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Han J, Li GC, Fang SY, Cui YM, Yang HH. Dermal Fibroblast-Derived Exosomes Promotes Bone-to-Tendon Interface Healing of Chronic Rotator Cuff Tear in Rabbit Model. Arthroscopy 2025:S0749-8063(25)00061-1. [PMID: 39914613 DOI: 10.1016/j.arthro.2025.01.043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Revised: 01/05/2025] [Accepted: 01/19/2025] [Indexed: 03/04/2025]
Abstract
PURPOSE To investigate the efficacy of exosomes derived from dermal fibroblasts (DF-Ex) on bone-to-tendon interface (BTI) healing in a chronic rotator cuff tear (RCT) model of rabbit. METHODS After extraction of DF-Ex, the characterization of DF-Ex was identified in the in vitro study. In the in vivo experiment, 48 rabbits were randomly allocated into 3 groups. To create chronic RCT models, transected tendons were left untreated for 6 weeks and then were repaired in a transosseous manner. Different materials were injected into repair site according to the allocated group (group A: saline, group B: fibrin glue only, group C: DF-Ex with fibrin glue; n = 16 for each). Genetic and immunofluorescence analyses were conducted at 4 weeks post-surgery. Furthermore, genetic, histologic, and biomechanical analyses were conducted at 12 weeks post-surgery. RESULTS In vitro analyses revealed the exosomal marker proteins CD9, CD63, and ALIX were positively expressed in DF-Ex, whereas negative control Calnexin was nearly absent. In vivo analyses showed that group C had the highest mRNA expression levels of COL1A1, COL3A1, and ACAN among all groups (P < .001, P = .007, and P = .002, respectively) at 4 weeks postsurgery. Meanwhile, there were more preliminary fibrocartilaginous matrix (aggrecan+/collagen II+) formation in group C. At 12 weeks postsurgery, group C had better collagen fiber continuity and orientation, denser collagen fibers, more mature bone-to-tendon junction, and greater fibrocartilage layer formation compared with the other groups (all P < .05). Moreover, group C also had greater load-to-failure value (53.3 ± 6.1 N/kg, P < .001). CONCLUSIONS Topical DF-Ex administration effectively promoted BTI healing by upregulating the COL1A1, COL3A1, and ACAN mRNA expression levels at an early stage and enhancing the structural and biomechanical properties at 12 weeks after surgical repair of a chronic RCT model of rabbit. CLINICAL RELEVANCE The study could be a transitional study to investigate the efficacy of DF-Ex on BTI healing for surgical repair of chronic RCTs as a powerful biological agent in humans.
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Affiliation(s)
- Jian Han
- Department of Orthopaedic Surgery, The First People's Hospital of Huzhou, First Affiliated Hospital of Huzhou University, Huzhou, Zhejiang, China
| | - Guan-Cong Li
- Department of Orthopaedic Surgery, The First People's Hospital of Huzhou, First Affiliated Hospital of Huzhou University, Huzhou, Zhejiang, China
| | - Shen-Yun Fang
- Department of Orthopaedic Surgery, The First People's Hospital of Huzhou, First Affiliated Hospital of Huzhou University, Huzhou, Zhejiang, China
| | - Yun-Mei Cui
- Department of Pediatrics, The First People's Hospital of Huzhou, First Affiliated Hospital of Huzhou University, Huzhou, Zhejiang, China
| | - Hong-Hang Yang
- Department of Orthopaedic Surgery, The First People's Hospital of Huzhou, First Affiliated Hospital of Huzhou University, Huzhou, Zhejiang, China.
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Razavi ZS, Aliniay Sharafshadehi S, Yousefi MH, Javaheri F, Rahimi Barghani MR, Afkhami H, Heidari F. Application of novel strategies in chronic wound management with focusing on pressure ulcers: new perspective. Arch Dermatol Res 2025; 317:320. [PMID: 39888392 DOI: 10.1007/s00403-024-03790-8] [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: 11/10/2024] [Revised: 12/27/2024] [Accepted: 12/29/2024] [Indexed: 02/01/2025]
Abstract
Invading blood cells, extracellular tissue, and soluble mediators all play important roles in the wound-healing process. There is a substantial global burden of disease and mortality attributable to skin defects that do not heal. About 1% to 2% of the population in industrialized nations suffers from chronic wounds that don't heal, despite healthcare breakthroughs; this condition is very costly, costing about $25 billion each year in the US alone. Amputation, infection (affecting as many as 25% of chronic wounds), sepsis, and dermal replacements are all consequences of conventional therapeutic approaches like growth factor therapy and diabetic foot ulcers account for 85% of lower limb amputations. Despite these obstacles, scientists are constantly looking for new ways to speed healing and close wounds. The unique immunomodulatory capabilities and multipotency of mesenchymal stem cells (MSCs) have made them a potential therapeutic choice in tissue engineering and regenerative medicine. Animal models of wound healing have shown that MSCs can speed up the process by as much as 40% through enhancing angiogenesis, modulating inflammation, and promoting fibroblast migration. Clinical trials provide more evidence of their effectiveness; for instance, one RCT found that, after 12 weeks, patients treated with MSCs had a 72% smaller wound size than those in the control group. This review offers a thorough examination of MSCs by combining the latest research with preclinical evidence. Highlighting their potential to transform treatment paradigms, it delves into their biological properties, how they work during regeneration and healing, and therapeutic usefulness in controlling chronic wounds.
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Affiliation(s)
- Zahra Sadat Razavi
- Physiology Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Shahrzad Aliniay Sharafshadehi
- Department of Microbiology, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mohammad Hasan Yousefi
- Department of Tissue Engineering and Applied Cell Sciences, School of Medicine, Qom University of Medical Sciences, Qom, Iran
- Cellular and Molecular Research Center, Qom University of Medical Sciences, Qom, Iran
| | - Fatemeh Javaheri
- Cellular and Molecular Research Center, Qom University of Medical Sciences, Qom, Iran
| | | | - Hamed Afkhami
- Cellular and Molecular Research Center, Qom University of Medical Sciences, Qom, Iran.
- Nervous System Stem Cells Research Center, Semnan University of Medical Sciences, Semnan, Iran.
- Department of Medical Microbiology, Faculty of Medicine, Shahed University, Tehran, Iran.
| | - Fatemeh Heidari
- Cellular and Molecular Research Center, Qom University of Medical Sciences, Qom, Iran.
- Department of Anatomy, Faculty of Medicine, Qom University of Medical Sciences, Qom, Iran.
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Carrillo-Gálvez AB, Zurita F, Guerra-Valverde JA, Aguilar-González A, Abril-García D, Padial-Molina M, Olaechea A, Martín-Morales N, Martín F, O’Valle F, Galindo-Moreno P. NLRP3 and AIM2 inflammasomes expression is modified by LPS and titanium ions increasing the release of active IL-1β in alveolar bone-derived MSCs. Stem Cells Transl Med 2024; 13:826-841. [PMID: 39013640 PMCID: PMC11328940 DOI: 10.1093/stcltm/szae042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2023] [Accepted: 05/19/2024] [Indexed: 07/18/2024] Open
Abstract
Periodontitis and peri-implantitis are inflammatory diseases of infectious etiology that lead to the destruction of the supporting tissues located around teeth or implants. Although both pathologies share several characteristics, it is also known that they show important differences which could be due to the release of particles and metal ions from the implant surface. The activation of the inflammasome pathway is one of the main triggers of the inflammatory process. The inflammatory process in patients who suffer periodontitis or peri-implantitis has been mainly studied on cells of the immune system; however, it is also important to consider other cell types with high relevance in the regulation of the inflammatory response. In that context, mesenchymal stromal cells (MSCs) play an essential role in the regulation of inflammation due to their ability to modulate the immune response. This study shows that the induction of NLRP3 and absent in melanoma 2 (AIM2) inflammasome pathways mediated by bacterial components increases the secretion of active IL-1β and the pyroptotic process on human alveolar bone-derived mesenchymal stromal cells (hABSCs). Interestingly, when bacterial components are combined with titanium ions, NLRP3 expression is further increased while AIM2 expression is reduced. Furthermore, decrease of NLRP3 or AIM2 expression in hABSCs partially reverses the negative effect observed on the progression of the inflammatory process as well as on cell survival. In summary, our data suggest that the progression of the inflammatory process in peri-implantitis could be more acute due to the combined action of organic and inorganic components.
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Affiliation(s)
- Ana Belén Carrillo-Gálvez
- Department of Oral Surgery and Implant Dentistry, School of Dentistry, University of Granada, 18071 Granada, Spain
- Instituto de Investigación Biosanitaria (IBS) de Granada, 18012 Granada, Spain
| | - Federico Zurita
- Department of Genetics and Institute of Biotechnology, University of Granada, 18071 Granada, Spain
| | - José Antonio Guerra-Valverde
- Instituto de Investigación Biosanitaria (IBS) de Granada, 18012 Granada, Spain
- PhD Program in Clinical Medicine and Public Health, University of Granada,18071 Granada, Spain
| | - Araceli Aguilar-González
- Instituto de Investigación Biosanitaria (IBS) de Granada, 18012 Granada, Spain
- GENYO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government PTS Granada, 18016 Granada, Spain
- Department of Medicinal and Organic Chemistry and Excellence Research Unit of Chemistry Applied to Bio-Medicine and the Environment, Faculty of Pharmacy, University of Granada, 18071 Granada, Spain
| | - Darío Abril-García
- Department of Oral Surgery and Implant Dentistry, School of Dentistry, University of Granada, 18071 Granada, Spain
- Instituto de Investigación Biosanitaria (IBS) de Granada, 18012 Granada, Spain
| | - Miguel Padial-Molina
- Department of Oral Surgery and Implant Dentistry, School of Dentistry, University of Granada, 18071 Granada, Spain
- Instituto de Investigación Biosanitaria (IBS) de Granada, 18012 Granada, Spain
| | - Allinson Olaechea
- Department of Oral Surgery and Implant Dentistry, School of Dentistry, University of Granada, 18071 Granada, Spain
- Instituto de Investigación Biosanitaria (IBS) de Granada, 18012 Granada, Spain
- PhD Program in Clinical Medicine and Public Health, University of Granada,18071 Granada, Spain
- GENYO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government PTS Granada, 18016 Granada, Spain
| | - Natividad Martín-Morales
- Department of Oral Surgery and Implant Dentistry, School of Dentistry, University of Granada, 18071 Granada, Spain
- Instituto de Investigación Biosanitaria (IBS) de Granada, 18012 Granada, Spain
- PhD Program in Biomedicine, University of Granada, 18071 Granada, Spain
- Department of Pathology, School of Medicine, University of Granada, 18071 Granada, Spain
| | - Francisco Martín
- Instituto de Investigación Biosanitaria (IBS) de Granada, 18012 Granada, Spain
- GENYO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government PTS Granada, 18016 Granada, Spain
- Department of Biochemistry and Molecular Biology III and Immunology, Faculty of Medicine, University of Granada, 18071 Granada, Spain
- Excellence Research Unit “Modeling Nature” (MNat), University of Granada, 18071 Granada, Spain
| | - Francisco O’Valle
- Instituto de Investigación Biosanitaria (IBS) de Granada, 18012 Granada, Spain
- Department of Pathology, School of Medicine, University of Granada, 18071 Granada, Spain
- Institute of Biopathology and Regenerative Medicine (IBIMER, CIBM), University of Granada, 18071 Granada, Spain
| | - Pablo Galindo-Moreno
- Department of Oral Surgery and Implant Dentistry, School of Dentistry, University of Granada, 18071 Granada, Spain
- Instituto de Investigación Biosanitaria (IBS) de Granada, 18012 Granada, Spain
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Grosu-Bularda A, Hodea FV, Cretu A, Lita FF, Bordeanu-Diaconescu EM, Vancea CV, Lascar I, Popescu SA. Reconstructive Paradigms: A Problem-Solving Approach in Complex Tissue Defects. J Clin Med 2024; 13:1728. [PMID: 38541953 PMCID: PMC10971357 DOI: 10.3390/jcm13061728] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Revised: 03/01/2024] [Accepted: 03/14/2024] [Indexed: 01/06/2025] Open
Abstract
The field of plastic surgery is continuously evolving, with faster-emerging technologies and therapeutic approaches, leading to the necessity of establishing novel protocols and solving models. Surgical decision-making in reconstructive surgery is significantly impacted by various factors, including the etiopathology of the defect, the need to restore form and function, the patient's characteristics, compliance and expectations, and the surgeon's expertise. A broad surgical armamentarium is currently available, comprising well-established surgical procedures, as well as emerging techniques and technologies. Reconstructive surgery paradigms guide therapeutic strategies in order to reduce morbidity, mortality and risks while maximizing safety, patient satisfaction and properly restoring form and function. The paradigms provide researchers with formulation and solving models for each unique problem, assembling complex entities composed of theoretical, practical, methodological and instrumental elements.
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Affiliation(s)
- Andreea Grosu-Bularda
- “Carol Davila” University of Medicine and Pharmacy Bucharest, 050474 București, Romania; (A.G.-B.); (I.L.); (S.A.P.)
- Clinic of Plastic Surgery and Reconstructive Microsurgery, Clinical Emergency Hospital Bucharest, 011602 București, Romania
| | - Florin-Vlad Hodea
- “Carol Davila” University of Medicine and Pharmacy Bucharest, 050474 București, Romania; (A.G.-B.); (I.L.); (S.A.P.)
- Clinic of Plastic Surgery and Reconstructive Microsurgery, Clinical Emergency Hospital Bucharest, 011602 București, Romania
| | - Andrei Cretu
- Clinic of Plastic Surgery and Reconstructive Microsurgery, Clinical Emergency Hospital Bucharest, 011602 București, Romania
| | - Flavia-Francesca Lita
- Clinic of Plastic Surgery and Reconstructive Microsurgery, Clinical Emergency Hospital Bucharest, 011602 București, Romania
- Clinic of Plastic Surgery and Reconstructive Microsurgery, Central Military Universitary Emergency Hospital “Carol Davila”, 010825 București, Romania
| | | | - Cristian-Vladimir Vancea
- Clinic of Plastic Surgery and Reconstructive Microsurgery, Clinical Emergency Hospital Bucharest, 011602 București, Romania
| | - Ioan Lascar
- “Carol Davila” University of Medicine and Pharmacy Bucharest, 050474 București, Romania; (A.G.-B.); (I.L.); (S.A.P.)
- Clinic of Plastic Surgery and Reconstructive Microsurgery, Clinical Emergency Hospital Bucharest, 011602 București, Romania
| | - Serban Arghir Popescu
- “Carol Davila” University of Medicine and Pharmacy Bucharest, 050474 București, Romania; (A.G.-B.); (I.L.); (S.A.P.)
- Clinic of Plastic Surgery and Reconstructive Microsurgery, Clinical Emergency Hospital Bucharest, 011602 București, Romania
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Cehakova M, Ivanisova D, Strecanska M, Plava J, Varchulova Novakova Z, Nicodemou A, Harsanyi S, Culenova M, Bernatova S, Danisovic L. Rheumatoid Synovial Fluid and Acidic Extracellular pH Modulate the Immunomodulatory Activity of Urine-Derived Stem Cells. Int J Mol Sci 2023; 24:15856. [PMID: 37958839 PMCID: PMC10648750 DOI: 10.3390/ijms242115856] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Revised: 10/28/2023] [Accepted: 10/30/2023] [Indexed: 11/15/2023] Open
Abstract
Urine-derived stem cells (UdSCs) possess a remarkable anti-inflammatory and immune-modulating activity. However, the clinical significance of UdSCs in autoimmune inflammatory diseases such as rheumatoid arthritis (RA) is yet to be explored. Hence, we tested the UdSCs response to an articular RA microenvironment. To simulate the inflamed RA joint more authentically in vitro, we treated cells with rheumatoid synovial fluids (RASFs) collected from RA patients, serum deprivation, acidosis (pH 7.0 and 6.5), and their combinations. Firstly, the RASFs pro-inflammatory status was assessed by cytokine quantification. Then, UdSCs were exposed to the RA environmental factors for 48 h and cell proliferation, gene expression and secretion of immunomodulatory factors were evaluated. The immunosuppressive potential of pre-conditioned UdSCs was also assessed via co-cultivation with activated peripheral blood mononuclear cells (PBMCs). In all experimental conditions, UdSCs' proliferation was not affected. Conversely, extracellular acidosis considerably impaired the viability/proliferation of adipose tissue-derived stem cells (ATSCs). In the majority of cases, exposure to RA components led to the upregulated expression of IL-6, TSG6, ICAM-1, VCAM-1, and PD-L1, all involved in immunomodulation. Upon RASFs and acidic stimulation, UdSCs secreted higher levels of immunomodulatory cytokines: IL-6, IL-8, MCP-1, RANTES, GM-CSF, and IL-4. Furthermore, RASFs and combined pretreatment with RASFs and acidosis promoted the UdSCs-mediated immunosuppression and the proliferation of activated PBMCs was significantly inhibited. Altogether, our data indicate that the RA microenvironment certainly has the capacity to enhance UdSCs' immunomodulatory function. For potential preclinical/clinical applications, the intra-articular injection might be a reasonable approach to maximize UdSCs' therapeutic efficiency in the RA treatment.
