida, Gainesville, Florida, United States of America
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