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Liang TY, Lu LH, Tang SY, Zheng ZH, Shi K, Liu JQ. Current status and prospects of basic research and clinical application of mesenchymal stem cells in acute respiratory distress syndrome. World J Stem Cells 2023; 15:150-164. [PMID: 37180997 PMCID: PMC10173811 DOI: 10.4252/wjsc.v15.i4.150] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 01/20/2023] [Accepted: 03/20/2023] [Indexed: 04/26/2023] Open
Abstract
Acute respiratory distress syndrome (ARDS) is a common and clinically devastating disease that causes respiratory failure. Morbidity and mortality of patients in intensive care units are stubbornly high, and various complications severely affect the quality of life of survivors. The pathophysiology of ARDS includes increased alveolar-capillary membrane permeability, an influx of protein-rich pulmonary edema fluid, and surfactant dysfunction leading to severe hypoxemia. At present, the main treatment for ARDS is mechanical treatment combined with diuretics to reduce pulmonary edema, which primarily improves symptoms, but the prognosis of patients with ARDS is still very poor. Mesenchymal stem cells (MSCs) are stromal cells that possess the capacity to self-renew and also exhibit multilineage differentiation. MSCs can be isolated from a variety of tissues, such as the umbilical cord, endometrial polyps, menstrual blood, bone marrow, and adipose tissues. Studies have confirmed the critical healing and immunomodulatory properties of MSCs in the treatment of a variety of diseases. Recently, the potential of stem cells in treating ARDS has been explored via basic research and clinical trials. The efficacy of MSCs has been shown in a variety of in vivo models of ARDS, reducing bacterial pneumonia and ischemia-reperfusion injury while promoting the repair of ventilator-induced lung injury. This article reviews the current basic research findings and clinical applications of MSCs in the treatment of ARDS in order to emphasize the clinical prospects of MSCs.
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Affiliation(s)
- Tian-Yu Liang
- Emergency and Critical Care Center, Intensive Care Unit, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou 310014, Zhejiang Province, China
| | - Li-Hai Lu
- Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou 310053, Zhejiang Province, China
| | - Si-Yu Tang
- The Second School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou 310053, Zhejiang Province, China
| | - Zi-Hao Zheng
- Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou 310053, Zhejiang Province, China
| | - Kai Shi
- Department of Respiratory Medicine, The Affiliated Hospital of Hangzhou Normal University, Hangzhou 310015, Zhejiang Province, China
| | - Jing-Quan Liu
- Emergency and Critical Care Center, Intensive Care Unit, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou 310014, Zhejiang Province, China.
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Mesenchymal stromal cells alleviate acute respiratory distress syndrome through the cholinergic anti-inflammatory pathway. Signal Transduct Target Ther 2022; 7:307. [PMID: 36064538 PMCID: PMC9441842 DOI: 10.1038/s41392-022-01124-6] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2021] [Revised: 06/22/2022] [Accepted: 07/12/2022] [Indexed: 11/24/2022] Open
Abstract
Mesenchymal stromal cells (MSCs) have been considered a promising alternative for treatment of acute respiratory distress syndrome (ARDS). However, there is significant heterogeneity in their therapeutic efficacy, largely owing to the incomplete understanding of the mechanisms underlying the therapeutic activities of MSCs. Here, we hypothesize that the cholinergic anti-inflammatory pathway (CAP), which is recognized as a neuroimmunological pathway, may be involved in the therapeutic mechanisms by which MSCs mitigate ARDS. Using lipopolysaccharide (LPS) and bacterial lung inflammation models, we found that inflammatory cell infiltration and Evans blue leakage were reduced and that the expression levels of choline acetyltransferase (ChAT) and vesicular acetylcholine transporter (VAChT) in lung tissue were significantly increased 6 hours after MSC infusion. When the vagus nerve was blocked or α7 nicotinic acetylcholine (ACh) receptor (α7nAChR)-knockout mice were used, the therapeutic effects of MSCs were significantly reduced, suggesting that the CAP may play an important role in the effects of MSCs in ARDS treatment. Our results further showed that MSC-derived prostaglandin E2 (PGE2) likely promoted ACh synthesis and release. Additionally, based on the efficacy of nAChR and α7nAChR agonists, we found that lobeline, the nicotinic cholinergic receptor excitation stimulant, may attenuate pulmonary inflammation and alleviate respiratory symptoms of ARDS patients in a clinical study (ChiCTR2100047403). In summary, we reveal a previously unrecognized MSC-mediated mechanism of CAP activation as the means by which MSCs alleviate ARDS-like syndrome, providing insight into the clinical translation of MSCs or CAP-related strategies for the treatment of patients with ARDS.
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Bunnell BA, Martin EC, Matossian MD, Brock CK, Nguyen K, Collins-Burow B, Burow ME. The effect of obesity on adipose-derived stromal cells and adipose tissue and their impact on cancer. Cancer Metastasis Rev 2022; 41:549-573. [PMID: 35999486 DOI: 10.1007/s10555-022-10063-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Accepted: 08/16/2022] [Indexed: 11/24/2022]
Abstract
The significant increase in the incidence of obesity represents the next global health crisis. As a result, scientific research has focused on gaining deeper insights into obesity and adipose tissue biology. As a result of the excessive accumulation of adipose tissue, obesity results from hyperplasia and hypertrophy within the adipose tissue. The functional alterations in the adipose tissue are a confounding contributing factor to many diseases, including cancer. The increased incidence and aggressiveness of several cancers, including colorectal, postmenopausal breast, endometrial, prostate, esophageal, hematological, malignant melanoma, and renal carcinomas, result from obesity as a contributing factor. The increased morbidity and mortality of obesity-associated cancers are attributable to increased hormones, adipokines, and cytokines produced by the adipose tissue. The increased adipose tissue levels observed in obese patients result in more adipose stromal/stem cells (ASCs) distributed throughout the body. ASCs have been shown to impact cancer progression in vitro and in preclinical animal models. ASCs influence tumor biology via multiple mechanisms, including the increased recruitment of ASCs to the tumor site and increased production of cytokines and growth factors by ASCs and other cells within the tumor stroma. Emerging evidence indicates that obesity induces alterations in the biological properties of ASCs, subsequently leading to enhanced tumorigenesis and metastasis of cancer cells. As the focus of this review is the interaction and impact of ASCs on cancer, the presentation is limited to preclinical data generated on cancers in which there is a demonstrated role for ASCs, such as postmenopausal breast, colorectal, prostate, ovarian, multiple myeloma, osteosarcoma, cervical, bladder, and gastrointestinal cancers. Our group has investigated the interactions between obesity and breast cancer and the mechanisms that regulate ASCs and adipocytes in these different contexts through interactions between cancer cells, immune cells, and other cell types present in the tumor microenvironment (TME) are discussed. The reciprocal and circular feedback loop between obesity and ASCs and the mechanisms by which ASCs from obese patients alter the biology of cancer cells and enhance tumorigenesis will be discussed. At present, the evidence for ASCs directly influencing human tumor growth is somewhat limited, though recent clinical studies suggest there may be some link.