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Affiliation(s)
- Michaela Cehakova
- National Institute of Rheumatic Diseases, Nabrezie I. Krasku 4, 921 12 Piestany, Slovakia; (M.S.); (Z.V.N.); (A.N.); (S.H.); (M.C.); (L.D.)
- Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University Bratislava, Sasinkova 4, 811 08 Bratislava, Slovakia; (D.I.); (J.P.); (S.B.)
| | - Dana Ivanisova
- Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University Bratislava, Sasinkova 4, 811 08 Bratislava, Slovakia; (D.I.); (J.P.); (S.B.)
| | - Magdalena Strecanska
- National Institute of Rheumatic Diseases, Nabrezie I. Krasku 4, 921 12 Piestany, Slovakia; (M.S.); (Z.V.N.); (A.N.); (S.H.); (M.C.); (L.D.)
- Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University Bratislava, Sasinkova 4, 811 08 Bratislava, Slovakia; (D.I.); (J.P.); (S.B.)
| | - Jana Plava
- Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University Bratislava, Sasinkova 4, 811 08 Bratislava, Slovakia; (D.I.); (J.P.); (S.B.)
- Biomedical Research Center of the Slovak Academy of Sciences, Dubravska Cesta 9, 845 05 Bratislava, Slovakia
| | - Zuzana Varchulova Novakova
- National Institute of Rheumatic Diseases, Nabrezie I. Krasku 4, 921 12 Piestany, Slovakia; (M.S.); (Z.V.N.); (A.N.); (S.H.); (M.C.); (L.D.)
- Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University Bratislava, Sasinkova 4, 811 08 Bratislava, Slovakia; (D.I.); (J.P.); (S.B.)
| | - Andreas Nicodemou
- National Institute of Rheumatic Diseases, Nabrezie I. Krasku 4, 921 12 Piestany, Slovakia; (M.S.); (Z.V.N.); (A.N.); (S.H.); (M.C.); (L.D.)
- Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University Bratislava, Sasinkova 4, 811 08 Bratislava, Slovakia; (D.I.); (J.P.); (S.B.)
| | - Stefan Harsanyi
- National Institute of Rheumatic Diseases, Nabrezie I. Krasku 4, 921 12 Piestany, Slovakia; (M.S.); (Z.V.N.); (A.N.); (S.H.); (M.C.); (L.D.)
- Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University Bratislava, Sasinkova 4, 811 08 Bratislava, Slovakia; (D.I.); (J.P.); (S.B.)
| | - Martina Culenova
- National Institute of Rheumatic Diseases, Nabrezie I. Krasku 4, 921 12 Piestany, Slovakia; (M.S.); (Z.V.N.); (A.N.); (S.H.); (M.C.); (L.D.)
- Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University Bratislava, Sasinkova 4, 811 08 Bratislava, Slovakia; (D.I.); (J.P.); (S.B.)
| | - Sona Bernatova
- Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University Bratislava, Sasinkova 4, 811 08 Bratislava, Slovakia; (D.I.); (J.P.); (S.B.)
| | - Lubos Danisovic
- National Institute of Rheumatic Diseases, Nabrezie I. Krasku 4, 921 12 Piestany, Slovakia; (M.S.); (Z.V.N.); (A.N.); (S.H.); (M.C.); (L.D.)
- Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University Bratislava, Sasinkova 4, 811 08 Bratislava, Slovakia; (D.I.); (J.P.); (S.B.)
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Mohammadi TC, Jazi K, Bolouriyan A, Soleymanitabar A. Stem cells in treatment of crohn's disease: Recent advances and future directions. Transpl Immunol 2023; 80:101903. [PMID: 37541629 DOI: 10.1016/j.trim.2023.101903] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Revised: 07/11/2023] [Accepted: 07/22/2023] [Indexed: 08/06/2023]
Abstract
BACKGROUND AND AIM Crohn's disease (CD) is an inflammatory bowel disease that can affect any part of the intestine. There is currently no recognized cure for CD because its cause is unknown. One of the modern approaches that have been suggested for the treatment of CD and other inflammatory-based disorders is cell therapy. METHODS Search terms were stem cell therapy, CD, adipose-derived stem cells, mesenchymal stem cells, and fistula. Of 302 related studies, we removed duplicate and irrelevant papers and identified the ones with proper information related to our scope of the research by reviewing all the abstracts and categorizing each study into the proper section. RESULTS AND CONCLUSION Nowadays, stem cell therapy is widely implied in treating CD. Although mesenchymal and adipose-derived tissue stem cells proved to be safe in treating Crohn's-associated fistula, there are still debates on an optimal protocol to use. Additionally, there is still a lack of evidence on the efficacy of stem cell therapy for intestinal involvement of CD. Future investigations should focus on preparing a standard protocol as well as luminal stem cell therapy in patients.
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Affiliation(s)
| | - Kimia Jazi
- Student Research Committee, Faculty of Medicine, Medical University of Qom, Qom, Iran
| | - Alireza Bolouriyan
- Student Research Committee, Baqiyatallah University of Medical Sciences, Tehran, Iran
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Obesity and Wound Healing: Focus on Mesenchymal Stem Cells. Life (Basel) 2023; 13:life13030717. [PMID: 36983872 PMCID: PMC10059997 DOI: 10.3390/life13030717] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Revised: 02/20/2023] [Accepted: 03/03/2023] [Indexed: 03/09/2023] Open
Abstract
Chronic wounds represent nowadays a major challenge for both clinicians and researchers in the regenerative setting. Obesity represents one of the major comorbidities in patients affected by chronic ulcers and therefore diverse studies aimed at assessing possible links between these two morbid conditions are currently ongoing. In particular, adipose tissue has recently been described as having metabolic and endocrine functions rather than serving as a mere fat storage deposit. In this setting, adipose-derived stem cells, a peculiar subset of mesenchymal stromal/stem cells (MSCs) located in adipose tissue, have been demonstrated to possess regenerative and immunological functions with a key role in regulating both adipocyte function and skin regeneration. The aim of the present review is to give an overview of the most recent findings on wound healing, with a special focus on adipose tissue biology and obesity.
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Akasaka Y. The Role of Mesenchymal Stromal Cells in Tissue Repair and Fibrosis. Adv Wound Care (New Rochelle) 2022; 11:561-574. [PMID: 34841889 DOI: 10.1089/wound.2021.0037] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
Significance: The present review covers an overview of the current understanding of biology of mesenchymal stromal cells (MSCs) and suggests an important role of their differential potential for clinical approaches associated with tissue repair and fibrosis. Recent Advances: Genetic lineage tracing technology has enabled the delineation of cellular hierarchies and examination of MSC cellular origins and myofibroblast sources. This technique has led to the characterization of perivascular MSC populations and suggests that pericytes might provide a local source of tissue-specific MSCs, which can differentiate into tissue-specific cells for tissue repair and fibrosis. Autologous adipose tissue MSCs led to the advance in tissue engineering for regeneration of damaged tissues. Critical Issues: Recent investigation has revealed that perivascular MSCs might be the origin of myofibroblasts during fibrosis development, and perivascular MSCs might be the major source of myofibroblasts in fibrogenic disease. Adipose tissue MSCs combined with cytokines and biomaterials are available in the treatment of soft tissue defect and skin wound healing. Future Directions: Further investigation of the roles of perivascular MSCs may enable new approaches in the treatment of fibrogenic disease; moreover, perivascular MSCs might have potential as an antifibrotic target for fibrogenic disease. Autologous adipose tissue MSCs combined with cytokines and biomaterials will be an alternative method for the treatment of soft tissue defect and skin wound healing.
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Affiliation(s)
- Yoshikiyo Akasaka
- Division of Research Promotion and Development, Advanced Research Center, Toho University Graduate School of Medicine, Ota-ku, Japan.,Department of Pathology, Toho University School of Medicine, Ota-ku, Japan
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Trébol J, Georgiev-Hristov T, Pascual-Miguelañez I, Guadalajara H, García-Arranz M, García-Olmo D. Stem cell therapy applied for digestive anastomosis: Current state and future perspectives. World J Stem Cells 2022; 14:117-141. [PMID: 35126832 PMCID: PMC8788180 DOI: 10.4252/wjsc.v14.i1.117] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 06/21/2021] [Accepted: 12/31/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Digestive tract resections are usually followed by an anastomosis. Anastomotic leakage, normally due to failed healing, is the most feared complication in digestive surgery because it is associated with high morbidity and mortality. Despite technical and technological advances and focused research, its rates have remained almost unchanged the last decades. In the last two decades, stem cells (SCs) have been shown to enhance healing in animal and human studies; hence, SCs have emerged since 2008 as an alternative to improve anastomoses outcomes.
AIM To summarise the published knowledge of SC utilisation as a preventative tool for hollow digestive viscera anastomotic or suture leaks.
METHODS PubMed, Science Direct, Scopus and Cochrane searches were performed using the key words “anastomosis”, “colorectal/colonic anastomoses”, “anastomotic leak”, “stem cells”, “progenitor cells”, “cellular therapy” and “cell therapy” in order to identify relevant articles published in English and Spanish during the years of 2000 to 2021. Studies employing SCs, performing digestive anastomoses in hollow viscera or digestive perforation sutures and monitoring healing were finally included. Reference lists from the selected articles were reviewed to identify additional pertinent articles.
Given the great variability in the study designs, anastomotic models, interventions (SCs, doses and vehicles) and outcome measures, performing a reliable meta-analysis was considered impossible, so we present the studies, their results and limitations.
RESULTS Eighteen preclinical studies and three review papers were identified; no clinical studies have been published and there are no registered clinical trials. Experimental studies, mainly in rat and porcine models and occasionally in very adverse conditions such as ischaemia or colitis, have been demonstrated SCs as safe and have shown some encouraging morphological, functional and even clinical results. Mesenchymal SCs are mostly employed, and delivery routes are mainly local injections and cell sheets followed by biosutures (sutures coated by SCs) or purely topical. As potential weaknesses, animal models need to be improved to make them more comparable and equivalent to clinical practice, and the SC isolation processes need to be standardised. There is notable heterogeneity in the studies, making them difficult to compare. Further investigations are needed to establish the indications, the administration system, potential adjuvants, the final efficacy and to confirm safety and exclude definitively oncological concerns.
CONCLUSION The future role of SC therapy to induce healing processes in digestive anastomoses/sutures still needs to be determined and seems to be currently far from clinical use.
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Affiliation(s)
- Jacobo Trébol
- Servicio de Cirugía General y del Aparato Digestivo, Complejo Asistencial Universitario de Salamanca, Salamanca 37007, Spain
- Departamento de Anatomía e Histología Humanas, Universidad de Salamanca, Salamanca 37007, Spain
| | - Tihomir Georgiev-Hristov
- Servicio de Cirugía General y del Aparato Digestivo, Hospital General Universitario de Villalba, Madrid 28400, Spain
| | - Isabel Pascual-Miguelañez
- Servicio de Cirugía General y del Aparato Digestivo, Hospital Universitario La Paz, Madrid 28046, Spain
| | - Hector Guadalajara
- Servicio de Cirugía General y del Aparato Digestivo, Hospital Universitario Fundación Jiménez Díaz, Madrid 28040, Spain
| | - Mariano García-Arranz
- Grupo de Investigación en Nuevas Terapias, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz, Madrid 28040, Spain
- Departamento de Cirugía, Universidad Autónoma de Madrid, Madrid 28029, Spain
| | - Damian García-Olmo
- Departamento de Cirugía, Universidad Autónoma de Madrid, Madrid 28029, Spain
- Servicio de Cirugía General y del Aparato Digestivo, Hospital Universitario Fundación Jiménez Díaz y Grupo Quiron-Salud Madrid, Madrid 28040, Spain
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10
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Nazari H, Naei VY, Tabasi AH, Badripour A, Akbari Asbagh R, Keramati MR, Sharifi A, Behboudi B, Kazemeini A, Abbasi M, Keshvari A, Ahmadi Tafti SM. Advanced Regenerative Medicine Strategies for Treatment of Perianal Fistula in Crohn's Disease. Inflamm Bowel Dis 2022; 28:133-142. [PMID: 34291798 DOI: 10.1093/ibd/izab151] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Indexed: 12/15/2022]
Abstract
Regenerative medicine is an emerging therapeutic method that aims to reconstruct tissues and organs. This advanced therapeutic approach has demonstrated great potential in addressing the limitations of medical and surgical procedures for treating perineal fistula in patients with Crohn's disease. Recent developments in stem cell technology have led to a massive good manufacturing practices (GMPs) production of various stem cells, including mesenchymal and embryonic cells, along with induction of pluripotent stem cells to repair damaged tissues in the fistula. The recent advances in separation and purification of exosomes, as biologic nanovesicles carrying anti-inflammatory and regenerative agents, have made them powerful tools to treat this inflammatory disease. Further, tremendous advances in nanotechnology, biomaterials, and scaffold fabrication methods enable tissue engineering methods to synthesize tissue-like structures to assist surgical techniques. This review focuses on advanced regenerative-based methods including stem cell therapy, exosome therapy, and tissue engineering used in the treatment of perianal fistula. Relevant in vitro and in vivo studies and the latest innovations in implementation of regenerative medicine for this disease are also separately reviewed. Additionally, current challenges regarding implementation of g stem cells, exosomes, and tissue engineering methods for bridging the gaps between laboratory findings and clinic application will be discussed.
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Affiliation(s)
- Hojjatollah Nazari
- Division of Colorectal Surgery, Department of Surgery, Tehran University of Medical Sciences, Tehran, Iran.,Colorectal Surgery Research Center, Imam Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran.,Research Center for Advanced Technologies in Cardiovascular Medicine, Tehran Heart Center Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Vahid Yaghoubi Naei
- Division of Colorectal Surgery, Department of Surgery, Tehran University of Medical Sciences, Tehran, Iran.,Colorectal Surgery Research Center, Imam Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
| | - Asieh Heirani Tabasi
- Division of Colorectal Surgery, Department of Surgery, Tehran University of Medical Sciences, Tehran, Iran.,Colorectal Surgery Research Center, Imam Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran.,Department of Cell Therapy and Hematology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Abolfazl Badripour
- Division of Colorectal Surgery, Department of Surgery, Tehran University of Medical Sciences, Tehran, Iran.,Colorectal Surgery Research Center, Imam Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
| | - Reza Akbari Asbagh
- Division of Colorectal Surgery, Department of Surgery, Tehran University of Medical Sciences, Tehran, Iran.,Colorectal Surgery Research Center, Imam Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Keramati
- Division of Colorectal Surgery, Department of Surgery, Tehran University of Medical Sciences, Tehran, Iran.,Colorectal Surgery Research Center, Imam Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
| | - Amirsina Sharifi
- Division of Colorectal Surgery, Department of Surgery, Tehran University of Medical Sciences, Tehran, Iran.,Colorectal Surgery Research Center, Imam Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
| | - Behnam Behboudi
- Division of Colorectal Surgery, Department of Surgery, Tehran University of Medical Sciences, Tehran, Iran.,Colorectal Surgery Research Center, Imam Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
| | - Alireza Kazemeini
- Division of Colorectal Surgery, Department of Surgery, Tehran University of Medical Sciences, Tehran, Iran.,Colorectal Surgery Research Center, Imam Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Amir Keshvari
- Division of Colorectal Surgery, Department of Surgery, Tehran University of Medical Sciences, Tehran, Iran.,Colorectal Surgery Research Center, Imam Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
| | - Seyed Mohsen Ahmadi Tafti
- Division of Colorectal Surgery, Department of Surgery, Tehran University of Medical Sciences, Tehran, Iran.,Colorectal Surgery Research Center, Imam Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
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11
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Debreova M, Culenova M, Smolinska V, Nicodemou A, Csobonyeiova M, Danisovic L. Rheumatoid arthritis: From synovium biology to cell-based therapy. Cytotherapy 2022; 24:365-375. [DOI: 10.1016/j.jcyt.2021.10.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 08/23/2021] [Accepted: 10/14/2021] [Indexed: 12/18/2022]
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12
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Erythropoietin improves effects of mesenchymal stem cells in an experimental model of sepsis. КЛИНИЧЕСКАЯ ПРАКТИКА 2021. [DOI: 10.17816/clinpract83687] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
In the last years several studies have shown that mesenchymal stem cells (MSCs) are able to reduce the systemic inflammatory response and mortality in experimental models of sepsis. As recently found, the surface of MSCs have receptors for erythropoietin (EPO). So we hypothesized that the introduction of EPO together with MSCs may enhance their effect and improve the results of sepsis treatment.
Aim: То evaluate morphologic and immunologic effects of combined treatment with EPO and MSC in an experimental LPS sepsis model in rats.
Methods: 50 Wistar rats were randomized into 5 groups: Group 1 - the healthy controls, Groups 2-5 were intraperitoneally introduced bacterial LPS 20 mg/kg. Two hours after LPS injection animals received the following intravenous treatments: Group 3 - 4xl05 allogeneic MSCs, Group 4 - 8.5 pg of recombinant EPO-beta, Group 5 - MSCs and EPO in the same doses. Surviving animals were euthanased on the 4th day. The morphological study of the liver, spleen, thymus, lungs, kidney tissues was performed. We analyzed the tissue changes, white blood cells count and serum level of IL-l, IL-2, IL-6, TNF-.
Results: Mortality in LPS groups did not differ. The highest white blood cells count was found in the group of combined treatment EPO+MSCs (8.15x106 cells/ml) compared with controls (2,15x10s cells/ml) and LPS controls (6,52x10s cells/ml). There were no differences in levels of TNF-, IL-2 and IL-6 between the groups, but serum IL-1 level in groups 2 and 4 was significantly higher than in treated with MSCs and MSCc + EPO animals. Histologically in the group 5 we observed significantly less leukocyte lung interalveolar septal infiltration and kidney tubular dystrophy. The most significant differences in group LPS + EPO were found in the lymphoid tissue - considerable hyperplasia of spleen white pulp and thymus cortex, whereas in the other groups different degrees of atrophy of the corresponding zones were noted.
Conclusions: Combined treatment with EPO and MSCs can reduce acute lung injury and kidney damage, cause hyperplasia of lymphoid tissue and enhance the immune response more than separate treatment in an experimental model of sepsis in rats.
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13
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Sánchez N, Fierravanti L, Núñez J, Vignoletti F, González-Zamora M, Santamaría S, Suárez-Sancho S, Fernández-Santos ME, Figuero E, Herrera D, García-Sanz JA, Sanz M. Periodontal regeneration using a xenogeneic bone substitute seeded with autologous periodontal ligament-derived mesenchymal stem cells: A 12-month quasi-randomized controlled pilot clinical trial. J Clin Periodontol 2021; 47:1391-1402. [PMID: 32946590 DOI: 10.1111/jcpe.13368] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Revised: 08/25/2020] [Accepted: 09/05/2020] [Indexed: 12/20/2022]
Abstract
AIM To evaluate the safety and efficacy of autologous periodontal ligament-derived mesenchymal stem cells (PDL-MSCs) embedded in a xenogeneic bone substitute (XBS) for the regenerative treatment of intra-bony periodontal defects. MATERIAL AND METHODS This quasi-randomized controlled pilot phase II clinical trial included patients requiring a tooth extraction and presence of one intra-bony lesion (1-2 walls). Patients were allocated to either the experimental (XBS + 10 × 106 PDL-MSCs/100 mg) or the control group (XBS). Clinical and radiographical parameters were recorded at baseline, 6, 9 and 12 months. The presence of adverse events was also evaluated. Chi-square, Student's t test, Mann-Whitney U, repeated-measures ANOVA and regression models were used. RESULTS Twenty patients were included. No serious adverse events were reported. Patients in the experimental group (n = 9) showed greater clinical attachment level (CAL) gain (1.44, standard deviation [SD] = 1.87) and probing pocket depth (PPD) reduction (2.33, SD = 1.32) than the control group (n = 10; CAL gain = 0.88, SD = 1.68, and PPD reduction = 2.10, SD = 2.46), without statistically significant differences. CONCLUSION The application of PDL-MSCs to XBS for the treatment of one- to two-wall intra-bony lesions was safe and resulted in low postoperative morbidity and appropriate healing, although its additional benefit, when compared with the XBS alone, was not demonstrated.
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Affiliation(s)
- Nerea Sánchez
- ETEP (Etiology and Therapy of Periodontal and Peri-implant Diseases) Research Group, University Complutense, Madrid, Spain
| | - Ludovica Fierravanti
- ETEP (Etiology and Therapy of Periodontal and Peri-implant Diseases) Research Group, University Complutense, Madrid, Spain
| | - Javier Núñez
- ETEP (Etiology and Therapy of Periodontal and Peri-implant Diseases) Research Group, University Complutense, Madrid, Spain
| | - Fabio Vignoletti
- ETEP (Etiology and Therapy of Periodontal and Peri-implant Diseases) Research Group, University Complutense, Madrid, Spain
| | - María González-Zamora
- ETEP (Etiology and Therapy of Periodontal and Peri-implant Diseases) Research Group, University Complutense, Madrid, Spain
| | - Silvia Santamaría
- Margarita Salas Center for Biological Research (CIB-CSIC), Madrid, Spain
| | - Susana Suárez-Sancho
- GMP-Cell Production Unit, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Red de Terapia Celular (TERCEL) and CIBER Cardiovascular (CIBERCV), Instituto de Salud Carlos III, Madrid, Spain
| | - María Eugenia Fernández-Santos
- GMP-Cell Production Unit, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Red de Terapia Celular (TERCEL) and CIBER Cardiovascular (CIBERCV), Instituto de Salud Carlos III, Madrid, Spain
| | - Elena Figuero
- ETEP (Etiology and Therapy of Periodontal and Peri-implant Diseases) Research Group, University Complutense, Madrid, Spain
| | - David Herrera
- ETEP (Etiology and Therapy of Periodontal and Peri-implant Diseases) Research Group, University Complutense, Madrid, Spain
| | - Jose A García-Sanz
- Margarita Salas Center for Biological Research (CIB-CSIC), Madrid, Spain
| | - Mariano Sanz
- ETEP (Etiology and Therapy of Periodontal and Peri-implant Diseases) Research Group, University Complutense, Madrid, Spain
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14
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Miotti G, Zingaretti N, Guarneri GF, Manfrè V, Errichetti E, Stinco G, Parodi PC. Autologous micrografts and methotrexate in plantar erosive lichen planus: healing and pain control. A case report. CASE REPORTS IN PLASTIC SURGERY AND HAND SURGERY 2020; 7:134-138. [PMID: 33457454 PMCID: PMC7782279 DOI: 10.1080/23320885.2020.1848434] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Erosive lichen planus is an uncommon variant of lichen planus. We report a case of longstanding and refractory plantar ELPs causing disabling and opiate-resistant pain treated with ‘classic’ meshed skin graft combined with Rigenera® micrografts. After approximately 9 months follow-up, no clinical recurrence or pain were observed. Erosive lichen planus (ELP) is an uncommon variant of lichen planus, involving oral cavity and genitalia and, less often plantar areas, where it usually presents with chronic erosions of the soles, along with intense, disabling pain and progressive loss of toenails. An abnormal immune cellular response (CD8+ lymphocytes and macrophages) and the consequent altered production of multiple mediators (interleukin-12, interferon-γ, tumor necrosis factor-α, RANTES and MMP-9), seem to play a crucial role in the pathogenesis, although the etiology remains uncertain. From a histological point of view, ELP shows keratinocyte apoptosis, intense inflammatory response and basal epithelial keratinocytes TNF-α overexpression. Several therapies have been proposed, with variable and controversial results. While topical corticosteroids and topical calcineurin inhibitors are the treatments of choice for localized forms, short pulses of systemic glucocorticoids, phototherapy, and systemic immunosuppressants are recommended for generalized cases. Surgery has been reported as a possible therapeutic option in refractory and stable cases with localized lesions, either alone or with cyclosporine. Herein, we report a case of longstanding and refractory plantar ELPS causing disabling and opiate-resistant pain treated with ‘classic’ meshed skin graft combined with Rigenera® micrografts.
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Affiliation(s)
- G Miotti
- Department of Plastic and Recostructive Surgery, "Santa Maria della Misericordia" University Hospital, Udine, Italy
| | - N Zingaretti
- Department of Plastic and Recostructive Surgery, "Santa Maria della Misericordia" University Hospital, Udine, Italy
| | - G F Guarneri
- Department of Plastic and Recostructive Surgery, "Santa Maria della Misericordia" University Hospital, Udine, Italy
| | - V Manfrè
- Department of Plastic and Recostructive Surgery, "Santa Maria della Misericordia" University Hospital, Udine, Italy
| | - E Errichetti
- Institute of Dermatology, Department of Medicine, "Santa Maria della Misericordia" University Hospital, Udine, Italy
| | - G Stinco
- Institute of Dermatology, Department of Medicine, "Santa Maria della Misericordia" University Hospital, Udine, Italy
| | - P C Parodi
- Department of Plastic and Recostructive Surgery, "Santa Maria della Misericordia" University Hospital, Udine, Italy
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15
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Maseda R, Martínez-Santamaría L, Sacedón R, Butta N, de Arriba MDC, García-Barcenilla S, García M, Illera N, Pérez-Conde I, Carretero M, Jiménez E, Melen G, Borobia AM, Jiménez-Yuste V, Vicente Á, del Río M, de Lucas R, Escámez MJ. Beneficial Effect of Systemic Allogeneic Adipose Derived Mesenchymal Cells on the Clinical, Inflammatory and Immunologic Status of a Patient With Recessive Dystrophic Epidermolysis Bullosa: A Case Report. Front Med (Lausanne) 2020; 7:576558. [PMID: 33324660 PMCID: PMC7726418 DOI: 10.3389/fmed.2020.576558] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Accepted: 11/02/2020] [Indexed: 12/22/2022] Open
Abstract
Recessive dystrophic epidermolysis bullosa (RDEB) is an incurable inherited mucocutaneous fragility disorder characterized by recurrent blisters, erosions, and wounds. Continuous blistering triggers overlapping cycles of never-ending healing and scarring commonly evolving to chronic systemic inflammation and fibrosis. The systemic treatment with allogeneic mesenchymal cells (MSC) from bone marrow has previously shown benefits in RDEB. MSC from adipose tissue (ADMSC) are easier to isolate. This is the first report on the use of systemic allogeneic ADMSC, correlating the clinical, inflammatory, and immunologic outcomes in RDEB indicating long-lasting benefits. We present the case of an RDEB patient harboring heterozygous biallelic COL7A1 gene mutations and with a diminished expression of C7. The patient presented with long-lasting refractory and painful oral ulcers distressing her quality of life. Histamine receptor antagonists, opioid analgesics, proton-pump inhibitors, and low-dose tricyclic antidepressants barely improved gastric symptoms, pain, and pruritus. Concomitantly, allogeneic ADMSC were provided as three separate intravenous injections of 106 cells/kg every 21 days. ADMSC treatment was well-tolerated. Improvements in wound healing, itch, pain and quality of life were observed, maximally at 6-9 months post-treatment, with the relief of symptoms still noticeable for up to 2 years. Remarkably, significant modifications in PBL participating in both the innate and adaptive responses, alongside regulation of levels of profibrotic factors, MCP-1/CCL2 and TGF-β, correlated with the health improvement. This treatment might represent an alternative for non-responding patients to conventional management. It seems critical to elucidate the paracrine modulation of the immune system by MSC for their rational use in regenerative/immunoregulatory therapies.
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Affiliation(s)
- Rocío Maseda
- Department of Dermatology, La Paz University Hospital, Madrid, Spain
| | - Lucía Martínez-Santamaría
- Department of Bioengineering, Carlos III University (UC3M), Madrid, Spain
- Rare Diseases Networking Biomedical Research Centre (CIBERER) U714, Madrid, Spain
- Regenerative Medicine and Tissue Engineering Group, Health Research Institute Foundation of the Jiménez Díaz Foundation, Madrid, Spain
- Centre for Energy, Environment and Technology Research (CIEMAT), Madrid, Spain
| | - Rosa Sacedón
- Department of Cell Biology, Faculty of Medicine, Complutense University, Madrid, Spain
| | - Nora Butta
- Hematology Unit, La Paz University Hospital-IdiPAZ, Madrid, Spain
| | - María del Carmen de Arriba
- Department of Bioengineering, Carlos III University (UC3M), Madrid, Spain
- Regenerative Medicine and Tissue Engineering Group, Health Research Institute Foundation of the Jiménez Díaz Foundation, Madrid, Spain
- Centre for Energy, Environment and Technology Research (CIEMAT), Madrid, Spain
| | | | - Marta García
- Department of Bioengineering, Carlos III University (UC3M), Madrid, Spain
- Rare Diseases Networking Biomedical Research Centre (CIBERER) U714, Madrid, Spain
- Regenerative Medicine and Tissue Engineering Group, Health Research Institute Foundation of the Jiménez Díaz Foundation, Madrid, Spain
- Centre for Energy, Environment and Technology Research (CIEMAT), Madrid, Spain
| | - Nuria Illera
- Rare Diseases Networking Biomedical Research Centre (CIBERER) U714, Madrid, Spain
- Regenerative Medicine and Tissue Engineering Group, Health Research Institute Foundation of the Jiménez Díaz Foundation, Madrid, Spain
- Centre for Energy, Environment and Technology Research (CIEMAT), Madrid, Spain
| | | | - Marta Carretero
- Rare Diseases Networking Biomedical Research Centre (CIBERER) U714, Madrid, Spain
- Regenerative Medicine and Tissue Engineering Group, Health Research Institute Foundation of the Jiménez Díaz Foundation, Madrid, Spain
- Centre for Energy, Environment and Technology Research (CIEMAT), Madrid, Spain
| | - Eva Jiménez
- Department of Cell Biology, Faculty of Medicine, Complutense University, Madrid, Spain
| | - Gustavo Melen
- Cell & Gene Therapies Laboratory, Niño Jesus University Hospital, Madrid, Spain
| | - Alberto M. Borobia
- Clinical Pharmacology Department, School of Medicine, La Paz University Hospital, IdiPAZ, Autonomous University of Madrid, Madrid, Spain
| | | | - Ángeles Vicente
- Department of Cell Biology, Faculty of Medicine, Complutense University, Madrid, Spain
| | - Marcela del Río
- Department of Bioengineering, Carlos III University (UC3M), Madrid, Spain
- Rare Diseases Networking Biomedical Research Centre (CIBERER) U714, Madrid, Spain
- Regenerative Medicine and Tissue Engineering Group, Health Research Institute Foundation of the Jiménez Díaz Foundation, Madrid, Spain
- Centre for Energy, Environment and Technology Research (CIEMAT), Madrid, Spain
| | - Raúl de Lucas
- Department of Dermatology, La Paz University Hospital, Madrid, Spain
| | - María José Escámez
- Department of Bioengineering, Carlos III University (UC3M), Madrid, Spain
- Rare Diseases Networking Biomedical Research Centre (CIBERER) U714, Madrid, Spain
- Regenerative Medicine and Tissue Engineering Group, Health Research Institute Foundation of the Jiménez Díaz Foundation, Madrid, Spain
- Centre for Energy, Environment and Technology Research (CIEMAT), Madrid, Spain
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16
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Garcia-Arranz M, Alonso-Gregorio S, Fontana-Portella P, Bravo E, Diez Sebastian J, Fernandez-Santos ME, Garcia-Olmo D. Two phase I/II clinical trials for the treatment of urinary incontinence with autologous mesenchymal stem cells. Stem Cells Transl Med 2020; 9:1500-1508. [PMID: 32864818 PMCID: PMC7695632 DOI: 10.1002/sctm.19-0431] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Revised: 06/06/2020] [Accepted: 07/19/2020] [Indexed: 12/21/2022] Open
Abstract
We evaluated the safety and feasibility of adipose‐derived mesenchymal stem cells to treat endoscopically urinary incontinence after radical prostatectomy in men or female stress urinary. We designed two prospective, nonrandomized phase I‐IIa clinical trials of urinary incontinence involving 9 men (8 treated) and 10 women to test the feasibility and safety of autologous mesenchymal stem cells for this use. Cells were obtained from liposuction containing 150 to 200 g of fat performed on every patient. After 4 to 6 weeks and under sedation, endoscopic intraurethral injection of the cells was performed. On each visit (baseline, 1, 3, 6, and 12 months), clinical parameters were measured, and blood samples, urine culture, and uroflowmetry were performed. Every patient underwent an urethrocystoscopy and urodynamic studies on the first and last visit. Data from pad test, quality‐of‐life and incontinence questionnaires, and pads used per day were collected at every visit. Statistical analysis was done by Wilcoxon signed‐rank test. No adverse effects were observed. Three men (37.5%) and five women (50%) showed an objective improvement of >50% (P < .05) and a subjective improvement of 70% to 80% from baseline. In conclusion, intraurethral application of stem cells derived from adipose tissue is a safe and feasible procedure to treat urinary incontinence after radical prostatectomy or in female stress urinary incontinence. A statistically significant difference was obtained for pad‐test improvement in 3/8 men and 5/10 women. Our results encourage studies to confirm safety and to analyze efficacy.