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Affiliation(s)
- Bruce A Bunnell
- Department of Microbiology, Immunology, and Genetics, University of North Texas Health Science Center, 3500 Camp Bowie Blvd., Fort Worth, TX, 76107, USA.
| | - Elizabeth C Martin
- Department of Biological and Agricultural Engineering, Louisiana State University, Baton Rouge, LA, USA
| | - Margarite D Matossian
- Department of Microbiology, Immunology and Genetics, University of Chicago, IL, Chicago, USA
| | - Courtney K Brock
- Section of Hematology and Oncology, Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA
| | - Khoa Nguyen
- Section of Hematology and Oncology, Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA
| | - Bridgette Collins-Burow
- Section of Hematology and Oncology, Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA
| | - Matthew E Burow
- Section of Hematology and Oncology, Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA
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Tan MI, Alfarafisa NM, Septiani P, Barlian A, Firmansyah M, Faizal A, Melani L, Nugrahapraja H. Potential Cell-Based and Cell-Free Therapy for Patients with COVID-19. Cells 2022; 11:2319. [PMID: 35954162 PMCID: PMC9367488 DOI: 10.3390/cells11152319] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2022] [Revised: 07/20/2022] [Accepted: 07/26/2022] [Indexed: 02/01/2023] Open
Abstract
Since it was first reported, the novel coronavirus disease 2019 (COVID-19) remains an unresolved puzzle for biomedical researchers in different fields. Various treatments, drugs, and interventions were explored as treatments for COVID. Nevertheless, there are no standard and effective therapeutic measures. Meanwhile, mesenchymal stem cell (MSC) therapy offers a new approach with minimal side effects. MSCs and MSC-based products possess several biological properties that potentially alleviate COVID-19 symptoms. Generally, there are three classifications of stem cell therapy: cell-based therapy, tissue engineering, and cell-free therapy. This review discusses the MSC-based and cell-free therapies for patients with COVID-19, their potential mechanisms of action, and clinical trials related to these therapies. Cell-based therapies involve the direct use and injection of MSCs into the target tissue or organ. On the other hand, cell-free therapy uses secreted products from cells as the primary material. Cell-free therapy materials can comprise cell secretomes and extracellular vesicles. Each therapeutic approach possesses different benefits and various risks. A better understanding of MSC-based and cell-free therapies is essential for supporting the development of safe and effective COVID-19 therapy.
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Affiliation(s)
- Marselina Irasonia Tan
- School of Life Sciences and Technology, Institut Teknologi Bandung, Bandung 40132, Indonesia; (P.S.); (A.B.); (M.F.); (A.F.); (L.M.); (H.N.)
| | - Nayla Majeda Alfarafisa
- Department of Biomedical Sciences, Faculty of Medicine, Universitas Padjadjaran, Sumedang 45363, Indonesia;
| | - Popi Septiani
- School of Life Sciences and Technology, Institut Teknologi Bandung, Bandung 40132, Indonesia; (P.S.); (A.B.); (M.F.); (A.F.); (L.M.); (H.N.)
| | - Anggraini Barlian
- School of Life Sciences and Technology, Institut Teknologi Bandung, Bandung 40132, Indonesia; (P.S.); (A.B.); (M.F.); (A.F.); (L.M.); (H.N.)
| | - Mochamad Firmansyah
- School of Life Sciences and Technology, Institut Teknologi Bandung, Bandung 40132, Indonesia; (P.S.); (A.B.); (M.F.); (A.F.); (L.M.); (H.N.)
| | - Ahmad Faizal
- School of Life Sciences and Technology, Institut Teknologi Bandung, Bandung 40132, Indonesia; (P.S.); (A.B.); (M.F.); (A.F.); (L.M.); (H.N.)
| | - Lili Melani
- School of Life Sciences and Technology, Institut Teknologi Bandung, Bandung 40132, Indonesia; (P.S.); (A.B.); (M.F.); (A.F.); (L.M.); (H.N.)
| | - Husna Nugrahapraja
- School of Life Sciences and Technology, Institut Teknologi Bandung, Bandung 40132, Indonesia; (P.S.); (A.B.); (M.F.); (A.F.); (L.M.); (H.N.)
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Wang Z, Yu T, Hou Y, Zhou W, Ding Y, Nie H. Mesenchymal Stem Cell Therapy for ALI/ARDS: Therapeutic Potential and Challenges. Curr Pharm Des 2022; 28:2234-2240. [PMID: 35796453 DOI: 10.2174/1381612828666220707104356] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Accepted: 05/24/2022] [Indexed: 11/22/2022]
Abstract
Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a serious clinical common disease, which may be caused by a variety of pathological factors and can induce a series of serious complications. There is still no specific and effective method for the treatment of ALI/ARDS. Mesenchymal stem cells (MSCs) have been one of the treatment methods for ALI, which can regulate related signal pathways such as PI3K/AKT, Wnt, and NF-κB to reduce inflammation. MSCs exist in a variety of tissues and have the ability of self-renewal and differentiation, which can be activated by specific substances or environments and home to the site of tissue damage, where they differentiate into new tissue cells and repair the damage. Both exosomes and cytokines involving the paracrine mechanism of MSCs have benefits on the treatment of ALI. Lung organoids produced by 3D culture technology can simulate the characteristics of the lung and help to research the pathophysiological process of ALI. This review summarizes the mechanisms by which MSCs treat ALI/ARDS and expects to use 3D models for future challenges in this field.
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Affiliation(s)
- Zhenxing Wang
- Department of Hematology and Breast Cancer, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, China
| | - Tong Yu
- Department of Stem Cells and Regenerative Medicine, College of Basic Medical Science, China Medical University, Shenyang, China
| | - Yapeng Hou
- Department of Stem Cells and Regenerative Medicine, College of Basic Medical Science, China Medical University, Shenyang, China
| | - Wei Zhou
- Department of Stem Cells and Regenerative Medicine, College of Basic Medical Science, China Medical University, Shenyang, China
| | - Yan Ding
- Department of Stem Cells and Regenerative Medicine, College of Basic Medical Science, China Medical University, Shenyang, China
| | - Hongguang Nie
- Department of Stem Cells and Regenerative Medicine, College of Basic Medical Science, China Medical University, Shenyang, China
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Shaw TD, Krasnodembskaya AD, Schroeder GN, Zumla A, Maeurer M, O’Kane CM. Mesenchymal Stromal Cells: an Antimicrobial and Host-Directed Therapy for Complex Infectious Diseases. Clin Microbiol Rev 2021; 34:e0006421. [PMID: 34612662 PMCID: PMC8510528 DOI: 10.1128/cmr.00064-21] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
There is an urgent need for new antimicrobial strategies for treating complex infections and emerging pathogens. Human mesenchymal stromal cells (MSCs) are adult multipotent cells with antimicrobial properties, mediated through direct bactericidal activity and modulation of host innate and adaptive immune cells. More than 30 in vivo studies have reported on the use of human MSCs for the treatment of infectious diseases, with many more studies of animal MSCs in same-species models of infection. MSCs demonstrate potent antimicrobial effects against the major classes of human pathogens (bacteria, viruses, fungi, and parasites) across a wide range of infection models. Mechanistic studies have yielded important insight into their immunomodulatory and bactericidal activity, which can be enhanced through various forms of preconditioning. MSCs are being investigated in over 80 clinical trials for difficult-to-treat infectious diseases, including sepsis and pulmonary, intra-abdominal, cutaneous, and viral infections. Completed trials consistently report MSCs to be safe and well tolerated, with signals of efficacy against some infectious diseases. Although significant obstacles must be overcome to produce a standardized, affordable, clinical-grade cell therapy, these studies suggest that MSCs may have particular potential as an adjunct therapy in complex or resistant infections.