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Affiliation(s)
- Mariano Garcia-Arranz
- New Therapies Laboratory, Health Research Institute-Fundación Jiménez Díaz University Hospital (IIS-FJD), Madrid, Spain.,Surgery Department, Autonoma University of Madrid, Madrid, Spain
| | | | | | - Elena Bravo
- Department of Plastic Surgery, La Paz University Hospital, Madrid, Spain
| | | | | | - Damian Garcia-Olmo
- New Therapies Laboratory, Health Research Institute-Fundación Jiménez Díaz University Hospital (IIS-FJD), Madrid, Spain.,Surgery Department, Autonoma University of Madrid, Madrid, Spain
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17
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Zhang G, Miao F, Xu J, Wang R. Mesenchymal stem cells from bone marrow regulate invasion and drug resistance of multiple myeloma cells by secreting chemokine CXCL13. Bosn J Basic Med Sci 2020; 20:209-217. [PMID: 31538911 PMCID: PMC7202187 DOI: 10.17305/bjbms.2019.4344] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2019] [Accepted: 08/08/2019] [Indexed: 12/11/2022] Open
Abstract
Multiple myeloma (MM) is a hematologic cancer arising from plasma cells. Mesenchymal stem cells (MSCs) are a heterogeneous cell population in the bone marrow microenvironment. In this study, we evaluated the regulatory effects of MSCs on the invasion and drug resistance of MM cells U266 and LP-1. Bone marrow samples from MM patients and healthy subjects were collected. MSCs were extracted from bone marrow and cultured, and their phenotypes were identified by flow cytometry. The level of CXCL13 in the supernatant of cultured MSCs was detected by ELISA. The protein expression of CXCR5 (a specific receptor of CXCL13) in U266 and LP-1 cells was detected by Western blot. The effects of MSCs on the invasion of U266 and LP-1 cells and the resistance to bortezomib were assessed by Transwell and CCK-8 assay, respectively. The mRNA and protein expressions of BTK, NF-κB, BCL-2, and MDR-1 were detected by RT-PCR and Western blot, respectively. CXCL13 was secreted by MSCs in the bone marrow microenvironment, and the level in MSCs from MM patients was significantly higher than that of healthy subjects. CXCR5 was expressed in both U266 and LP-1 cells. The resistance of MM cells to bortezomib was enhanced by MSCs through CXCL13 secretion. The invasion and proliferation of U266 and LP-1 cells were promoted, and the mRNA and protein expressions of BTK, NF-κB, BCL-2, and MDR-1 were upregulated by MSCs. The basic biological functions of MM cells U266 and LP-1 were affected by MSCs via the CXCL13-mediated signaling pathway. This study provides valuable experimental evidence for clinical MM therapy.
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Affiliation(s)
- Guihua Zhang
- Department of Hematology, The Second Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Faan Miao
- Department of Neurosurgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Jinge Xu
- Department of Hematology, The Second Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Rui Wang
- Department of Hematology, People's Hospital of Lianshui, Huaian, China
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18
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Garcia-Arranz M, Garcia-Olmo D, Herreros MD, Gracia-Solana J, Guadalajara H, de la Portilla F, Baixauli J, Garcia-Garcia J, Ramirez JM, Sanchez-Guijo F, Prosper F. Autologous adipose-derived stem cells for the treatment of complex cryptoglandular perianal fistula: A randomized clinical trial with long-term follow-up. Stem Cells Transl Med 2019; 9:295-301. [PMID: 31886629 PMCID: PMC7031651 DOI: 10.1002/sctm.19-0271] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2019] [Accepted: 11/05/2019] [Indexed: 12/13/2022] Open
Abstract
The aim of this clinical trial (ID Number NCT01803347) was to determine the safety and efficacy of autologous adipose‐derived stem cells (ASCs) for treatment of cryptoglandular fistula. This research was conducted following an analysis of the mistakes of a same previous phase III clinical trial. We designed a multicenter, randomized, single‐blind clinical trial, recruiting 57 patients. Forty‐four patients were categorized as belonging to the intent‐to‐treat group. Of these, 23 patients received 100 million ASCs plus intralesional fibrin glue (group A) and 21 received intralesional fibrin glue (group B), both after a deeper curettage of tracks and closure of internal openings. Fistula healing was defined as complete re‐epithelialization of external openings. Those patients in whom the fistula had not healed after 16 weeks were eligible for retreatment. Patients were evaluated at 1, 4, 16, 36, and 52 weeks and 2 years after treatment. Results were assessed by an evaluator blinded to the type of treatment. After 16 weeks, the healing rate was 30.4% in group A and 42.8% in group B, rising to 55.0% and 63.1%, respectively, at 52 weeks. At the end of the study (2 years after treatment), the healing rate remained at 50.0% in group A and had reduced to 26.3% in group B. The safety of the cellular treatment was confirmed and no impact on fecal continence was detected. The main conclusion was that autologous ASCs for the treatment of cryptoglandular perianal fistula is safe and can favor long‐term and sustained fistula healing.
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Affiliation(s)
- Mariano Garcia-Arranz
- Department of Surgery and New Therapy Laboratory, Health Research Institute Fundación Jiménez Díaz (FIIS-FJD), Universidad Autónoma de Madrid (UAM), Madrid, Spain
| | - Damián Garcia-Olmo
- Department of Surgery and New Therapy Laboratory, Health Research Institute Fundación Jiménez Díaz (FIIS-FJD), Universidad Autónoma de Madrid (UAM), Madrid, Spain
| | - María Dolores Herreros
- Department of Surgery and New Therapy Laboratory, Health Research Institute Fundación Jiménez Díaz (FIIS-FJD), Universidad Autónoma de Madrid (UAM), Madrid, Spain
| | - José Gracia-Solana
- Department of Colorectal Surgery, "Lozano Blesa" University Hospital, Aragon Health Sciences Institute, Zaragoza, Spain
| | - Héctor Guadalajara
- Department of Surgery and New Therapy Laboratory, Health Research Institute Fundación Jiménez Díaz (FIIS-FJD), Universidad Autónoma de Madrid (UAM), Madrid, Spain
| | - Fernando de la Portilla
- Coloproctology Unit, Gastrointestinal Surgery Department, Virgen del Rocio University Hospital, Sevilla, Spain
| | - Jorge Baixauli
- Coloproctology Unit, Department of General and Digestive Surgery, University Hospital of Salamanca, Salamanca, Spain
| | - Jacinto Garcia-Garcia
- Colorectal Surgery Unit, Department of General Surgery, Clínica Universitaria de Navarra, University of Navarra, Pamplona, Spain
| | - José Manuel Ramirez
- Department of Colorectal Surgery, "Lozano Blesa" University Hospital, Aragon Health Sciences Institute, Zaragoza, Spain
| | - Fermín Sanchez-Guijo
- Cell Therapy Area, IBSAL-University Hospital, University of Salamanca, Salamanca, Spain
| | - Felipe Prosper
- GMP Laboratory Cellular Therapy, Clínica Universitaria de Navarra, University of Navarra, Pamplona, Spain
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García Gómez-Heras S, Largo C, Larrea JL, Vega-Clemente L, Calderón Flores M, Ruiz-Pérez D, García-Olmo D, García-Arranz M. Main histological parameters to be evaluated in an experimental model of myocardial infarct treated by stem cells on pigs. PeerJ 2019; 7:e7160. [PMID: 31367480 PMCID: PMC6657680 DOI: 10.7717/peerj.7160] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Accepted: 05/22/2019] [Indexed: 12/22/2022] Open
Abstract
Myocardial infarction has been carefully studied in numerous experimental models. Most of these models are based on electrophysiological and functional data, and pay less attention to histological discoveries. During the last decade, treatment using advanced therapies, mainly cell therapy, has prevailed from among all the options to be studied for treating myocardial infarction. In our study we wanted to show the fundamental histological parameters to be evaluated during the development of an infarction on an experimental model as well as treatment with mesenchymal stem cells derived from adipose tissue applied intra-lesionally. The fundamental parameters to study in infarcted tissue at the histological level are the cells involved in the inflammatory process (lymphocytes, macrophages and M2, neutrophils, mast cells and plasma cells), neovascularization processes (capillaries and arterioles) and cardiac cells (cardiomyocytes and Purkinje fibers). In our study, we used intramyocardial injection of mesenchymal stem cells into the myocardial infarction area 1 hour after arterial occlusion and allowed 1 month of evolution before analyzing the modifications on the normal tissue inflammatory infiltrate. Acute inflammation was shortened, leading to chronic inflammation with abundant plasma cells and mast cells and complete disappearance of neutrophils. Another benefit was an increase in the number of vessels formed. Cardiomyocytes and Purkinje fibers were better conserved, both from a structural and metabolic point of view, possibly leading to reduced morbidity in the long term. With this study we present the main histological aspects to be evaluated in future assays, complementing or explaining the electrophysiological and functional findings.
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Affiliation(s)
| | - Carlota Largo
- Experimental Surgery, La Paz University Hospital, IdiPaz, Madrid, Spain
| | - Jose Luis Larrea
- Surgical Cardiology Department, La Paz University Hospital, Madrid, Spain
| | - Luz Vega-Clemente
- Cell Therapy laboratory, Health Research Institute, Fundación Jiménez Diaz, Madrid, Spain
| | | | - Daniel Ruiz-Pérez
- Experimental Surgery, La Paz University Hospital, IdiPaz, Madrid, Spain
| | - Damián García-Olmo
- Cell Therapy laboratory, Health Research Institute, Fundación Jiménez Diaz, Madrid, Spain
| | - Mariano García-Arranz
- Cell Therapy laboratory, Health Research Institute, Fundación Jiménez Diaz, Madrid, Spain
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20
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Ribaldone DG, Resegotti A, Pellicano R, Astegiano M, Saracco GM, Morino M. The role of topical therapy for perianal fistulizing Crohn's disease: are we forgetting something? MINERVA GASTROENTERO 2019; 65:130-135. [PMID: 30759975 DOI: 10.23736/s1121-421x.19.02565-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
INTRODUCTION Rectal inflammation is the principal risk factor for the development of perianal fistulizing Crohn's disease. However, no topical therapy direct to rectal healing is discussed in European' guidelines. The aim of this systematic review was to evaluate the role of topical therapy in healing the rectal inflammation in Crohn's disease. EVIDENCE ACQUISITION A MEDLINE search of all studies published in English until December 2018 was conducted. Articles were identified using the strings "Crohn's disease and topical therapy" or "perianal Crohn's disease and topical therapy." EVIDENCE SYNTHESIS Contradictory results about the efficacy of topical metronidazole were present. No benefit from topical tacrolimus use was demonstrated. Mesalazine suppositories induced and maintained remission of rectal inflammation in 50% of patients with rectal Crohn's disease. Few data were available about the role of local therapy for the fistulous tract in Crohn's disease. Local mesenchymal stem cells therapy could be a promising new approach. CONCLUSIONS Due to the disappoint success rate of current strategy in perianal fistulizing Crohn's disease, the role of rectal inflammation as a causative factor and the fair success rate of topical therapy with mesalazine suppositories in the healing of rectal inflammation without relevant side effects, more studies are advisable in this field.
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Affiliation(s)
| | - Andrea Resegotti
- General Surgery 1 U, Città della Salute e della Scienza, Turin, Italy
| | | | | | | | - Mario Morino
- Department of Surgical Sciences, University of Turin, Turin, Italy
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21
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Shi X, Chen S, Zhang Y, Xie W, Hu Z, Li H, Li J, Zhou Z, Tan W. Norcantharidin inhibits the DDR of bladder cancer stem-like cells through cdc6 degradation. Onco Targets Ther 2019; 12:4403-4413. [PMID: 31239709 PMCID: PMC6560209 DOI: 10.2147/ott.s209907] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2019] [Accepted: 05/14/2019] [Indexed: 01/16/2023] Open
Abstract
Introduction: Cancer stem cells (CSCs) are the main source of tumor resistance and recurrence. At present, the main treatment for patients with advanced or metastatic bladder cancer (BCa) is cisplatin-based combination chemotherapy. However, CSCs are not sensitive to DNA-damaging drugs due to their enhanced DNA damage response (DDR) activity. Materials and methods: Bladder cancer stem cell-like cells (BCSLCs) were obtained by treating UMUC3 cells with cisplatin. The characteristics of the BCSLCs were identified by qPCR, flow cytometry, scratch wound-healing assays, transwell assays, tumorigenic ability experiments, Edu assays and Western blot assays in vivo. After BCSLCs were treated with norcantharidin (NCTD), the expression of Cdc6 and activation of the ATR-Chk1 pathway were detected by Western blotting. A subcutaneous tumor model in nude mice was successfully established to assess the anti-tumor efficacy of NCTD and cisplatin either alone or in combination in vivo. The tumor tissues were detected by immunohistochemistry. Results: The derived BCSLCs showed higher expression of stemness markers, increased invasiveness, improved resistance to multiple chemotherapeutics, and higher tumorigenic capacity in vivo. The protein expression level of chromatin-binding Cdc6 was increased in BCSLCs; however, NCTD decreased the level of chromatin-binding Cdc6 and inhibited the activation of the ATR-Chk1 pathway, which ultimately led to reduction in DDR activity in BCSLCs. NCTD enhanced the killing effect of cisplatin on BCSLCs in vitro and vivo. NCTD combined with cisplatin enhanced cisplatin-induced DNA damage in BCSLCs. Conclusion: Long-term cisplatin treatment can enrich BCSLCs. However, NCTD enhanced the killing effect of cisplatin on BCSLCs in vitro and vivo. The mechanism is inhibiting the DDR activity by reducing the expression of chromatin-binding Cdc6.
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Affiliation(s)
- Xianghua Shi
- Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People’s Republic of China
- Department of Health Management, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, People’s Republic of China
| | - Sansan Chen
- Department of Urology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, Guangdong, People’s Republic of China
| | - Yongjun Zhang
- Institute of Biotherapy, School of Biotechnology, Southern Medical University, Guangzhou, Guangdong, People’s Republic of China
| | - Weiwei Xie
- Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People’s Republic of China
| | - Zhiming Hu
- Institute of Biotherapy, School of Biotechnology, Southern Medical University, Guangzhou, Guangdong, People’s Republic of China
| | - Hongwei Li
- Institute of Biotherapy, School of Biotechnology, Southern Medical University, Guangzhou, Guangdong, People’s Republic of China
| | - Jinlong Li
- Institute of Biotherapy, School of Biotechnology, Southern Medical University, Guangzhou, Guangdong, People’s Republic of China
| | - Zhongxin Zhou
- Department of Vascular Surgery, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, People’s Republic of China
- Zhongxin ZhouDepartment of Vascular Surgery, The Third Affiliated Hospital of Southern Medical University, No. 183, Zhongshan Avenue West, Guangzhou, Guangdong510630, People’s Republic of ChinaTel +861 852 037 6040Email
| | - Wanlong Tan
- Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People’s Republic of China
- Correspondence: Wanlong TanDepartment of Urology, Nanfang Hospital, Southern Medical University, No. 1838, Guangzhou Avenue North, Guangzhou, Guangdong510515, People’s Republic of ChinaTel +861 360 298 3938Email
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22
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Bermejo F, Guerra I, Algaba A, López-Sanromán A. Pharmacological Approach to the Management of Crohn's Disease Patients with Perianal Disease. Drugs 2018; 78:1-18. [PMID: 29139091 DOI: 10.1007/s40265-017-0842-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Perianal localization of Crohn's disease involves significant morbidity, affects quality of life and results in an increased use of healthcare resources. Medical and surgical therapies contribute to its management. The objective of this review is to address the current understanding in the management of perianal Crohn's disease, with the main focus in reviewing pharmacological therapies, including stem cells. In complex fistulas, once local sepsis has been controlled by surgical drainage and/or antibiotics, anti-TNF drugs (infliximab, adalimumab) are the first-line therapy, with or without associated immunomodulators. Combining surgery and anti-TNF therapy has additional benefits for healing. However, response is inadequate in up to half of cases. A possible role of new biological drugs in this context (vedolizumab, ustekinumab) is an area of ongoing investigation, as is the local application of autologous or allogeneic mesenchymal stem cells. These are non-hematopoietic multipotent cells with anti-inflammatory and immunomodulatory properties, the use of which may successfully treat refractory patients, and seem to be a promising and safe alternative to achieving fistula healing in Crohn's disease, without known systemic effects.
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Affiliation(s)
- Fernando Bermejo
- Department of Gastroenterology, University Hospital of Fuenlabrada, Madrid, Spain. .,Department of Medicine and Surgery, Universidad Rey Juan Carlos, Madrid, Spain.
| | - Iván Guerra
- Department of Gastroenterology, University Hospital of Fuenlabrada, Madrid, Spain
| | - Alicia Algaba
- Department of Gastroenterology, University Hospital of Fuenlabrada, Madrid, Spain
| | - Antonio López-Sanromán
- Department of Gastroenterology and Hepatology, University Hospital Ramón y Cajal, Madrid, Spain
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23
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Pérez-Castrillo S, González-Fernández ML, López-González ME, Villar-Suárez V. Effect of ascorbic and chondrogenic derived decellularized extracellular matrix from mesenchymal stem cells on their proliferation, viability and differentiation. Ann Anat 2018; 220:60-69. [PMID: 30114449 DOI: 10.1016/j.aanat.2018.07.006] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2018] [Revised: 07/24/2018] [Accepted: 07/25/2018] [Indexed: 11/19/2022]
Abstract
BACKGROUND The development and application of biomaterials to promote stem cell proliferation and differentiation has undergone major expansion over the last few years. Decellularized stem cell matrix (DSCMs) represent bioactive and biocompatible materials which achieve similar characteristics of native extracellular matrix. DSCMs have given promising outcomes in generating novel cell culture substrates mimicking specific niche microenvironments in tissue engineering. AIMS This research aims at producing two different DSCMs obtained from adipose derived mesenchymal stem cells and bone marrow mesenchymal stem cells, characterize them and evaluate the DSCMs bioactivity on mesenchymal stem cells. METHODS DSCMs were produced using ascorbic or chondrogenic medium, which were then used as a scaffold for adipose derived mesenchymal stem cells and bone marrow mesenchymal stem cells, respectively. The biological characteristics of both types of DSCMs, including cell attachment, morphology, proliferation, viability, and chondrogenic and osteogenic differentiation were evaluated and compared. RESULTS Differences between ascorbic derived-DSCMs and chondrogenic derived DSCMs were found. Chondrogenic derived-DSCMs remained compact and stronger during extraction and this made their handling easier. Ascorbic derived-DSCMs showed a different protein composition to chondrogenic-DSCMs. Bioactive characteristics analyzed were different depending on the cellular origin of DSCM and the method used to produce them. CONCLUSIONS The DSCMs obtained in this work constitutes favorable structure- and growth factors providing a microenvironment which is very similar to that of native ECM, which results in enhanced biological potential of the MSCs and responsiveness to the induction of differentiation. We found differences between ascorbic derived-DSCMs and chondrogenic derived DSCMs. Our results suggest that the cell source used to produce DSCMs is highly related to the bioactive characteristics of DSCMs.
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Affiliation(s)
- S Pérez-Castrillo
- Department of Anatomy, Faculty of Veterinary Sciences, University of León-Universidad de León, Campus de Vegazana s/n, 24071, León, Spain
| | - M L González-Fernández
- Department of Anatomy, Faculty of Veterinary Sciences, University of León-Universidad de León, Campus de Vegazana s/n, 24071, León, Spain
| | - M E López-González
- Department of Anatomy, Faculty of Veterinary Sciences, University of León-Universidad de León, Campus de Vegazana s/n, 24071, León, Spain
| | - V Villar-Suárez
- Department of Anatomy, Faculty of Veterinary Sciences, University of León-Universidad de León, Campus de Vegazana s/n, 24071, León, Spain; Institute of Biomedicine (IBIOMED), University of León-Universidad de León, Campus de Vegazana s/n, 24071, León, Spain.
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24
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Trébol J, Carabias-Orgaz A, García-Arranz M, García-Olmo D. Stem cell therapy for faecal incontinence: Current state and future perspectives. World J Stem Cells 2018; 10:82-105. [PMID: 30079130 PMCID: PMC6068732 DOI: 10.4252/wjsc.v10.i7.82] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2018] [Revised: 06/26/2018] [Accepted: 06/30/2018] [Indexed: 02/06/2023] Open
Abstract
Faecal continence is a complex function involving different organs and systems. Faecal incontinence is a common disorder with different pathogeneses, disabling consequences and high repercussions for quality of life. Current management modalities are not ideal, and the development of new treatments is needed. Since 2008, stem cell therapies have been validated, 36 publications have appeared (29 in preclinical models and seven in clinical settings), and six registered clinical trials are currently ongoing. Some publications have combined stem cells with bioengineering technologies. The aim of this review is to identify and summarise the existing published knowledge of stem cell utilization as a treatment for faecal incontinence. A narrative or descriptive review is presented. Preclinical studies have demonstrated that cellular therapy, mainly in the form of local injections of muscle-derived (muscle derived stem cells or myoblasts derived from them) or mesenchymal (bone-marrow- or adipose-derived) stem cells, is safe. Cellular therapy has also been shown to stimulate the repair of both acute and subacute anal sphincter injuries, and some encouraging functional results have been obtained. Stem cells combined with normal cells on bioengineered scaffolds have achieved the successful creation and implantation of intrinsically-innervated anal sphincter constructs. The clinical evidence, based on adipose-derived stem cells and myoblasts, is extremely limited yet has yielded some promising results, and appears to be safe. Further investigation in both animal models and clinical settings is necessary to drawing conclusions. Nevertheless, if the preliminary results are confirmed, stem cell therapy for faecal incontinence may well become a clinical reality in the near future.
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Affiliation(s)
- Jacobo Trébol
- General and Digestive Tract Surgery Department, Salamanca University Healthcare Centre, Salamanca 37007, Spain
| | - Ana Carabias-Orgaz
- Anaesthesiology Department, Complejo Asistencial de Ávila, Ávila 05004, Spain
| | - Mariano García-Arranz
- New Therapies Laboratory, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz, Madrid 28040, Spain
| | - Damián García-Olmo
- General and Digestive Tract Surgery Department, Quiron-Salud Hospitals, Madrid 28040, Spain
- Surgery Department, Universidad Autónoma, Madrid 28040, Spain
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25
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Evaluation of the Safety and Efficacy of the Therapeutic Potential of Adipose-Derived Stem Cells Injected in the Cerebral Ischemic Penumbra. J Stroke Cerebrovasc Dis 2018; 27:2453-2465. [PMID: 30029838 DOI: 10.1016/j.jstrokecerebrovasdis.2018.05.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2016] [Revised: 04/24/2018] [Accepted: 05/01/2018] [Indexed: 01/01/2023] Open
Abstract
INTRODUCTION Stroke represents an attractive target for cell therapy. Although different types of cells have been employed in animal models with variable results, the human adipose-derived stem cells (hASCs) have demonstrated favorable characteristics in the treatment of diseases with inflammatory substrate, but experience in their intracerebral administration is lacking. The purpose of this study is to evaluate the effect and safety of the intracerebral application of hASCs in a stroke model. METHODS A first group of Athymic Nude mice after stroke received a stereotactic injection of hASCs at a concentration of 4 × 104/µL at the penumbra area, a second group without stroke received the same cell concentration, and a third group had only stroke and no cells. After 7, 15, and 30 days, the animals underwent fluorodeoxyglucose-positron emission tomography and magnetic resonance imaging; subsequently, they were sacrificed for histological evaluation (HuNu, GFAP, IBA-1, Ki67, DCX) of the penumbra area and ipsilateral subventricular zone (iSVZ). RESULTS The in vitro studies found no alterations in the molecular karyotype, clonogenic capacity, and expression of 62 kDa transcription factor and telomerase. Animals implanted with cells showed no adverse events. The implanted cells showed no evidence of proliferation or differentiation. However, there was an increase of capillaries, less astrocytes and microglia, and increased bromodeoxyuridine and doublecortin-positive cells in the iSVZ and in the vicinity of ischemic injury. CONCLUSIONS These results suggest that hASCs in the implanted dose modulate inflammation, promote endogenous neurogenesis, and do not proliferate or migrate in the brain. These data confirm the safety of cell therapy with hASCs.
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26
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Bor R, Fábián A, Farkas K, Molnár T, Szepes Z. Human mesenchymal stem cell therapy in the management of luminal and perianal fistulizing Crohn’s disease – review of pathomechanism and existing clinical data. Expert Opin Biol Ther 2018; 18:737-745. [DOI: 10.1080/14712598.2018.1492543] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- Renáta Bor
- First Department of Medicine, University of Szeged, Szeged, Hungary
| | - Anna Fábián
- First Department of Medicine, University of Szeged, Szeged, Hungary
| | - Klaudia Farkas
- First Department of Medicine, University of Szeged, Szeged, Hungary
| | - Tamás Molnár
- First Department of Medicine, University of Szeged, Szeged, Hungary
| | - Zoltán Szepes
- First Department of Medicine, University of Szeged, Szeged, Hungary
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27
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de la Portilla F, Yuste Y, Pereira S, Olano C, Maestre MV, Padillo FJ. Local Mesenchymal Stem Cell Therapy in Experimentally Induced Colitis in the Rat. Int J Stem Cells 2018; 11:39-47. [PMID: 29699385 PMCID: PMC5984057 DOI: 10.15283/ijsc17074] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2017] [Revised: 03/05/2018] [Accepted: 03/11/2018] [Indexed: 12/16/2022] Open
Abstract
Background Multipotent mesenchymal stem cells (MSCs) have been used in inflammatory bowel diseases because of their immunomodulatory and regenerative properties. We investigated their local use in an experimental model of colitis in the rat. Materials and Methods Colitis was induced into 20 Wistar rats with local TNBS instillation. Allogeneic stem cells were derived from rat adipose tissue and labeled with PKH2 linker dye with creation of a control and a second group treated by a local injection into the rectal wall of 2×106 allogeneic adipose tissue-derived stem cells (ADSCs). The thicknesses of different components of the rectum were measured with comparisons made in different parts of the colon of the Hunter inflammatory score. PKH2-dyed ADSCs were detected by fluorescence microscopy. Results and Conclusions Total colitis was induced in 19/20 rats with homing of fluorescent ADSCs. to the crypt base and perivascular space of the submucosa. There were no differences in component rectal wall thicknesses with a higher Hunter score in the treated group compared with the controls, in the rectum (3.8±2.74 vs. 1.5±2.37, respectively; p=0.017) and in right colon (2.5±1.08 vs. 0.20±0.42, respectively; p=0.0001). Local colonic injection of allogeneic adipose stem cells. in experimental colitis is feasible and safe. There is demonstrable homing of cells in chemically-induced colitis both to the treated region and parts of the colon distant to the MSC treatment site. Such cells readily proliferate in vitro and could potentially be a source for future treatment of resistant disease.
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Affiliation(s)
- Fernando de la Portilla
- Department of General and Digestive Surgery, Unit Colorectal Surgery, "Virgen del Rocío" University Hospital/IBiS/CSIC/University of Seville, Seville, Spain
| | - Yaiza Yuste
- Institute of Biomedicine of Seville (IBiS), "Virgen del Rocío" University Hospital/IBiS/CSIC/University of Seville, Seville, Spain
| | - Sheila Pereira
- Institute of Biomedicine of Seville (IBiS), "Virgen del Rocío" University Hospital/IBiS/CSIC/University of Seville, Seville, Spain
| | - Carolina Olano
- National Institute of Toxicology and Forensic Sciences, Seville, Spain
| | - Maria Victoria Maestre
- Department of General and Digestive Surgery, Unit Colorectal Surgery, "Virgen del Rocío" University Hospital/IBiS/CSIC/University of Seville, Seville, Spain
| | - Francisco Javier Padillo
- Department of General and Digestive Surgery, Unit Colorectal Surgery, "Virgen del Rocío" University Hospital/IBiS/CSIC/University of Seville, Seville, Spain
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Knuth CA, Kiernan CH, Palomares Cabeza V, Lehmann J, Witte-Bouma J, Ten Berge D, Brama PA, Wolvius EB, Strabbing EM, Koudstaal MJ, Narcisi R, Farrell E. Isolating Pediatric Mesenchymal Stem Cells with Enhanced Expansion and Differentiation Capabilities. Tissue Eng Part C Methods 2018; 24:313-321. [PMID: 29631483 DOI: 10.1089/ten.tec.2018.0031] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Mesenchymal stem cells/marrow stromal cells (MSCs) are attractive for applications ranging from research and development to use in clinical therapeutics. However, the most commonly studied MSCs, adult bone marrow MSCs (A-MSCs), are limited by significant donor variation resulting in inconsistent expansion rates and multilineage differentiation capabilities. We have recently obtained permission to isolate pediatric MSCs (P-MSCs) from surplus iliac crest bone chips. Here, we developed a simple and easily replicable isolation protocol yielding P-MSCs, which adhere to MSC defining guidelines. After confirming immunophenotypic marker expression, we compared expansion rates, senescence, morphology, and trilineage differentiation of P-MSCs to A-MSCs for multiple donors. We found P-MSCs have faster in vitro replication, consistently show significantly lower senescence, and are capable of more reproducible multilineage differentiation than A-MSCs. We, therefore, believe P-MSCs are a promising candidate for use in research applications and potentially as part of an allogeneic therapeutic treatment.
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Affiliation(s)
- Callie An Knuth
- 1 Department of Oral and Maxillofacial Surgery, Special Dental Care and Orthodontics, Erasmus MC, University Medical Center Rotterdam , Rotterdam, The Netherlands
| | - Caoimhe H Kiernan
- 1 Department of Oral and Maxillofacial Surgery, Special Dental Care and Orthodontics, Erasmus MC, University Medical Center Rotterdam , Rotterdam, The Netherlands
| | - Virginia Palomares Cabeza
- 1 Department of Oral and Maxillofacial Surgery, Special Dental Care and Orthodontics, Erasmus MC, University Medical Center Rotterdam , Rotterdam, The Netherlands .,2 Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam , Rotterdam, The Netherlands .,3 School of Veterinary Medicine, Veterinary Science Centre, University College Dublin , Dublin, Ireland
| | - Johannes Lehmann
- 4 Department of Cell Biology, Erasmus MC, University Medical Center Rotterdam , Rotterdam, The Netherlands .,5 Department of Otorhinolaryngology, Head and Neck Surgery, Erasmus MC, University Medical Center Rotterdam , Rotterdam, The Netherlands
| | - Janneke Witte-Bouma
- 1 Department of Oral and Maxillofacial Surgery, Special Dental Care and Orthodontics, Erasmus MC, University Medical Center Rotterdam , Rotterdam, The Netherlands
| | - Derk Ten Berge
- 4 Department of Cell Biology, Erasmus MC, University Medical Center Rotterdam , Rotterdam, The Netherlands
| | - Pieter A Brama
- 3 School of Veterinary Medicine, Veterinary Science Centre, University College Dublin , Dublin, Ireland
| | - Eppo B Wolvius
- 1 Department of Oral and Maxillofacial Surgery, Special Dental Care and Orthodontics, Erasmus MC, University Medical Center Rotterdam , Rotterdam, The Netherlands
| | - Elske M Strabbing
- 1 Department of Oral and Maxillofacial Surgery, Special Dental Care and Orthodontics, Erasmus MC, University Medical Center Rotterdam , Rotterdam, The Netherlands
| | - Maarten J Koudstaal
- 1 Department of Oral and Maxillofacial Surgery, Special Dental Care and Orthodontics, Erasmus MC, University Medical Center Rotterdam , Rotterdam, The Netherlands
| | - Roberto Narcisi
- 6 Department of Orthopedics, Erasmus MC, University Medical Center Rotterdam , Rotterdam, The Netherlands
| | - Eric Farrell
- 1 Department of Oral and Maxillofacial Surgery, Special Dental Care and Orthodontics, Erasmus MC, University Medical Center Rotterdam , Rotterdam, The Netherlands
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Liu X, Ji C, Xu L, Yu T, Dong C, Luo J. Hmox1 promotes osteogenic differentiation at the expense of reduced adipogenic differentiation induced by BMP9 in C3H10T1/2 cells. J Cell Biochem 2018; 119:5503-5516. [PMID: 29377252 DOI: 10.1002/jcb.26714] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2017] [Accepted: 01/24/2018] [Indexed: 12/12/2022]
Abstract
Mesenchymal stem cells (MSCs) are multipotent progenitors that can differentiate into a variety of cell types under proper stimuli. Bone morphogenetic protein 9 (BMP9) is able to simultaneously induce both adipogenic and osteogenic differentiation of MSCs although the regulatory molecules involved remain to be fully identified and characterized. Heme oxygenase 1 (Hmox1) plays an essential role not only in fat metabolism, but also in bone development. In the present study, we investigated the functional role of Hmox1 in BMP9-induced osteogenic/adipogenic differentiation in MSCs line C3H10T1/2 and probed the possible mechanism involved. We found that BMP9 promoted the endogenous expression of Hmox1 in C3H10T1/2 cells. Overexpression of Hmox1 or cobalt protoporphyrin (CoPP), an inducer of Hmox1, increased BMP9-induced osteogenic differentiation in vitro. Subcutaneous stem cell implantation in nude mice further confirmed that Hmox1 potentiated BMP9-induced ectopic bone formation in vivo. In contrast, Hmox1 reduced BMP9-induced adipogenic differentiation in C3H10T1/2 cells. Although had no obvious effect on BMP9-induced Smad1/5/8 phosphorylation, Hmox1 enhanced phosphorylation of p38, and AKT, while decreased phosphorylation of ERK1/2. Furthermore, Hmox1 increased total β-catenin protein level, and promoted the nuclear translocation of β-catenin in C3H10T1/2 cells. Taken together, our study strongly suggests that Hmox1 is likely to potentiate osteogenic differentiation and yet decrease adipogenic differentiation induced by BMP9 possibly through regulation of multiple signaling pathways.