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Affiliation(s)
- Timothy D. Shaw
- Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University, Belfast, United Kingdom
| | - Anna D. Krasnodembskaya
- Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University, Belfast, United Kingdom
| | - Gunnar N. Schroeder
- Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University, Belfast, United Kingdom
| | - Alimuddin Zumla
- Center for Clinical Microbiology, Division of Infection and Immunity, University College London, NIHR Biomedical Research Centre, UCL Hospitals NHS Foundation Trust, London, United Kingdom
| | - Markus Maeurer
- Immunosurgery Unit, Champalimaud Centre for the Unknown, Lisbon, Portugal
- Department of Oncology and Haematology, Krankenhaus Nordwest, Frankfurt, Germany
| | - Cecilia M. O’Kane
- Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University, Belfast, United Kingdom
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Fu JD, Gao CH, Li SW, Tian Y, Li SC, Wei YE, Xian LW. Atractylenolide III alleviates sepsis-mediated lung injury via inhibition of FoxO1 and VNN1 protein. Acta Cir Bras 2021; 36:e360802. [PMID: 34644770 PMCID: PMC8516425 DOI: 10.1590/acb360802] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 06/10/2021] [Accepted: 07/13/2021] [Indexed: 12/21/2022] Open
Abstract
PURPOSE To evaluate the influence of atractylenolide (Atr) III on sepsis-induced lung damage. METHODS We constructed a mouse sepsis model through cecal ligation and puncture. These mice were allocated to the normal, sepsis, sepsis + Atr III-L (2 mg/kg), as well as Atr III-H (8 mg/kg) group. Lung injury and pulmonary fibrosis were accessed via hematoxylin-eosin (HE) and Masson's staining. We used terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and flow cytometry for detecting sepsis-induced lung cell apoptosis. The contents of the inflammatory cytokines in lung tissue were measured via enzyme-linked immunosorbent assay (ELISA). RESULTS Atr III-H did not only reduce sepsis-induced lung injury and apoptosis level, but also curbed the secretion of inflammatory factors. Atr III-H substantially ameliorated lung function and raised Bcl-2 expression. Atr III-H eased the pulmonary fibrosis damage and Bax, caspase-3, Vanin-1 (VNN1), as well as Forkhead Box Protein O1 (FoxO1) expression. CONCLUSIONS Atr III alleviates sepsis-mediated lung injury via inhibition of FoxO1 and VNN1 protein.
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Affiliation(s)
- Ji-ding Fu
- MD. Department of Intensive Care Unit - Affiliated Cancer Hospital
& Institute of Guangzhou Medical University - Guangzhou, China
| | - Chun-hui Gao
- MD. Department of Intensive Care Unit - Affiliated Cancer Hospital
& Institute of Guangzhou Medical University - Guangzhou, China
| | - Shi-wei Li
- MD. Department of Intensive Care Unit - Affiliated Cancer Hospital
& Institute of Guangzhou Medical University - Guangzhou, China
| | - Yan Tian
- MD. Department of Intensive Care Unit - Affiliated Cancer Hospital
& Institute of Guangzhou Medical University - Guangzhou, China
| | - Shi-cheng Li
- MD. Department of Intensive Care Unit - Affiliated Cancer Hospital
& Institute of Guangzhou Medical University - Guangzhou, China
| | - Yi-er Wei
- MD. Department of Intensive Care Unit - Affiliated Cancer Hospital
& Institute of Guangzhou Medical University - Guangzhou, China
| | - Le-wu Xian
- MD. Department of Intensive Care Unit - Affiliated Cancer Hospital
& Institute of Guangzhou Medical University - Guangzhou, China
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Increased In Vitro Intercellular Barrier Function of Lung Epithelial Cells Using Adipose-Derived Mesenchymal Stem/Stromal Cells. Pharmaceutics 2021; 13:pharmaceutics13081264. [PMID: 34452225 PMCID: PMC8401152 DOI: 10.3390/pharmaceutics13081264] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 08/11/2021] [Accepted: 08/13/2021] [Indexed: 11/17/2022] Open
Abstract
With the emergence of coronavirus disease-2019, researchers have gained interest in the therapeutic efficacy of mesenchymal stem/stromal cells (MSCs) in acute respiratory distress syndrome; however, the mechanisms of the therapeutic effects of MSCs are unclear. We have previously reported that adipose-derived MSCs (AD-MSCs) strengthen the barrier function of the pulmonary vessels in scaffold-based bioengineered rat lungs. In this study, we evaluated whether AD-MSCs could enhance the intercellular barrier function of lung epithelial cells in vitro using a transwell coculture system. Transepithelial electrical resistance (TEER) measurements revealed that the peak TEER value was significantly higher in the AD-MSC coculture group than in the AD-MSC non-coculture group. Similarly, the permeability coefficient was significantly decreased in the AD-MSC coculture group compared to that in the AD-MSC non-coculture group. Immunostaining of insert membranes showed that zonula occuldens-1 expression was significantly high at cell junctions in the AD-MSC coculture group. Moreover, cell junction-related gene profiling showed that the expression of some claudin genes, including claudin-4, was upregulated in the AD-MSC coculture group. Taken together, these results showed that AD-MSCs enhanced the barrier function between lung epithelial cells, suggesting that both direct adhesion and indirect paracrine effects strengthened the barrier function of lung alveolar epithelium in vitro.
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Adipose-Derived Stem Cells Secretome and Its Potential Application in "Stem Cell-Free Therapy". Biomolecules 2021; 11:biom11060878. [PMID: 34199330 PMCID: PMC8231996 DOI: 10.3390/biom11060878] [Citation(s) in RCA: 113] [Impact Index Per Article: 28.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Revised: 06/09/2021] [Accepted: 06/11/2021] [Indexed: 12/11/2022] Open
Abstract
Adipose-derived stem cells (ASCs) secrete many cytokines, proteins, growth factors, and extracellular vesicles with beneficial outcomes that can be used in regenerative medicine. It has great potential, and the development of new treatment strategies using the ASCs secretome is of global interest. Besides cytokines, proteins, and growth factors, the therapeutic effect of secretome is hidden in non-coding RNAs such as miR-21, miR-24, and miR-26 carried via exosomes secreted by adequate cells. The whole secretome, including ASC-derived exosomes (ASC-exos) has been proven in many studies to have immunomodulatory, proangiogenic, neurotrophic, and epithelization activity and can potentially be used for neurodegenerative, cardiovascular, respiratory, inflammatory, and autoimmune diseases as well as wound healing treatment. Due to limitations in the use of stem cells in cell-based therapy, its secretome with emphasis on exosomes seems to be a reasonable and safer alternative with increased effectiveness and fewer side effects. Moreover, the great advantage of cell-free therapy is the possibility of biobanking the ASCs secretome. In this review, we focus on the current state of knowledge on the use of the ASCs secretome in stem cell-free therapy.