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Affiliation(s)
- Xiaohua Liu
- Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, P.R. China
| | - Caixia Ji
- Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, P.R. China
| | - Li Xu
- Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, P.R. China
| | - TingTing Yu
- Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, P.R. China
| | - Chaoqun Dong
- Department of Orthorpedic, Children Hospital of Chongqing Medical University, Chongqing, P.R. China
| | - Jinyong Luo
- Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, P.R. China
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30
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Tang YH, Thompson RW, Nathan C, Alexander JS, Lian T. Stem cells enhance reperfusion following ischemia: Validation using laser speckle imaging in predicting tissue repair. Laryngoscope 2018; 128:E198-E205. [DOI: 10.1002/lary.27110] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2017] [Revised: 12/27/2017] [Accepted: 12/29/2017] [Indexed: 12/17/2022]
Affiliation(s)
- Ya Hui Tang
- Department of Otolaryngology/HNSLSU Health Sciences CenterShreveport Louisiana U.S.A
| | - R. Will Thompson
- Department of Otolaryngology/HNSLSU Health Sciences CenterShreveport Louisiana U.S.A
| | - Cherie‐Ann Nathan
- Department of Otolaryngology/HNSLSU Health Sciences CenterShreveport Louisiana U.S.A
| | | | - Timothy Lian
- Department of Molecular and Cellular PhysiologyLSU Health Sciences CenterShreveport Louisiana U.S.A
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31
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Wainstein C, Quera R, Fluxá D, Kronberg U, Conejero A, López-Köstner F, Jofre C, Zarate AJ. Stem Cell Therapy in Refractory Perineal Crohn's Disease: Long-term Follow-up. Colorectal Dis 2018; 20. [PMID: 29316139 DOI: 10.1111/codi.14002] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2017] [Accepted: 12/01/2017] [Indexed: 12/12/2022]
Abstract
AIM To describe the long-term outcomes of adipose-mesenchymal stem cells, platelet-rich plasma, and endorectal advancement flaps in patients with Perineal Crohn's Disease. METHOD This was a single-center, prospective, observational pilot study performed between March 2013 and December 2016. The study included adult patients diagnosed with Perianal Crohn's Disease (with complex perianal fistulas) refractory to previous surgical and/or biological treatment. Patients underwent surgical treatment in two stages. Stage 1: Fistula mapping, drainage, seton placement and lipoaspiration to obtain adipose-mesenchymal stem cells were performed. Stage 2: The setons were removed, and the fistula tract was debrided. A small endorectal advancement flap was created, with closure of the previous internal fistula opening. Then, 100-120 million adipose-mesenchymal stem cells mixed with platelet-rich plasma were injected into the internal fistula opening and fistula tract. RESULTS The study included nine patients (seven females), with a median age of 36 years (r = 23-57). Eleven fistula tracks were treated, of which, two were pouch-vaginal fistulas. The median follow-up period was 31 months (r=21-37). At the end of the follow-up period, 10/11 (91%) fistulas were completely healed and 1/11 (9%) was partially healed. At the end of this period, there was no evidence of fistula relapse or adverse reactions in any patients. The Perianal Disease Activity Index and Inflammatory Bowel Disease Questionnaire scores significantly improved after the procedure. CONCLUSION Combined therapy with adipose-mesenchymal stem cells, platelet-rich plasma and endorectal advancement flaps yielded good results in patients with refractory Perineal Crohn's Disease. This article is protected by copyright. All rights reserved.
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Affiliation(s)
| | - Rodrigo Quera
- Inflammatory Bowel Disease Program, Gastroenterology Department, Clínica Las Condes, Santiago, Chile
| | - Daniela Fluxá
- Fellow in "Management of Intestinal Diseases", Gastroenterology Department, Clínica Las Condes, Santiago, Chile
| | - Udo Kronberg
- Inflammatory Bowel Disease Program, Colorectal Surgery Unit, Clínica Las Condes, Santiago, Chile
| | | | | | - Claudio Jofre
- PhD in Biotechnology, Laboratory for Tissue Engineering, Clínica Las Condes, Santiago, Chile
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Ratajczak MZ, Ciechanowicz AK, Kucharska-Mazur J, Samochowiec J. Stem cells and their potential clinical applications in psychiatric disorders. Prog Neuropsychopharmacol Biol Psychiatry 2018; 80:3-9. [PMID: 28435007 PMCID: PMC5623088 DOI: 10.1016/j.pnpbp.2017.04.020] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2017] [Revised: 04/17/2017] [Accepted: 04/19/2017] [Indexed: 12/23/2022]
Abstract
The robustness of stem cells is one of the major factors that directly impacts life quality and life span. Evidence has accumulated that changes in the stem cell compartment affect human mental health and serve as an indicator of psychiatric problems. It is well known that stem cells continuously replace differentiated cells and tissues that are used up during life, although this replacement occurs at a different pace in the various organs. However, the participation of local neural stem cells in regeneration of the central nervous system is controversial. It is known that low numbers of stem cells circulate continuously in peripheral blood (PB) and lymph and undergo a circadian rhythm in their PB level, with the peak occurring early in the morning and the nadir at night, and recent evidence suggests that the number and pattern of circulating stem cells in PB changes in psychotic disorders. On the other hand, progress in the creation of induced pluripotent stem cells (iPSCs) from patient somatic cells provides valuable tools with which to study changes in gene expression in psychotic patients. We will discuss the various potential sources of stem cells that are currently employed in regenerative medicine and the mechanisms that explain some of their beneficial effects as well as the emerging problems with stem cell therapies. However, the main question remains: Will it be possible in the future to modulate the stem cell compartment to reverse psychiatric problems?
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Affiliation(s)
- Mariusz Z Ratajczak
- Stem Cell Institute, 500 South Floyd Street, James Graham Brown Cancer Center, University of Louisville, Louisville 40202, KY, USA; Department of Regenerative Medicine Warsaw Medical University, Warsaw, Poland.
| | | | | | - Jerzy Samochowiec
- Department of Psychiatry, Pomeranian Medical University, Szczecin, Poland
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33
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Norderval S, Lundby L, Hougaard H, Buntzen S, Weum S, de Weerd L. Efficacy of autologous fat graft injection in the treatment of anovaginal fistulas. Tech Coloproctol 2017; 22:45-51. [PMID: 29285682 DOI: 10.1007/s10151-017-1739-0] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2017] [Accepted: 11/23/2017] [Indexed: 12/18/2022]
Abstract
BACKGROUND Injection of autologous fat is an established method within plastic surgery for soft tissue augmentation. The aim of the present study was to determine whether transperineal fat graft injection could promote healing of anovaginal fistulas. METHODS The procedures were performed at the University Hospital of North Norway, Tromsø, Norway, and at Aarhus University Hospital, Aarhus, Denmark, between May 2009 and September 2016. After abdominal liposuction, fat was injected around the fistula tract that was finally transected percutaneously with a sharp cannula and fat injected between the cut parts. The internal opening was closed with a suture. Patients had a minimum follow-up of 6 months after last fat graft injection. RESULTS Twenty-seven women underwent 48 procedures. The cause of fistula was obstetric (n = 9), abscess (n = 9), Crohn's disease (n = 7), radiation for anal cancer (n = 1) and endoscopic surgery after radiation for rectal cancer (n = 1). The mean amount of injected fat was 73 ml (SD ± 20 ml), and operating time was 63 min (SD ± 21 min). At median follow-up of 20 months (range 6-87 months) after the last injection, fistulas were healed in 21 women (77%), in 8 women after just one procedure. Healing was achieved in 6 of 7 women (86%) with Crohn's disease and in both women who had undergone radiation therapy. One woman developed an abscess and additional trans-sphincteric fistula 8 weeks after injection. CONCLUSIONS Fat graft injection for anovaginal fistulas is effective and safe.
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Affiliation(s)
- S Norderval
- Department of Gastrointestinal Surgery, University Hospital of North Norway, 9038, Tromsø, Norway. .,Gastrosurgical Research Group, Department of Clinical Medicine, UiT the Arctic University of Norway, Tromsø, Norway. .,Norwegian National Advisory Unit on Incontinence and Pelvic Floor Health of Norway, University Hospital of North Norway, Tromsø, Norway.
| | - L Lundby
- Department of Surgery, Pelvic Floor Unit, Aarhus University Hospital, Aarhus, Denmark
| | - H Hougaard
- Department of Surgery, Pelvic Floor Unit, Aarhus University Hospital, Aarhus, Denmark
| | - S Buntzen
- Department of Gastrointestinal Surgery, University Hospital of North Norway, 9038, Tromsø, Norway.,Gastrosurgical Research Group, Department of Clinical Medicine, UiT the Arctic University of Norway, Tromsø, Norway.,Norwegian National Advisory Unit on Incontinence and Pelvic Floor Health of Norway, University Hospital of North Norway, Tromsø, Norway
| | - S Weum
- Department of Radiology, University Hospital of North Norway, Tromsø, Norway.,Medical Imaging Research Group, Department of Clinical Medicine, UiT The Arctic University of Norway, Tromsø, Norway
| | - L de Weerd
- Medical Imaging Research Group, Department of Clinical Medicine, UiT The Arctic University of Norway, Tromsø, Norway.,Department of Plastic Surgery, University Hospital of North Norway, Tromsø, Norway
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34
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Wang Y, Feng Q, Ji C, Liu X, Li L, Luo J. RUNX3 plays an important role in mediating the BMP9-induced osteogenic differentiation of mesenchymal stem cells. Int J Mol Med 2017; 40:1991-1999. [PMID: 29039519 DOI: 10.3892/ijmm.2017.3155] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2016] [Accepted: 09/08/2017] [Indexed: 11/06/2022] Open
Abstract
Although bone morphogenetic protein 9 (BMP9) is highly capable of promoting the osteogenic differentiation of mesenchymal stem cells (MSCs) both in vitro and in vivo, the molecular mechanisms involved remain to be fully elucidated. Runt-related transcription factor (RUNX)3 is an essential regulator of osteoblast/chondrocyte maturation. However, the exact role of RUNX3 in BMP9 osteoinductive activity is unknown. In this study, we sought to investigate the functional role of RUNX3 in the BMP9-induced osteogenic differentiation of MSCs. We found that BMP9 upregulated the endogenous expression of RUNX3 in MSCs. The overexpression or/and knockdown of RUNX3 both increased the levels of alkaline phosphatase (ALP) a marker of BMP9-induced early osteogenic differentiation. Nevertheless, matrix mineralization, a marker of BMP9-induced late osteogenic differentiation was enhanced by the overexpression of RUNX3, whereas it was inhibited by the knockdown of RUNX3. The BMP9-induced expression of osteogenic pivotal transcription factors [inhibitor of differentiation (Id)3, distal-less homeobox 5 (DLX5) and RUNX2)] was further increased by the overexpression of RUNX3; however, it was reduced by the knockdown of RUNX3. However, the expression levels of Id1 and Id2 were both enhanced by the overexpression or/and knockdown of RUNX3. The BMP9-induced phosphorylation of Smad1/5/8 was increased with the overexpression of RUNX3, and yet was decreased with the knockdown of RUNX3. Collectively, our findings suggest that RUNX3 is an essential modulator of the BMP9-induced osteoblast lineage differentiation of MSCs.
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Affiliation(s)
- Yufeng Wang
- Key Laboratory of Diagnostic Medicine Designated by The Chinese Ministry of Education, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Qiaoling Feng
- Key Laboratory of Diagnostic Medicine Designated by The Chinese Ministry of Education, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Caixia Ji
- Key Laboratory of Diagnostic Medicine Designated by The Chinese Ministry of Education, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Xiaohua Liu
- Key Laboratory of Diagnostic Medicine Designated by The Chinese Ministry of Education, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Li Li
- Key Laboratory of Diagnostic Medicine Designated by The Chinese Ministry of Education, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Jinyong Luo
- Key Laboratory of Diagnostic Medicine Designated by The Chinese Ministry of Education, Chongqing Medical University, Chongqing 400016, P.R. China
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35
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Ansari S, Chen C, Hasani-Sadrabadi MM, Yu B, Zadeh HH, Wu BM, Moshaverinia A. Hydrogel elasticity and microarchitecture regulate dental-derived mesenchymal stem cell-host immune system cross-talk. Acta Biomater 2017; 60:181-189. [PMID: 28711686 DOI: 10.1016/j.actbio.2017.07.017] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2017] [Revised: 06/22/2017] [Accepted: 07/10/2017] [Indexed: 12/20/2022]
Abstract
The host immune system (T-lymphocytes and their pro-inflammatory cytokines) has been shown to compromise bone regeneration ability of mesenchymal stem cells (MSCs). We have recently shown that hydrogel, used as an encapsulating biomaterial affects the cross-talk among host immune cells and MSCs. However, the role of hydrogel elasticity and porosity in regulation of cross-talk between dental-derived MSCs and immune cells is unclear. In this study, we demonstrate that the modulus of elasticity and porosity of the scaffold influence T-lymphocyte-dental MSC interplay by regulating the penetration of inflammatory T cells and their cytokines. Moreover, we demonstrated that alginate hydrogels with different elasticity and microporous structure can regulate the viability and determine the fate of the encapsulated MSCs through modulation of NF-kB pathway. Our in vivo data show that alginate hydrogels with smaller pores and higher elasticity could prevent pro-inflammatory cytokine-induced MSC apoptosis by down-regulating the Caspase-3- and 8- associated proapoptotic cascades, leading to higher amounts of ectopic bone regeneration. Additionally, dental-derived MSCs encapsulated in hydrogel with higher elasticity exhibited lower expression levels of NF-kB p65 and Cox-2 in vivo. Taken together, our findings demonstrate that the mechanical characteristics and microarchitecture of the microenvironment encapsulating MSCs, in addition to presence of T-lymphocytes and their pro-inflammatory cytokines, affect the fate of encapsulated dental-derived MSCs. STATEMENT OF SIGNIFICANCE In this study, we demonstrate that alginate hydrogel regulates the viability and the fate of the encapsulated dental-derived MSCs through modulation of NF-kB pathway. Alginate hydrogels with smaller pores and higher elasticity prevent pro-inflammatory cytokine-induced MSC apoptosis by down-regulating the Caspase-3- and 8- associated proapoptotic cascade, leading to higher amounts of ectopic bone regeneration. MSCs encapsulated in hydrogel with higher elasticity exhibited lower expression levels of NF-kB p65 and Cox-2 in vivo. These findings confirm that the fate of encapsulated MSCs are affected by the stiffness and microarchitecture of the encapsulating hydrogel biomaterial, as well as presence of T-lymphocytes/pro-inflammatory cytokines providing evidence concerning material science, stem cell biology, the molecular mechanism of dental-derived MSC-associated therapies, and the potential clinical therapeutic impact of MSCs.
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Ji C, Liu X, Xu L, Yu T, Dong C, Luo J. RUNX1 Plays an Important Role in Mediating BMP9-Induced Osteogenic Differentiation of Mesenchymal Stem Cells Line C3H10T1/2, Murine Multi-Lineage Cells Lines C2C12 and MEFs. Int J Mol Sci 2017. [PMID: 28644396 PMCID: PMC5535841 DOI: 10.3390/ijms18071348] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
As one of the least studied bone morphogenetic proteins (BMPs), BMP9 is highly capable of promoting osteogenic differentiation. However, the underlying mechanism involved remains largely unknown. Recent studies have demonstrated that RUNX1 (runt-related transcription factor 1) is essential in osteoblast/chondrocyte maturation. In this study, we investigated the function of RUNX1 in BMP9-induced osteogenic of murine mesenchymal stem cell line (C3H10T1/2) and murine multi-lineage cell lines (C2C12 and MEFs). Our data showed that BMP9 promoted the endogenous expression of RUNX1 in C3H10T1/2, C2C12 and MEFs. Moreover, RUNX1 was probably a direct target of BMP9/Smad signaling. BMP9-induced osteogenic differentiation was enhanced by overexpression of RUNX1, whereas inhibited by knockdown RUNX1 in C3H10T1/2, C2C12 and MEFs. Further mechanism studies demonstrated that RUNX1 might affect BMP9-induced phosphorylation of Smad1/5/8, but not the phosphorylation of p38 and ERK1/2.Our results suggest that RUNX1 may be an essential modulator in BMP9- induced osteogenic differentiation of MSCs (Mesenchymal stem cells).
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Affiliation(s)
- Caixia Ji
- Department of Laboratory Medicine, M.O.E. Key Laboratory of Laboratory Medicine Diagnostics, Chongqing Medical University, Chongqing 400016,China.
| | - Xiaohua Liu
- Department of Laboratory Medicine, M.O.E. Key Laboratory of Laboratory Medicine Diagnostics, Chongqing Medical University, Chongqing 400016,China.
| | - Li Xu
- Department of Laboratory Medicine, M.O.E. Key Laboratory of Laboratory Medicine Diagnostics, Chongqing Medical University, Chongqing 400016,China.
| | - Tingting Yu
- Department of Laboratory Medicine, M.O.E. Key Laboratory of Laboratory Medicine Diagnostics, Chongqing Medical University, Chongqing 400016,China.
| | - Chaoqun Dong
- Department of Laboratory Medicine, M.O.E. Key Laboratory of Laboratory Medicine Diagnostics, Chongqing Medical University, Chongqing 400016,China.
| | - Jinyong Luo
- Department of Laboratory Medicine, M.O.E. Key Laboratory of Laboratory Medicine Diagnostics, Chongqing Medical University, Chongqing 400016,China.
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Diaz de la Guardia R, Lopez-Millan B, Lavoie JR, Bueno C, Castaño J, Gómez-Casares M, Vives S, Palomo L, Juan M, Delgado J, Blanco ML, Nomdedeu J, Chaparro A, Fuster JL, Anguita E, Rosu-Myles M, Menéndez P. Detailed Characterization of Mesenchymal Stem/Stromal Cells from a Large Cohort of AML Patients Demonstrates a Definitive Link to Treatment Outcomes. Stem Cell Reports 2017; 8:1573-1586. [PMID: 28528702 PMCID: PMC5470078 DOI: 10.1016/j.stemcr.2017.04.019] [Citation(s) in RCA: 76] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2017] [Revised: 04/15/2017] [Accepted: 04/18/2017] [Indexed: 01/01/2023] Open
Abstract
Bone marrow mesenchymal stem/stromal cells (BM-MSCs) are key components of the hematopoietic niche thought to have a direct role in leukemia pathogenesis. BM-MSCs from patients with acute myeloid leukemia (AML) have been poorly characterized due to disease heterogeneity. We report a functional, genetic, and immunological characterization of BM-MSC cultures from 46 AML patients, stratified by molecular/cytogenetics into low-risk (LR), intermediate-risk (IR), and high-risk (HR) subgroups. Stable MSC cultures were successfully established and characterized from 40 of 46 AML patients irrespective of the risk subgroup. AML-derived BM-MSCs never harbored tumor-specific cytogenetic/molecular alterations present in blasts, but displayed higher clonogenic potential than healthy donor (HD)-derived BM-MSCs. Although HD- and AML-derived BM-MSCs equally provided chemoprotection to AML cells in vitro, AML-derived BM-MSCs were more immunosuppressive/anti-inflammatory, enhanced suppression of lymphocyte proliferation, and diminished secretion of pro-inflammatory cytokines. Multivariate analysis revealed that the level of interleukin-10 produced by AML-derived BM-MSCs as an independent prognostic factor negatively affected overall survival. Collectively our data show that AML-derived BM-MSCs are not tumor related, but display functional differences contributing to therapy resistance and disease evolution.