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Garcia-Contreras M, Thakor AS. Human adipose tissue-derived mesenchymal stem cells and their extracellular vesicles modulate lipopolysaccharide activated human microglia. Cell Death Discov 2021; 7:98. [PMID: 33972507 PMCID: PMC8110535 DOI: 10.1038/s41420-021-00471-7] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Revised: 02/05/2021] [Accepted: 04/07/2021] [Indexed: 12/16/2022] Open
Abstract
Neurodegenerative diseases (NDs), such as Alzheimer's disease (AD), are driven by neuroinflammation triggered by activated microglial cells; hence, the phenotypic regulation of these cells is an appealing target for intervention. Human adipose tissue-derived mesenchymal stem cells (hAD-MSCs) may be a potential therapeutic candidate to treat NDs given their immunomodulatory properties. Evidence suggests that the mechanism of action of hAD-MSCs is through their secretome, which includes secreted factors such as cytokines, chemokines, or growth factors as well as extracellular vesicles (EVs). Recently, EVs have emerged as important mediators in cell communication given, they can transfer proteins, lipids, and RNA species (i.e., miRNA, mRNA, and tRNAs) to modulate recipient cells. However, the therapeutic potential of hAD-MSCs and their secreted EVs has not been fully elucidated with respect to human microglia. In this study, we determined the therapeutic potential of different hAD-MSCs doses (200,000, 100,000, and 50,000 cells) or their secreted EVs (50, 20, or 10 µg/ml), on human microglial cells (HMC3) that were activated by lipopolysaccharides (LPS). Upregulation of inducible nitric oxide synthase (iNOS), an activation marker of HMC3 cells, was prevented when they were cocultured with hAD-MSCs and EVs. Moreover, hAD-MSCs inhibited the secretion of proinflammatory factors, such as IL-6, IL-8, and MCP-1, while their secreted EVs promoted the expression of anti-inflammatory mediators such as IL-10 or TIMP-1 in activated microglia. The present data therefore support a role for hAD-MSCs and their secreted EVs, as potential therapeutic candidates for the treatment of NDs.
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Affiliation(s)
- Marta Garcia-Contreras
- Interventional Regenerative Medicine and Imaging Laboratory, Department of Radiology, Stanford University, Palo Alto, CA, 94304, USA
| | - Avnesh S Thakor
- Interventional Regenerative Medicine and Imaging Laboratory, Department of Radiology, Stanford University, Palo Alto, CA, 94304, USA.
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Laloze J, Fiévet L, Desmoulière A. Adipose-Derived Mesenchymal Stromal Cells in Regenerative Medicine: State of Play, Current Clinical Trials, and Future Prospects. Adv Wound Care (New Rochelle) 2021; 10:24-48. [PMID: 32470315 PMCID: PMC7698876 DOI: 10.1089/wound.2020.1175] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Accepted: 04/21/2020] [Indexed: 12/13/2022] Open
Abstract
Significance: Wound healing is a complex process involving pain and inflammation, where innervation plays a central role. Managing wound healing and pain remains an important issue, especially in pathologies such as excessive scarring (often leading to fibrosis) or deficient healing, leading to chronic wounds. Recent Advances: Advances in therapies using mesenchymal stromal cells offer new insights for treating indications that previously lacked options. Adipose-derived mesenchymal stromal cells (AD-MSCs) are now being used to a much greater extent in clinical trials for regenerative medicine. However, to be really valid, these randomized trials must imperatively follow strict guidelines such as consolidated standards of reporting trials (CONSORT) statement. Indeed, AD-MSCs, because of their paracrine activities and multipotency, have potential to cure degenerative and/or inflammatory diseases. Combined with their relatively easy access (from adipose tissue) and proliferation capacity, AD-MSCs represent an excellent candidate for allogeneic treatments. Critical Issues: The success of AD-MSC therapy may depend on the robustness of the biological functions of AD-MSCs, which requires controlling source heterogeneity and production processes, and development of biomarkers that predict desired responses. Several studies have investigated the effect of AD-MSCs on innervation, wound repair, or pain management separately, but systematic evaluation of how those effects could be combined is lacking. Future Directions: Future studies that explore how AD-MSC therapy can be used to treat difficult-to-heal wounds, underlining the need to thoroughly characterize the cells used, and standardization of preparation processes are needed. Finally, how this a priori easy-to-use cell therapy treatment fits into clinical management of pain, improvement of tissue healing, and patient quality of life, all need to be explored.
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Affiliation(s)
- Jérôme Laloze
- Faculties of Medicine and Pharmacy, University of Limoges, Myelin Maintenance and Peripheral Neuropathies (EA 6309), Limoges, France
- Department of Maxillo-Facial and Reconstructive Surgery and Stomatology, University Hospital Dupuytren, Limoges, France
| | - Loïc Fiévet
- STROMALab, Etablissement Français du Sang (EFS)-Occitanie, INSERM 1031, National Veterinary School of Toulouse (ENVT), ERL5311 CNRS, University of Toulouse, Toulouse, France
| | - Alexis Desmoulière
- Faculties of Medicine and Pharmacy, University of Limoges, Myelin Maintenance and Peripheral Neuropathies (EA 6309), Limoges, France
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12
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Gorman E, Millar J, McAuley D, O'Kane C. Mesenchymal stromal cells for acute respiratory distress syndrome (ARDS), sepsis, and COVID-19 infection: optimizing the therapeutic potential. Expert Rev Respir Med 2020; 15:301-324. [PMID: 33172313 DOI: 10.1080/17476348.2021.1848555] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Introduction: Mesenchymal stromal (stem) cell (MSC) therapies are emerging as a promising therapeutic intervention in patients with Acute Respiratory Distress Syndrome (ARDS) and sepsis due to their reparative, immunomodulatory, and antimicrobial properties.Areas covered: This review provides an overview of Mesenchymal stromal cells (MSCs) and their mechanisms of effect in ARDS and sepsis. The preclinical and clinical evidence to support MSC therapy in ARDS and sepsis is discussed. The potential for MSC therapy in COVID-19 ARDS is discussed with insights from respiratory viral models and early clinical reports of MSC therapy in COVID-19. Strategies to optimize the therapeutic potential of MSCs in ARDS and sepsis are considered including preconditioning, altered gene expression, and alternative cell-free MSC-derived products, such as extracellular vesicles and conditioned medium.Expert opinion: MSC products present considerable therapeutic promise for ARDS and sepsis. Preclinical investigations report significant benefits and early phase clinical studies have not highlighted safety concerns. Optimization of MSC function in preclinical models of ARDS and sepsis has enhanced their beneficial effects. MSC-derived products, as cell-free alternatives, may provide further advantages in this field. These strategies present opportunity for the clinical development of MSCs and MSC-derived products with enhanced therapeutic efficacy.
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Affiliation(s)
- Ellen Gorman
- School of Medicine Dentistry and Biomedical Science, Queen's University Belfast, UK
| | - Jonathan Millar
- Division of Functional Genetics and Development, Roslin Institute, University of Edinburgh, Edinburgh, UK
| | - Danny McAuley
- School of Medicine Dentistry and Biomedical Science, Queen's University Belfast, UK
| | - Cecilia O'Kane
- School of Medicine Dentistry and Biomedical Science, Queen's University Belfast, UK
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13
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Jung YJ, Park YY, Huh JW, Hong SB. The effect of human adipose-derived stem cells on lipopolysaccharide-induced acute respiratory distress syndrome in mice. ANNALS OF TRANSLATIONAL MEDICINE 2019; 7:674. [PMID: 31930075 DOI: 10.21037/atm.2019.10.48] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Background Acute respiratory distress syndrome (ARDS) is a type of acute respiratory failure in critically ill patients. Recently, several treatment modalities have been proposed for ARDS, but it still has a high mortality rate. In general, the role of mesenchymal stem cells (MSCs) in controlling inflammatory responses has been studied in various immune-associated diseases in humans and animals. However, only a few studies reported adipose-derived stem cells (ASCs), which are easier to isolate, are currently emerging as an attractive treatment option in ARDS. Therefore, in this study, we investigated the therapeutic effects of human ASCs and the regulation of inflammatory responses in an ARDS mouse model. Methods In the ARDS model, lipopolysaccharide (LPS) (5 mg/kg) was administered via the intra tracheal injection method. The mice were divided into the following four groups: (I) saline + medium; (II) saline + ASCs (2×105); (III) LPS + medium; (IV) LPS + ASCs. The ARDS observation time was divided into short and long term. LPS administration increased the concentration of proinflammatory cytokines, which was a consistent systemic inflammatory response. Results LPS/ASC group showed less neutrophil infiltration and less alveolar hemorrhage or congestion than did the LPS group. The lung injury scores of the LPS/ASC group were lower than those of the LPS group (3.8±0.9 vs. 6.8±1.1; P=0.03) at day 2. Compared to the LPS group, LPS/ASC group showed reduced collagen deposition around the vessels and fibrosis accompanied by alveolar septal or interstitial thickening and lower MPO levels than did the LPS group (453.2±26.2 vs. 670.2±65.9 pg/mL; P<0.01) at day 7. Conclusions ASC therapy can inhibit neutrophil recruitment, which shows trend of reducing short term lung injury (day 2) and affecting fibrosis in long term (day 7). Further studies are warranted to understand the mechanism and improve the therapeutic effect of ASCs.
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Affiliation(s)
- Young Ju Jung
- Department of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea; Asan Life Institute, Seoul, Korea
| | - Yun Young Park
- Department of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea; Asan Life Institute, Seoul, Korea
| | - Jin Won Huh
- Department of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea; Asan Life Institute, Seoul, Korea
| | - Sang-Bum Hong
- Department of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea; Asan Life Institute, Seoul, Korea
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14
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Human Adipose Tissue-Derived Stromal Cells Attenuate the Multiple Organ Injuries Induced by Sepsis and Mechanical Ventilation in Mice. Inflammation 2019; 42:485-495. [PMID: 30317531 DOI: 10.1007/s10753-018-0905-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Mechanical ventilation (MV) can augment sepsis-induced organ injury. Previous studies indicate that human mesenchymal stem cells (hMSCs) have immune-modulatory effect. We hypothesize that human adipose tissue-derived stromal cells (hADSCs) could attenuate MV and sepsis-induced organ injury. Male C57BL/6 mice were randomized to five groups: Sham group; MV group; cecal ligation and puncture (CLP) group; CLP + MV group; and CLP + MV + hADSC group. Anesthetized mice were subjected to cecal ligation and puncture surgery. The mice then received mechanical ventilation (12 ml/kg), with or without the intervention of hADSCs. The survival rate, organ injury of the liver and kidney, total protein and cells in bronchoalveolar lavage fluid (BALF), and histological changes of the lung and liver were examined. The level of IL-6 in BALF was measured by ELISA. Real-time quantitative PCR was used to analyze mRNA of IL-6 and tumor necrosis factor-α (TNF-α). hADSC treatment increased survival rate of septic mice with MV. hADSCs attenuated dysfunction of the liver and kidney and decreased lung inflammation and tissue injury of the liver and lung. IL-6 level in BALF and TNF-α and IL-6 mRNA expression in the tissue of the lung, liver, and kidney were significantly reduced by hADSC treatment. MV with conventional tidal volume aggravates CLP-induced multiple organ injuries. hADSCs inhibited the compound injuries possibly through modulation of immune responses.
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15
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Xu AL, Rodriguez LA, Walker KP, Mohammadipoor A, Kamucheka RM, Cancio LC, Batchinsky AI, Antebi B. Mesenchymal Stem Cells Reconditioned in Their Own Serum Exhibit Augmented Therapeutic Properties in the Setting of Acute Respiratory Distress Syndrome. Stem Cells Transl Med 2019; 8:1092-1106. [PMID: 31219247 PMCID: PMC6766690 DOI: 10.1002/sctm.18-0236] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Accepted: 04/03/2019] [Indexed: 12/13/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are a promising form of therapy for acute respiratory distress syndrome (ARDS). The objective of this study was twofold: (a) to characterize cytokine expression in serum from ARDS subjects receiving MSCs and (b) to determine MSC function following “preconditioning” with ARDS serum. In phase I, serum from three cohorts of animals (uninjured [no ARDS, n = 4], injured untreated [n = 5], and injured treated with approximately 6 million per kilogram MSCs [n = 7]) was analyzed for expression of inflammatory mediators. In phase II, the functional properties of bone marrow porcine MSCs were assessed following “preconditioning” with serum from the three cohorts. In phase III, the findings from the previous phases were validated using human bone marrow MSCs (hBM‐MSCs) and lipopolysaccharide (LPS). Serum from injured treated animals had significantly lower levels of interferon‐γ and significantly higher levels of interleukin (IL)‐1 receptor antagonist (IL‐1RA) and IL‐6. Similarly, upon exposure to the injured treated serum ex vivo, the MSCs secreted higher levels of IL‐1RA and IL‐10, dampened the secretion of proinflammatory cytokines, exhibited upregulation of toll‐like receptor 4 (TLR‐4) and vascular endothelial growth factor (VEGF) genes, and triggered a strong immunomodulatory response via prostaglandin E2 (PGE2). hBM‐MSCs demonstrated a similar augmented therapeutic function following reconditioning in a LPS milieu. Administration of MSCs modulated the inflammatory milieu following ARDS. Exposure to ARDS serum ex vivo paralleled the trends seen in vivo, which appear to be mediated, in part, through TLR‐4 and VEGF and PGE2. Reconditioning MSCs in their own serum potentiates their immunotherapeutic function, a technique that can be used in clinical applications. stem cells translational medicine2019;8:1092–1106