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Affiliation(s)
- Rafael Diaz de la Guardia
- Josep Carreras Leukemia Research Institute, Department of Biomedicine, School of Medicine, Universitat de Barcelona, Casanova 143, Barcelona 08036, Spain; Centro de Investigación Biomédica en Red-Oncología (CIBERONC), ISCIII, Madrid 28031, Spain.
| | - Belen Lopez-Millan
- Josep Carreras Leukemia Research Institute, Department of Biomedicine, School of Medicine, Universitat de Barcelona, Casanova 143, Barcelona 08036, Spain; Centro de Investigación Biomédica en Red-Oncología (CIBERONC), ISCIII, Madrid 28031, Spain
| | - Jessie R Lavoie
- Regulatory Research Division, Centre for Biologics Evaluation, Biologics and Genetic Therapies Directorate, Health Canada, Ottawa, ON K1A 0L2, Canada
| | - Clara Bueno
- Josep Carreras Leukemia Research Institute, Department of Biomedicine, School of Medicine, Universitat de Barcelona, Casanova 143, Barcelona 08036, Spain; Centro de Investigación Biomédica en Red-Oncología (CIBERONC), ISCIII, Madrid 28031, Spain
| | - Julio Castaño
- Josep Carreras Leukemia Research Institute, Department of Biomedicine, School of Medicine, Universitat de Barcelona, Casanova 143, Barcelona 08036, Spain; Centro de Investigación Biomédica en Red-Oncología (CIBERONC), ISCIII, Madrid 28031, Spain
| | - Maite Gómez-Casares
- Servicio de Hematología, Hospital Universitario de Gran Canaria Dr. Negrin, Las Palmas de Gran Canaria 35010, Spain
| | - Susana Vives
- Hematology Department, ICO-Hospital Germans Trias i Pujol, Badalona 08916, Spain; Josep Carreras Leukemia Research Institute, Universitat Autònoma Barcelona, Barcelona 08193, Spain
| | - Laura Palomo
- Hematology Department, ICO-Hospital Germans Trias i Pujol, Badalona 08916, Spain; Josep Carreras Leukemia Research Institute, Universitat Autònoma Barcelona, Barcelona 08193, Spain
| | - Manel Juan
- Servicio de Inmunología, Hospital Clínico de Barcelona, Barcelona 08036, Spain
| | - Julio Delgado
- Centro de Investigación Biomédica en Red-Oncología (CIBERONC), ISCIII, Madrid 28031, Spain; Servicio de Hematología, Hospital Clínico de Barcelona, Barcelona 08036, Spain
| | - Maria L Blanco
- Servicio de Hematología, Hospital de la Santa Creu I Sant Pau, Barcelona 08041, Spain
| | - Josep Nomdedeu
- Servicio de Hematología, Hospital de la Santa Creu I Sant Pau, Barcelona 08041, Spain
| | - Alberto Chaparro
- Hematology Department, Hospital Clínico San Carlos, Universidad Complutense de Madrid, Madrid 28040, Spain
| | - Jose Luis Fuster
- Sección de Oncohematología Pediátrica, Hospital Clínico Virgen de Arrixaca, Murcia 30120, Spain
| | - Eduardo Anguita
- Hematology Department, Hospital Clínico San Carlos, Universidad Complutense de Madrid, Madrid 28040, Spain
| | - Michael Rosu-Myles
- Regulatory Research Division, Centre for Biologics Evaluation, Biologics and Genetic Therapies Directorate, Health Canada, Ottawa, ON K1A 0L2, Canada.
| | - Pablo Menéndez
- Josep Carreras Leukemia Research Institute, Department of Biomedicine, School of Medicine, Universitat de Barcelona, Casanova 143, Barcelona 08036, Spain; Centro de Investigación Biomédica en Red-Oncología (CIBERONC), ISCIII, Madrid 28031, Spain; Instituciò Catalana de Recerca i Estudis Avançats (ICREA), Barcelona 08010, Spain.
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Hypoxia modulates cell migration and proliferation in placenta-derived mesenchymal stem cells. J Thorac Cardiovasc Surg 2017; 154:543-552.e3. [PMID: 28526501 DOI: 10.1016/j.jtcvs.2017.03.141] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2016] [Revised: 02/28/2017] [Accepted: 03/13/2017] [Indexed: 12/26/2022]
Abstract
OBJECTIVES For more than a decade, stem cells isolated from different tissues have been evaluated in cell therapy. Among them, the human bone marrow-derived mesenchymal stem cells (hBM-MSCs) were investigated extensively in the treatment of myocardial infarction. Recently, the human placenta-derived mesenchymal stem cells (hPD-MSCs), which are readily available from a biological waste, appear to be a viable alternative to hBM-MSCs. METHODS C-X-C chemokine receptor type 4 (CXCR4) gene expression and localization were detected and validated in hPD-MSCs and hBM-MSCs via polymerase chain reaction and immunofluorescence. Subsequently, cell culture conditions for CXCR4 expression were optimized in stromal-derived factor-1 alpha (SDF1-α), glucose, and cobalt chloride (CoCl2) by the use of cell viability, proliferation, and migration assays. To elucidate the cell signaling pathway, protein expression of CXCR4, hypoxia-inducible factor-1α, interleukin-6, Akt, and extracellular signal-regulated kinase were analyzed by Western blot. CXCR4-positive cells were sorted and analyzed by florescence-activated cell sorting. RESULTS CXCR4 was expressed on both hPD-MSCs and hBM-MSCs at the basal level. HPD-MSCs were shown to have a greater sensitivity to SDF-1α-dependent cell migration compared with hBM-MSCs. In addition, CXCR4 expression was significantly greater in both hPD-MSCs and hBM-MSCs with SDF-1α or CoCl2-induced hypoxia treatment. However, CXCR4+ hPD-MSCs population increased by 10-fold in CoCl2-induced hypoxia. In contrast, only a 2-fold increase was observed in the CXCR4+ hBM-MSCs population in similar conditions. After CoCl2-induced hypoxia, the CXCR4/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase signaling pathway was activated prominently in hPD-MSCs, whereas in hBM-MSCs, the CXCR4/phosphatidylinositol 3-kinase/Akt pathway was triggered. CONCLUSIONS Our current results suggest that hPD-MSCs could represent a viable and effective alternative to hBM-MSCs for translational studies in cardiocellular repair.
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"Neuronal-Like Differentiation of Murine Mesenchymal Stem Cell Line: Stimulation by Juglans regia L. Oil". Appl Biochem Biotechnol 2017; 183:385-395. [PMID: 28289857 DOI: 10.1007/s12010-017-2452-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2016] [Accepted: 03/02/2017] [Indexed: 10/20/2022]
Abstract
Mesenchymal stem cells have been extensively used for cell-based therapies especially in neuronal diseases. Studies still continue to delineate mechanisms involved in differentiating mesenchymal stem cells into neuronal cells under experimental conditions as they have low mortality rate and hence, the number of cells available for experiments is much more limited. Culturing and differentiating of neuronal cell is more challenging as they do not undergo cell division thus, bringing them to differentiate proves to be a difficult task. Here, the aim of this study is to investigate whether Juglans regia L. (walnut oil) differentiates multipotent, C3H10T1/2 cells, a murine mesenchymal stem cell line, into neuronal cells. A simple treatment protocol induced C3H10T1/2 cells to exhibit a neuronal phenotype. With this optimal differentiation protocol, almost all cells exhibited neuronal morphology. The cell bodies extended long processes. C3H10T1/2 cells were plated and treated with walnut oil post 24 h of plating. The treatment was given (with walnut oil treated cultures with or without control cultures) at different concentrations. The cultured cells were then stained with cresyl violet acetate solution which was used to stain the Nissl substance in the cytoplasm of the induced neuronal culture. The results indicated that the C3H10T1/2 cells differentiated into neuronal-like cells with long outgrowths of axon-like structures able to take up the cresyl violet acetate stain indicating their preliminary differentiation into neuronal-like morphology with walnut oil treatment. Treating the mesenchymal stem cells can in future establish a cultured mesenchymal stem cell line as neuronal differentiating cell line model.
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Perrod G, Pidial L, Camilleri S, Bellucci A, Casanova A, Viel T, Tavitian B, Cellier C, Clément O, Rahmi G. ADSC-sheet Transplantation to Prevent Stricture after Extended Esophageal Endoscopic Submucosal Dissection. J Vis Exp 2017. [PMID: 28287510 DOI: 10.3791/55018] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
In past years, the cell-sheet construct has spurred wide interest in regenerative medicine, especially for reconstructive surgery procedures. The development of diversified technologies combining adipose tissue-derived stromal cells (ADSCs) with various biomaterials has led to the construction of numerous types of tissue-engineered substitutes, such as bone, cartilage, and adipose tissues from rodent, porcine, or human ADSCs. Extended esophageal endoscopic submucosal dissection (ESD) is responsible for esophageal stricture formation. Stricture prevention remains challenging, with no efficient treatments available. Previous studies reported the effectiveness of mucosal cell-sheet transplantation in a canine model and in humans. ADSCs are attributed anti-inflammatory properties, local immune modulating effects, neovascularization induction, and differentiation abilities into mesenchymal and non-mesenchymal lineages. This original study describes the endoscopic transplantation of an ADSC tissue-engineered construct to prevent esophageal stricture in a swine model. The ADSC construct was composed of two allogenic ADSC sheets layered upon each other on a paper support membrane. The ADSCs were labeled with the PKH67 fluorophore to allow probe-based confocal laser endomicroscopy (pCLE) monitoring. On the day of transplantation, a 5-cm and hemi-circumferential ESD known to induce esophageal stricture was performed. Animals were immediately endoscopically transplanted with 4 ADSC constructs. The complete adhesion of the ADSC constructs was obtained after 10 min of gentle application. Animals were sacrificed on day 28. All animals were successfully transplanted. Transplantation was confirmed on day 3 with a positive pCLE evaluation. Compared to transplanted animals, control animals developed severe strictures, with major fibrotic tissue development, more frequent alimentary trouble, and reduced weight gain. In our model, the transplantation of allogenic ADSCs, organized in double cell sheets, after extended ESD was successful and strongly associated with a lower esophageal stricture rate.
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Affiliation(s)
- Guillaume Perrod
- Assistance Publique-Hôpitaux de Paris, Université Paris Descartes Sorbonne Paris Cité; Department of Gastroenterology, Hôpital Européen Georges Pompidou; UMR-S970, Université Paris Descartes Sorbonne Paris Cité
| | | | - Sophie Camilleri
- Assistance Publique-Hôpitaux de Paris, Université Paris Descartes Sorbonne Paris Cité; Department of Pathology, Hôpital Européen Georges Pompidou
| | - Alexandre Bellucci
- Assistance Publique-Hôpitaux de Paris, Université Paris Descartes Sorbonne Paris Cité; UMR-S970, Université Paris Descartes Sorbonne Paris Cité; Department of Radiology, Hôpital Européen Georges Pompidou
| | | | - Thomas Viel
- UMR-S970, Université Paris Descartes Sorbonne Paris Cité
| | - Bertrand Tavitian
- Assistance Publique-Hôpitaux de Paris, Université Paris Descartes Sorbonne Paris Cité; UMR-S970, Université Paris Descartes Sorbonne Paris Cité; Department of Radiology, Hôpital Européen Georges Pompidou
| | - Chirstophe Cellier
- Assistance Publique-Hôpitaux de Paris, Université Paris Descartes Sorbonne Paris Cité; Department of Gastroenterology, Hôpital Européen Georges Pompidou
| | - Olivier Clément
- Assistance Publique-Hôpitaux de Paris, Université Paris Descartes Sorbonne Paris Cité; UMR-S970, Université Paris Descartes Sorbonne Paris Cité; Department of Radiology, Hôpital Européen Georges Pompidou
| | - Gabriel Rahmi
- Assistance Publique-Hôpitaux de Paris, Université Paris Descartes Sorbonne Paris Cité; Department of Gastroenterology, Hôpital Européen Georges Pompidou; UMR-S970, Université Paris Descartes Sorbonne Paris Cité;
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De Francesco F, Graziano A, Trovato L, Ceccarelli G, Romano M, Marcarelli M, Cusella De Angelis GM, Cillo U, Riccio M, Ferraro GA. A Regenerative Approach with Dermal Micrografts in the Treatment of Chronic Ulcers. Stem Cell Rev Rep 2016; 13:139-148. [DOI: 10.1007/s12015-016-9692-2] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
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Valencia J, Blanco B, Yáñez R, Vázquez M, Herrero Sánchez C, Fernández-García M, Rodríguez Serrano C, Pescador D, Blanco JF, Hernando-Rodríguez M, Sánchez-Guijo F, Lamana ML, Segovia JC, Vicente Á, Del Cañizo C, Zapata AG. Comparative analysis of the immunomodulatory capacities of human bone marrow– and adipose tissue–derived mesenchymal stromal cells from the same donor. Cytotherapy 2016; 18:1297-311. [DOI: 10.1016/j.jcyt.2016.07.006] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2016] [Revised: 07/01/2016] [Accepted: 07/28/2016] [Indexed: 02/09/2023]
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Tang YH, Pennington LA, Scordino JW, Alexander JS, Lian T. Dynamics of early stem cell recruitment in skin flaps subjected to ischemia reperfusion injury. ACTA ACUST UNITED AC 2016; 23:221-8. [PMID: 27480360 DOI: 10.1016/j.pathophys.2016.07.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2016] [Revised: 07/15/2016] [Accepted: 07/24/2016] [Indexed: 12/17/2022]
Abstract
OBJECTIVE Bone marrow-derived stromal cell (BMSCs) therapy improves survival of skin flaps subject to ischemia/reperfusion (I/R) injury. However, very little is known about the trafficking and distribution of BMSCs in post-ischemic skin tissue following intravenous administration. The aim of this study was to assess the behavior of BMSCs in post-ischemic skin flaps and to compare the magnitude and kinetics of accumulation of BMSCs and leukocytes following I/R. METHODS Cutaneous flaps perfused by the inferior epigastric vessels were created in C57Bl6 mice. The flaps were subjected to 3.5h of ischemia followed by reperfusion. Wound healing and vascular perfusion were assessed in 3 groups of mice (sham, I/R, and I/R+BMSCs treatment) on days 3, 5, 7 and 14 post-reperfusion. The kinetics and magnitude of BMSCs and leukocyte recruitment were quantified in additional 2 groups (Sham and I/R) after I/R using intravital fluorescence microscopy at 2 and 4h after the intravenous injection of fluorescently labeled BMSCs. RESULTS Wound healing after I/R was significantly enhanced in skin flaps of mice treated with BMSCs, compared to controls. The rolling velocity of BMSCs was higher compared to leukocytes both in control mice (32.4±3.7μm/s vs 24.0±2.2μm/s, p<0.05) and in I/R mice (34.6±3.8μm/s vs 20.2±2.3μm/s, p<0.005). However, the rolling velocity of both cell populations was not altered by I/R. The firm adhesion and transendothelial migration of BMSCs did not differ from the values detected for leukocytes for both control and I/R mice. CONCLUSIONS The magnitude and kinetics of BMSCs recruitment in skin flaps subjected to I/R are not significantly different from the responses noted for leukocytes, suggesting that similar mechanisms may be involved in the recruitment of both cell populations following I/R.