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Affiliation(s)
- Amy L Xu
- Department of Expeditionary Critical Care, U.S. Army Institute of Surgical Research, San Antonio, Texas, USA.,Department of Human Biology, Stanford University, Stanford, California, USA
| | - Luis A Rodriguez
- Department of Expeditionary Critical Care, U.S. Army Institute of Surgical Research, San Antonio, Texas, USA.,Oak Ridge Institute for Science and Education, Oak Ridge, Tennessee, USA
| | - Kerfoot P Walker
- Department of Expeditionary Critical Care, U.S. Army Institute of Surgical Research, San Antonio, Texas, USA.,Oak Ridge Institute for Science and Education, Oak Ridge, Tennessee, USA
| | - Arezoo Mohammadipoor
- Department of Expeditionary Critical Care, U.S. Army Institute of Surgical Research, San Antonio, Texas, USA.,Oak Ridge Institute for Science and Education, Oak Ridge, Tennessee, USA
| | - Robin M Kamucheka
- Department of Expeditionary Critical Care, U.S. Army Institute of Surgical Research, San Antonio, Texas, USA
| | - Leopoldo C Cancio
- Department of Expeditionary Critical Care, U.S. Army Institute of Surgical Research, San Antonio, Texas, USA
| | - Andriy I Batchinsky
- Department of Expeditionary Critical Care, U.S. Army Institute of Surgical Research, San Antonio, Texas, USA.,The Geneva Foundation, Tacoma, Washington, USA
| | - Ben Antebi
- Department of Expeditionary Critical Care, U.S. Army Institute of Surgical Research, San Antonio, Texas, USA.,Department of Biomedical Engineering, University of Texas at San Antonio, San Antonio, Texas, USA
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16
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Xiao P, Sun S, Cao J, Wang J, Li H, Hou S, Ding H, Liu Z, Fang Y, Bai S, Qin X, Yu F, Liu J, Wang X, Lv Q, Fan H. Expression profile of microRNAs in bronchoalveolar lavage fluid of rats as predictors for smoke inhalation injury. Burns 2018; 44:2042-2050. [DOI: 10.1016/j.burns.2018.07.009] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2018] [Revised: 06/08/2018] [Accepted: 07/19/2018] [Indexed: 02/08/2023]
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17
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Peng CK, Wu SY, Tang SE, Li MH, Lin SS, Chu SJ, Huang KL. Protective Effects of Neural Crest-Derived Stem Cell-Conditioned Media against Ischemia-Reperfusion-Induced Lung Injury in Rats. Inflammation 2018; 40:1532-1542. [PMID: 28534140 PMCID: PMC7102066 DOI: 10.1007/s10753-017-0594-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Current treatments for ischemia-reperfusion (IR)-induced acute lung injury are limited. Mesenchymal stem cell-conditioned medium (CM) has been reported to attenuate lung injury. Neural crest stem cells (NCSCs), a type of multipotent stem cells, are more easily obtained than mesenchymal stem cells. We hypothesize that NCSC-CM has anti-inflammatory properties that could protect against IR-induced lung injury in rats. In this study, NCSC-CM was derived from rat NCSCs. Typical acute lung injury was induced by 30-min ischemia followed by 90-min reperfusion in adult male Sprague–Dawley rats. Bronchoalveolar lavage fluid (BALF) and lung tissues were collected to analyze the degree of lung injury after the experiment. NCSC-CM was administered before ischemia and after reperfusion. NCSC-CM treatment significantly attenuated IR-induced lung edema, as indicated by decreases in pulmonary vascular permeability, lung weight gain, wet to dry weight ratio, lung weight to body weight ratio, pulmonary arterial pressure, and protein level in BALF. The levels of tumor necrosis factor-α and interleukin-6 in the BALF were also significantly decreased. Additionally, NCSC-CM improved lung pathology and neutrophil infiltration in the lung tissue, and significantly suppressed nuclear factor (NF)-κB activity and IκB-α degradation in the lung. However, heating NCSC-CM eliminated these protective effects. Our experiment demonstrates that NCSC-CM treatment decreases IR-induced acute lung injury and that the protective mechanism may be attributable to the inhibition of NF-κB activation and the inflammatory response. Therefore, NCSC-CM may be a novel approach for treating IR-induced lung injury.
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Affiliation(s)
- Chung-Kan Peng
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Shu-Yu Wu
- Institute of Aerospace and Undersea Medicine, National Defense Medical Center, Taipei, Taiwan
| | - Shih-En Tang
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Min-Hui Li
- Department of Physical Medicine and Rehabilitation, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| | - Shih-Shiuan Lin
- Institute of Aerospace and Undersea Medicine, National Defense Medical Center, Taipei, Taiwan
| | - Shi-Jye Chu
- Division of Rheumatology, Immunology and Allergy, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan. .,Institute of Aerospace and Undersea Medicine, National Defense Medical Center, 161 Ming-Chuan East Road, Section 6, Neihu 114, Taipei, Taiwan, Republic of China.
| | - Kun-Lun Huang
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan. .,Institute of Aerospace and Undersea Medicine, National Defense Medical Center, Taipei, Taiwan. .,Institute of Aerospace and Undersea Medicine, National Defense Medical Center, 161 Ming-Chuan East Road, Section 6, Neihu 114, Taipei, Taiwan, Republic of China.
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18
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Evaluation of Oxidative Stress and Mitophagy during Adipogenic Differentiation of Adipose-Derived Stem Cells Isolated from Equine Metabolic Syndrome (EMS) Horses. Stem Cells Int 2018; 2018:5340756. [PMID: 29977307 PMCID: PMC6011082 DOI: 10.1155/2018/5340756] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Revised: 03/08/2018] [Accepted: 04/18/2018] [Indexed: 01/14/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are frequently used in both human and veterinary medicine because their unique properties, such as modulating the immune response and differentiating into multiple lineages, make them a valuable tool in cell-based therapies. However, many studies have indicated the age-, lifestyle-, and disease-related deterioration of MSC regenerative characteristics. However, it still needs to be elucidated how the patient's health status affects the effectiveness of MSC differentiation. In the present study, we isolated mesenchymal stem cells from adipose tissue (adipose-derived mesenchymal stem cells (ASCs)) from horses diagnosed with equine metabolic syndrome (EMS), a common metabolic disorder characterized by pathological obesity and insulin resistance. We investigated the metabolic status of isolated cells during adipogenic differentiation using multiple research methods, such as flow cytometry, PCR, immunofluorescence, or transmission and confocal microscopy. The results indicated the impaired differentiation potential of ASCEMS. Excessive ROS accumulation and ER stress are most likely the major factors limiting the multipotency of these cells. However, we observed autophagic flux during differentiation as a protective mechanism that allows cells to maintain homeostasis and remove dysfunctional mitochondria.
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19
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Xia X, Chiu PWY, Lam PK, Chin WC, Ng EKW, Lau JYW. Secretome from hypoxia-conditioned adipose-derived mesenchymal stem cells promotes the healing of gastric mucosal injury in a rodent model. Biochim Biophys Acta Mol Basis Dis 2017; 1864:178-188. [PMID: 28993190 DOI: 10.1016/j.bbadis.2017.10.009] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2017] [Revised: 08/08/2017] [Accepted: 10/05/2017] [Indexed: 12/17/2022]
Abstract
Studies have indicated that the definitive engraftment and transdifferentiation potential of stem cells do not seem crucial for its property of tissue repair. Our previous study showed that transplantation of adipose-derived mesenchymal stem cells (ADMSCs) enhanced the healing of sutured gastric perforation. This study aimed to investigate the paracrine role of ADMSCs in the experimental gastric mucosal injury. Normoxia-conditioned medium (Nor CM) and hypoxia (HPO) CM were obtained after culturing ADMSCs in 20% O2 and 5% O2 for 48h. Cell migration, proliferation, viability, and angiogenesis in vitro were significantly enhanced upon incubation with CM, especially the HPO CM. Experiments in vivo using a rodent model of gastric ulcer demonstrated that HPO CM treatment significantly accelerated wound healing by suppressing inflammation and promoting neovascularization and re-epithelization. Meanwhile, the infusion of HPO CM activated the COX2-PGE2 axis both in vitro and in vivo. And the upregulation of COX2 was further dependent on the activation of ErK1/2-MAPK pathway. In addition, vascular endothelial growth factor, tissue inhibitors of metalloproteinases-1, and chemokine (C-C motif) ligand 20 (CCL-20) were analyzed as being highly abundant factors secreted by ADMSCs under hypoxic condition. Notably, the blockade of CCL-20 abrogated the HPO CM-induced COX2 signaling in the primary gastric mucosal epithelial cells, while incubation with recombinant CCL-20 increased the expression of COX2. In conclusion, the secretome from hypoxia-conditioned ADMSCs facilitates the repair of gastric mucosal injury through the enhancement of angiogenesis and re-epithelization, as well as the activation of COX2-PGE2 axis with a paracrine activity involving CCL-20 factor.
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Affiliation(s)
- Xianfeng Xia
- Department of Surgery, Institute of Digestive Disease, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong; Chow Yuk Ho Technology Center for Innovative Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong
| | - Philip Wai Yan Chiu
- Department of Surgery, Institute of Digestive Disease, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong; Chow Yuk Ho Technology Center for Innovative Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong.
| | - Ping Kuen Lam
- Chow Tai Fook-Cheng Yu Tung Surgical Stem Cell Research Centre, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong
| | - Wai Ching Chin
- Chow Tai Fook-Cheng Yu Tung Surgical Stem Cell Research Centre, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong
| | - Enders Kwok Wai Ng
- Department of Surgery, Institute of Digestive Disease, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong
| | - James Yun Wong Lau
- Department of Surgery, Institute of Digestive Disease, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong; Chow Yuk Ho Technology Center for Innovative Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong
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20
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Rybalko V, Hsieh PL, Ricles LM, Chung E, Farrar RP, Suggs LJ. Therapeutic potential of adipose-derived stem cells and macrophages for ischemic skeletal muscle repair. Regen Med 2017; 12:153-167. [PMID: 28244825 DOI: 10.2217/rme-2016-0094] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
AIM Progressive ischemia due to peripheral artery disease causes muscle damage and reduced strength of the lower extremities. Autologous cell therapy is an attractive treatment to restore perfusion and improve muscle function. Adipose-derived stem cells (ASCs) have therapeutic potential in tissue repair, including polarizing effects on macrophages (MPs). MATERIALS & METHODS Co-culture systems of ASCs and MPs were analyzed for gene and protein expression modifications in ASC-conditioned MPs. Co-transplantation of MPs/ASCs in vivo led to improved skeletal muscle regeneration in a mouse model of peripheral artery disease. RESULTS ASCs/MPs therapy restored muscle function, increased perfusion and reduced inflammatory infiltrate. CONCLUSION Combined MPs/ASCs cell therapy is a promising approach to restore muscle function and stimulate local angiogenesis in the ischemic limb.
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Affiliation(s)
- Viktoriya Rybalko
- Biomedical Engineering, Cockrell School of Engineering, The University of Texas at Austin, 107 W Dean Keeton, Austin, TX 78712, USA
| | - Pei-Ling Hsieh
- Department of Kinesiology, The University of Texas at Austin, 1 University Station D3700, Austin, TX 78712, USA
| | - Laura M Ricles
- Biomedical Engineering, Cockrell School of Engineering, The University of Texas at Austin, 107 W Dean Keeton, Austin, TX 78712, USA
| | - Eunna Chung
- Biomedical Engineering, Cockrell School of Engineering, The University of Texas at Austin, 107 W Dean Keeton, Austin, TX 78712, USA
| | - Roger P Farrar
- Department of Kinesiology, The University of Texas at Austin, 1 University Station D3700, Austin, TX 78712, USA
| | - Laura J Suggs
- Biomedical Engineering, Cockrell School of Engineering, The University of Texas at Austin, 107 W Dean Keeton, Austin, TX 78712, USA
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21
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Bowles AC, Wise RM, Bunnell BA. Anti-inflammatory Effects of Adipose-Derived Stem Cells (ASCs). ACTA ACUST UNITED AC 2016. [DOI: 10.1007/978-3-319-46733-7_4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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22
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Liang J, Zhang Y, Xie T, Liu N, Chen H, Geng Y, Kurkciyan A, Mena JM, Stripp BR, Jiang D, Noble PW. Hyaluronan and TLR4 promote surfactant-protein-C-positive alveolar progenitor cell renewal and prevent severe pulmonary fibrosis in mice. Nat Med 2016; 22:1285-1293. [PMID: 27694932 PMCID: PMC5503150 DOI: 10.1038/nm.4192] [Citation(s) in RCA: 225] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2016] [Accepted: 08/29/2016] [Indexed: 02/08/2023]
Abstract
Successful recovery from lung injury requires the repair and regeneration of alveolar epithelial cells to restore the integrity of gas-exchanging regions within the lung and preserve organ function. Improper regeneration of the alveolar epithelium is often associated with severe pulmonary fibrosis, the latter of which involves the recruitment and activation of fibroblasts, as well as matrix accumulation. Type 2 alveolar epithelial cells (AEC2s) are stem cells in the adult lung that contribute to the lung repair process. The mechanisms that regulate AEC2 renewal are incompletely understood. We provide evidence that expression of the innate immune receptor Toll-like receptor 4 (TLR4) and the extracellular matrix glycosaminoglycan hyaluronan (HA) on AEC2s are important for AEC2 renewal, repair of lung injury and limiting the extent of fibrosis. Either deletion of TLR4 or HA synthase 2 in surfactant-protein-C-positive AEC2s leads to impaired renewal capacity, severe fibrosis and mortality. Furthermore, AEC2s from patients with severe pulmonary fibrosis have reduced cell surface HA and impaired renewal capacity, suggesting that HA and TLR4 are key contributors to lung stem cell renewal and that severe pulmonary fibrosis is the result of distal epithelial stem cell failure.