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Affiliation(s)
- Ya Hui Tang
- Department of Otolaryngology/HNS, LSU Health Sciences Center, Shreveport, LA 71130, United States.
| | - Lindsey A Pennington
- Department of Otolaryngology/HNS, LSU Health Sciences Center, Shreveport, LA 71130, United States
| | - Jessica W Scordino
- Department of Otolaryngology/HNS, LSU Health Sciences Center, Shreveport, LA 71130, United States
| | | | - Timothy Lian
- Department of Otolaryngology/HNS, LSU Health Sciences Center, Shreveport, LA 71130, United States
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Perrod G, Rahmi G, Pidial L, Camilleri S, Bellucci A, Casanova A, Viel T, Tavitian B, Cellier C, Clement O. Cell Sheet Transplantation for Esophageal Stricture Prevention after Endoscopic Submucosal Dissection in a Porcine Model. PLoS One 2016; 11:e0148249. [PMID: 26930409 PMCID: PMC4773126 DOI: 10.1371/journal.pone.0148249] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2015] [Accepted: 01/16/2016] [Indexed: 12/25/2022] Open
Abstract
Background & Aims Extended esophageal endoscopic submucosal dissection (ESD) is highly responsible for esophageal stricture. We conducted a comparative study in a porcine model to evaluate the effectiveness of adipose tissue-derived stromal cell (ADSC) double cell sheet transplantation. Methods Twelve female pigs were treated with 5 cm long hemi-circumferential ESD and randomized in two groups. ADSC group (n = 6) received 4 double cell sheets of allogenic ADSC on a paper support membrane and control group (n = 6) received 4 paper support membranes. ADSC were labelled with PKH-67 fluorophore to allow probe-based confocal laser endomicroscopie (pCLE) monitoring. After 28 days follow-up, animals were sacrificed. At days 3, 14 and 28, endoscopic evaluation with pCLE and esophagography were performed. Results One animal from the control group was excluded (anesthetic complication). Animals from ADSC group showed less frequent alimentary trouble (17% vs 80%; P = 0.08) and higher gain weight on day 28. pCLE demonstrated a compatible cell signal in 4 animals of the ADSC group at day 3. In ADSC group, endoscopy showed that 1 out of 6(17%) animals developed a severe esophageal stricture comparatively to 100% (5/5) in the control group; P = 0.015. Esophagography demonstrated a decreased degree of stricture in the ADSC group on day 14 (44% vs 81%; P = 0.017) and day 28 (46% vs 90%; P = 0.035). Histological analysis showed a decreased fibrosis development in the ADSC group, in terms of surface (9.7 vs 26.1 mm²; P = 0.017) and maximal depth (1.6 vs 3.2 mm; P = 0.052). Conclusion In this model, transplantation of allogenic ADSC organized in double cell sheets after extended esophegeal ESD is strongly associated with a lower esophageal stricture’s rate.
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Affiliation(s)
- Guillaume Perrod
- Université Paris Descartes Sorbonne Paris cité, Assistance Publique-Hôpitaux de Paris, Department of Gastroenterology, Hôpital Européen Georges Pompidou, 20 rue Leblanc, 75015 Paris, France
- Université Paris Descartes Sorbonne Paris cité, Laboratoire imagerie de l’angiogenèse et plateforme d’imagerie du petit animal, UMR-S970, 56 rue Leblanc, 75015 Paris, France
- Université Paris Descartes Sorbonne Paris cité, Laboratory of biosurgical research, UMR-U633, 56 rue Leblanc, 75015 Paris, France
| | - Gabriel Rahmi
- Université Paris Descartes Sorbonne Paris cité, Assistance Publique-Hôpitaux de Paris, Department of Gastroenterology, Hôpital Européen Georges Pompidou, 20 rue Leblanc, 75015 Paris, France
- Université Paris Descartes Sorbonne Paris cité, Laboratoire imagerie de l’angiogenèse et plateforme d’imagerie du petit animal, UMR-S970, 56 rue Leblanc, 75015 Paris, France
- Université Paris Descartes Sorbonne Paris cité, Laboratory of biosurgical research, UMR-U633, 56 rue Leblanc, 75015 Paris, France
- * E-mail:
| | - Laetitia Pidial
- Université Paris Descartes Sorbonne Paris cité, Laboratoire imagerie de l’angiogenèse et plateforme d’imagerie du petit animal, UMR-S970, 56 rue Leblanc, 75015 Paris, France
| | - Sophie Camilleri
- Université Paris Descartes Sorbonne Paris cité, Assistance Publique-Hôpitaux de Paris, Department of Pathology, Hôpital Européen Georges Pompidou, 20 rue Leblanc, 75015 Paris, France
| | - Alexandre Bellucci
- Université Paris Descartes Sorbonne Paris cité, Laboratoire imagerie de l’angiogenèse et plateforme d’imagerie du petit animal, UMR-S970, 56 rue Leblanc, 75015 Paris, France
- Université Paris Descartes Sorbonne Paris cité Assistance Publique-Hôpitaux de Paris, Department of Radiology, Hôpital Européen Georges Pompidou, 20 rue Leblanc, 75015 Paris, France
| | - Amaury Casanova
- Université Paris Descartes Sorbonne Paris cité, Laboratoire imagerie de l’angiogenèse et plateforme d’imagerie du petit animal, UMR-S970, 56 rue Leblanc, 75015 Paris, France
| | - Thomas Viel
- Université Paris Descartes Sorbonne Paris cité, Laboratoire imagerie de l’angiogenèse et plateforme d’imagerie du petit animal, UMR-S970, 56 rue Leblanc, 75015 Paris, France
| | - Bertrand Tavitian
- Université Paris Descartes Sorbonne Paris cité, Laboratoire imagerie de l’angiogenèse et plateforme d’imagerie du petit animal, UMR-S970, 56 rue Leblanc, 75015 Paris, France
- Université Paris Descartes Sorbonne Paris cité Assistance Publique-Hôpitaux de Paris, Department of Radiology, Hôpital Européen Georges Pompidou, 20 rue Leblanc, 75015 Paris, France
| | - Christophe Cellier
- Université Paris Descartes Sorbonne Paris cité, Assistance Publique-Hôpitaux de Paris, Department of Gastroenterology, Hôpital Européen Georges Pompidou, 20 rue Leblanc, 75015 Paris, France
| | - Olivier Clement
- Université Paris Descartes Sorbonne Paris cité, Laboratoire imagerie de l’angiogenèse et plateforme d’imagerie du petit animal, UMR-S970, 56 rue Leblanc, 75015 Paris, France
- Université Paris Descartes Sorbonne Paris cité Assistance Publique-Hôpitaux de Paris, Department of Radiology, Hôpital Européen Georges Pompidou, 20 rue Leblanc, 75015 Paris, France
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Modern Treatments and Stem Cell Therapies for Perianal Crohn's Fistulas. Can J Gastroenterol Hepatol 2016; 2016:1651570. [PMID: 28053967 PMCID: PMC5174164 DOI: 10.1155/2016/1651570] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/29/2016] [Accepted: 11/03/2016] [Indexed: 12/16/2022] Open
Abstract
Crohn's disease (CD) is a complex disorder with important incidence in North America. Perianal fistulas occur in about 20% of patients with CD and are almost always classified as complex fistulas. Conventional treatment options have shown different success rates, yet there are data indicating that these approaches cannot achieve total cure and may not improve quality of life of these patients. Fibrin glue, fistula plug, topical tacrolimus, local injection of infliximab, and use of hematopoietic stem cells (HSC) and mesenchymal stem cells (MSC) are newly suggested therapies with variable success rates. Here, we aim to review these novel therapies for the treatment of complex fistulizing CD. Although initial results are promising, randomized studies are needed to prove efficacy of these approaches in curing fistulizing perianal CD.
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Díaz-Agero Álvarez PJ, Bellido-Reyes YA, Sánchez-Girón JG, García-Olmo D, García-Arranz M. Novel bronchoscopic treatment for bronchopleural fistula using adipose-derived stromal cells. Cytotherapy 2015; 18:36-40. [PMID: 26552766 DOI: 10.1016/j.jcyt.2015.10.003] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2015] [Revised: 09/18/2015] [Accepted: 10/01/2015] [Indexed: 12/01/2022]
Abstract
BACKGROUND AIMS In this report, we describe the successful bronchoscopic management of bronchopleural fistula in two patients, using autologous adipose-derived stromal cells. Cell therapy was considered for 2 cases of bronchopleural fistula refractory to conventional surgical treatment after control of the primary disease was confirmed and active pleural infection was ruled out. Briefly, adipose-derived stem cells were first isolated from lipoaspirate and used without cell expansion. In 24 months, we have not received more patients with bronchopleural fistula in our hospital and we have not been able to include more patients. METHODS Briefly, adipose-derived stem cells were first isolated from lipo-aspirate and used without cell expansion. A bronchopleural fistula was identified through bronchoscopy, and the mucosa surrounding the fistula was ablated with an argon plasma coagulator. Isolated stem cells were then endoscopically injected into the de-epithelialized area and fistulous tract. If an open thoracostomy was present at the time of the intervention, the same procedure was performed on the pleural side. Bronchoscopic follow-up was scheduled weekly during the first month, monthly during the first year, and then yearly. The underlying etiologies were left pneumonectomy and right lower video-assisted lobectomy for non-small-cell lung cancer. The sizes of the fistulas were 6 mm and 3 mm in diameter, respectively. RESULTS Both patients were discharged on the first postoperative day. The 3-year follow-up revealed a successful and maintained fistula closure, no treatment-related adverse reactions, nonlocal malignant recurrence and improved quality of life. CONCLUSIONS This preliminary study showed that bronchoscopic application of autologous adipose-derived stem cells is a feasible, safe and effective procedure for treating bronchopleural fistula.
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Affiliation(s)
| | | | | | - Damián García-Olmo
- Health Research Institute-Fundación Jiménez Díaz, (IIS-FJD), Madrid, Spain; Department of Surgery, Universidad Autónoma de Madrid, Madrid, Spain
| | - Mariano García-Arranz
- Health Research Institute-Fundación Jiménez Díaz, (IIS-FJD), Madrid, Spain; Department of Surgery, Universidad Autónoma de Madrid, Madrid, Spain.
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Cao Y, Xiong J, Mei S, Wang F, Zhao Z, Wang S, Liu Y. Aspirin promotes bone marrow mesenchymal stem cell-based calvarial bone regeneration in mini swine. Stem Cell Res Ther 2015; 6:210. [PMID: 26519141 PMCID: PMC4628405 DOI: 10.1186/s13287-015-0200-4] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2015] [Revised: 03/17/2015] [Accepted: 10/08/2015] [Indexed: 01/08/2023] Open
Abstract
INTRODUCTION Stem cells have great therapeutic potential due to their capacity for self-renewal and their potential for differentiating into multiple cell lineages. It has been recently shown that the host immune system has fundamental effects on the fate of transplanted mesenchymal stem cells during bone repair, where the topical administration of aspirin is capable of improving calvarial bone repair in rodents by inhibiting tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) production. This study investigates whether aspirin is capable of accelerating the regenerative potential of bone marrow mesenchymal stem cells (BMSC) in a mini swine calvarial bone defect model. METHODS Calvarial bone defects (3 cm × 1.8 cm oval defect) in mini swine were treated with BMSC pretreated with 75 μg/ml aspirin for 24 h seeded onto hydroxyaptite/tricalcium phosphatel (HA/TCP), or with BMSC with HA/TCP, or with HA/TCP only, or remained untreated. Animals were scanned with micro-computed tomography (microCT) at 2 days and 6 months postsurgery and were sacrificed at 6 months postsurgery with decalcified tissues being processed for histomorphometric examination. The cytokine levels, including TNF-α and IFN-γ, were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS Aspirin at 75 μg/ml promoted the osteogenesis of BMSC in vitro and in vivo, shown by Alizarin Red staining and new bone volume in the nude mice transplantation model (p < 0.01), respectively. Defects treated with aspirin-BMSC showed significantly greater new bone fill compared with other three groups at 6 months postsurgery (p < 0.01). Aspirin-BMSC treatment has significantly decreased the concentration of TNF-α and IFN-γ (p < 0.05). CONCLUSIONS The present study shows that BMSC pretreated with aspirin have a greater capacity to repair calvarial bone defects in a mini swine model. The results suggest that the administration of aspirin is capable of improving BMSC-mediated calvarial bone regeneration in a big animal model.
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Affiliation(s)
- Yu Cao
- Department of General Dentistry, School of Stomatology, Capital Medical University, Beijing, P. R. China.
| | - Jimin Xiong
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Tian Tan Xi Li No.4, Beijing, 100050, P. R. China.
| | - Shenghui Mei
- Department of Pharmacy, Beijing Tiantan Hospital, Capital Medical University, Beijing, P. R. China.
| | - Fu Wang
- Molecular Laboratory for Gene Therapy and Tooth Regeneration, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Beijing, P. R. China.
| | - Zhigang Zhao
- Department of Pharmacy, Beijing Tiantan Hospital, Capital Medical University, Beijing, P. R. China.
| | - Songlin Wang
- Molecular Laboratory for Gene Therapy and Tooth Regeneration, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Beijing, P. R. China.
| | - Yi Liu
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Tian Tan Xi Li No.4, Beijing, 100050, P. R. China.
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Ramírez M, García-Castro J, Melen GJ, González-Murillo Á, Franco-Luzón L. Patient-derived mesenchymal stem cells as delivery vehicles for oncolytic virotherapy: novel state-of-the-art technology. Oncolytic Virother 2015; 4:149-55. [PMID: 27512678 PMCID: PMC4918392 DOI: 10.2147/ov.s66010] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Oncolytic virotherapy is gaining interest in the clinic as a new weapon against cancer. In vivo administration of oncolytic viruses showed important limitations that decrease their effectiveness very significantly: the antiviral immune response causes the elimination of the therapeutic effect, and the poor natural ability of oncolytic viruses to infect micrometastatic lesions significantly minimizes the effective dose of virus. This review will focus on updating the technical and scientific foundations of one of the strategies developed to overcome these limitations, ie, using cells as vehicles for oncolytic viruses. Among many candidates, a special type of adult stem cell, mesenchymal stem cells (MSCs), have already been used in the clinic as cell vehicles for oncolytic viruses, partly due to the fact that these cells are actively being evaluated for other indications. MSC carrier cells are used as Trojan horses loaded with oncoviruses, are administered systemically, and release their cargos at the right places. MSCs are equipped with an array of molecules involved in cell arrest in the capillaries (integrins and selectins), migration toward specific parenchymal locations within tissues (chemokine receptors), and invasion and degradation of the extracellular matrix (proteases). In addition to anatomical targeting capacity, MSCs have a well-recognized role in modulating immune responses by affecting cells of the innate (antigen-presenting cells, natural killer cells) and adaptive immune system (effector and regulatory lymphocytes). Therefore, carrier MSCs may also modulate the immune responses taking place after therapy, ie, the antiviral and the antitumor immune responses.
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Affiliation(s)
- Manuel Ramírez
- Oncohematología, Hospital Universitario Niño Jesús, Madrid, Spain
| | | | - Gustavo J Melen
- Oncohematología, Hospital Universitario Niño Jesús, Madrid, Spain
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Garcia-Olmo D, Schwartz DA. Cumulative Evidence That Mesenchymal Stem Cells Promote Healing of Perianal Fistulas of Patients With Crohn's Disease--Going From Bench to Bedside. Gastroenterology 2015; 149:853-7. [PMID: 26311275 DOI: 10.1053/j.gastro.2015.08.038] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Affiliation(s)
- Damian Garcia-Olmo
- Department of Surgery (Fundacion Jimenez Diaz), Universidad Autonoma de Madrid, Madrid, Spain.
| | - David A Schwartz
- Inflammatory Bowel Disease Center, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
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Jo H, Jung M, Seo DJ, Park DJ. The effect of rat bone marrow derived mesenchymal stem cells transplantation for restoration of olfactory disorder. Biochem Biophys Res Commun 2015; 467:395-9. [PMID: 26427869 DOI: 10.1016/j.bbrc.2015.09.142] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2015] [Accepted: 09/26/2015] [Indexed: 11/15/2022]
Abstract
The purpose of the study was to investigate the effect of bone marrow-derived mesenchymal stem cells (BMSCs) transplantation on olfactory epithelium (OE) of morphologic and functional restoration following neural Sensorineural Disorder in rats. Except the Normal group, twenty-one rats underwent Triton X-100 (TX-100) irrigation to induce degeneration of OE, and then BMSCs and PBS were treated from the both medial canthus to the rear part of the both nasal cavity into the experimental group and then were observed for restoration according to time point. At two and four weeks after transplantation with BMSCs, restoration of OE was observed with olfactory marker protein (OMP) and behavioral test. And we observed the expression of OMP, nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF). After TX-100 irrigation, the OE almost disappeared in 3 days. At four weeks after transplantation with BMSCs, the thickness and cellular composition of OE was considerably restored to normal group and expression of OMP was markedly increased when compared with PBS group and reduced the searching time in the behavioral test. Furthermore at two weeks after treatment with BMSCs, expression of NGF and BDNF was greatly increased when compared with PBS group. However at four weeks after treatment with BMSCs, expression of NGF and BDNF was slightly decreased. Our results suggest the BMSCs transplantation affect restoration of OE and olfaction, most likely via regulation of the neurotrophic factor expression, especially the expression of NGF and BDNF and has a possibility of a new therapeutic strategy for the treatment of olfactory disorder caused by the degeneration of OE.
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Affiliation(s)
- Hyogyeong Jo
- Department of Otorhinolaryngology, Yonsei University Wonju College of Medicine, 20 Ilsan-ro, Wonju, 220-701, South Korea
| | - Minyoung Jung
- Institute of Lifestyle Medicine, Yonsei University Wonju College of Medicine, 20 Ilsan-ro, Wonju, 220-701, South Korea
| | - Dong Jin Seo
- Central Research Laboratory Yonsei University Wonju College of Medicine, 20 Ilsan-ro, Wonju, 220-701, South Korea
| | - Dong Joon Park
- Department of Otorhinolaryngology, Yonsei University Wonju College of Medicine, 20 Ilsan-ro, Wonju, 220-701, South Korea.
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