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Affiliation(s)
- Jiurong Liang
- Department of Medicine and Women’s Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Yanli Zhang
- Department of Medicine and Women’s Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Ting Xie
- Department of Medicine and Women’s Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Ningshan Liu
- Department of Medicine and Women’s Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Huaiyong Chen
- Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA
| | - Yan Geng
- Department of Medicine and Women’s Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Adrianne Kurkciyan
- Department of Medicine and Women’s Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Jessica Monterrosa Mena
- Department of Medicine and Women’s Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Barry R. Stripp
- Department of Medicine and Women’s Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Dianhua Jiang
- Department of Medicine and Women’s Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Paul W. Noble
- Department of Medicine and Women’s Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
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Miao CM, Jiang XW, He K, Li PZ, Liu ZJ, Cao D, Ou ZB, Gong JP, Liu CA, Cheng Y. Bone marrow stromal cells attenuate LPS-induced mouse acute liver injury via the prostaglandin E 2-dependent repression of the NLRP3 inflammasome in Kupffer cells. Immunol Lett 2016; 179:102-113. [PMID: 27666012 DOI: 10.1016/j.imlet.2016.09.009] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2016] [Revised: 08/23/2016] [Accepted: 09/21/2016] [Indexed: 12/18/2022]
Abstract
The nucleotide-binding and oligomerization domain-like receptor 3 (NLRP3) inflammasome participates in the pathogenesis of acute liver injury during sepsis. Bone marrow mesenchymal stem cells (BMSCs) attenuate sepsis through prostaglandin E 2 (PGE2) by increasing the interleukin-10 (IL-10) production of macrophages; moreover, NLRP3 inflammasome assembly is effectively regulated by IL-10 during infection. Whether BMSCs have an effect on the activation of the NLRP3 inflammasome and its underlying mechanism is unclear. Administering of BMSCs to mice or KCs after LPS stimulating have improved liver function and reduced activation of NLRP3 inflammasome in KCs. The beneficial effect of BMSCs was enhanced by over-expression of PGE2 and eliminated by silence of PGE2. Additionally, The IL-10 levels in the serum and supernatant were increased by given BMSCs and further increase by PGE2 over-expressed BMSCs, but decreased markedly by PGE2 silenced BMSCs. Furthermore, extracellular signal-regulated kinase 1 (ERK1) inhibitor reduced IL-10 production in KCs and blocked the inhibitory effect of PGE2 on the activation of the NLRP3 inflammasome. Our data reveal a novel mechanism of BMSC-mediated suppression of the activation of KCs through the secretion of PGE2 by BMSCs, which promotes KCs to secrete IL-10, leading to the inhibition of the NLRP3 inflammasome in KCs.
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Affiliation(s)
- Chun-Mu Miao
- Chongqing Key Laboratory of Hepatobiliary Surgery and Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xiao-Wei Jiang
- Chongqing Key Laboratory of Hepatobiliary Surgery and Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Kun He
- Chongqing Key Laboratory of Hepatobiliary Surgery and Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Pei-Zhi Li
- Chongqing Key Laboratory of Hepatobiliary Surgery and Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Zuo-Jin Liu
- Chongqing Key Laboratory of Hepatobiliary Surgery and Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Ding Cao
- Chongqing Key Laboratory of Hepatobiliary Surgery and Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Zhi-Bing Ou
- Chongqing Key Laboratory of Hepatobiliary Surgery and Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jian-Ping Gong
- Chongqing Key Laboratory of Hepatobiliary Surgery and Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Chang-An Liu
- Chongqing Key Laboratory of Hepatobiliary Surgery and Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
| | - Yao Cheng
- Chongqing Key Laboratory of Hepatobiliary Surgery and Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
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24
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Pan J, Xu T, Xu F, Zhang Y, Liu Z, Chen W, Fu W, Dai Y, Zhao Y, Feng J, Liang G. Development of resveratrol-curcumin hybrids as potential therapeutic agents for inflammatory lung diseases. Eur J Med Chem 2016; 125:478-491. [PMID: 27689730 DOI: 10.1016/j.ejmech.2016.09.033] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2016] [Revised: 09/08/2016] [Accepted: 09/09/2016] [Indexed: 01/20/2023]
Abstract
Acute lung injury (ALI) is a major cause of acute respiratory failure in critically-ill patients. Resveratrol and curcumin are proven to have potent anti-inflammatory efficacy, but their clinical application is limited by their metabolic instability. Here, a series of resveratrol and the Mono-carbonyl analogs of curcumin (MCAs) hybrids were designed and synthesized by efficient aldol construction strategy, and then screened for anti-inflammatory activities in vitro and in vivo. The results showed that the majority of analogs effectively inhibited the LPS-induced production of IL-6 and TNF-α. Five analogs, a9, a18, a19, a20 and a24 exhibited excellent anti-inflammatory activity in a dose-dependent manner along with low toxicity in vitro. Structure activity relationship study revealed that the electron-withdrawing groups at meta-position and methoxyl group (OCH3) at the para position of the phenyl ring were important for anti-inflammatory activities. The most promising compound a18 decreased LPS induced TNF-α, IL-6, IL-12, and IL-33 mRNA expression. Additionally, a18 significantly protected against LPS-induced acute lung injury in the in vivo mouse model. The research of resveratrol and MCAs hybrids could bring insight into the treatment of inflammatory diseases and compound a18 may serve as a lead compound for the development of anti-ALI agents.
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Affiliation(s)
- Jialing Pan
- Chemical Biology Research Center at School of Pharmaceutical Sciences, Wenzhou Medical University, 1210 University Town, Wenzhou, Zhejiang 325035, China
| | - Tingting Xu
- Department of Respiration, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China
| | - Fengli Xu
- Department of Respiration, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China
| | - Yali Zhang
- Chemical Biology Research Center at School of Pharmaceutical Sciences, Wenzhou Medical University, 1210 University Town, Wenzhou, Zhejiang 325035, China
| | - Zhiguo Liu
- Chemical Biology Research Center at School of Pharmaceutical Sciences, Wenzhou Medical University, 1210 University Town, Wenzhou, Zhejiang 325035, China
| | - Wenbo Chen
- Chemical Biology Research Center at School of Pharmaceutical Sciences, Wenzhou Medical University, 1210 University Town, Wenzhou, Zhejiang 325035, China
| | - Weitao Fu
- Chemical Biology Research Center at School of Pharmaceutical Sciences, Wenzhou Medical University, 1210 University Town, Wenzhou, Zhejiang 325035, China
| | - Yuanrong Dai
- Department of Respiration, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China
| | - Yunjie Zhao
- Chemical Biology Research Center at School of Pharmaceutical Sciences, Wenzhou Medical University, 1210 University Town, Wenzhou, Zhejiang 325035, China.
| | - Jianpeng Feng
- Chemical Biology Research Center at School of Pharmaceutical Sciences, Wenzhou Medical University, 1210 University Town, Wenzhou, Zhejiang 325035, China; Wenzhou University, 1210 University Town, Wenzhou, Zhejiang 325035, China.
| | - Guang Liang
- Chemical Biology Research Center at School of Pharmaceutical Sciences, Wenzhou Medical University, 1210 University Town, Wenzhou, Zhejiang 325035, China
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Zhu H, Xu T, Qiu C, Wu B, Zhang Y, Chen L, Xia Q, Li C, Zhou B, Liu Z, Liang G. Synthesis and optimization of novel allylated mono-carbonyl analogs of curcumin (MACs) act as potent anti-inflammatory agents against LPS-induced acute lung injury (ALI) in rats. Eur J Med Chem 2016; 121:181-193. [PMID: 27240273 DOI: 10.1016/j.ejmech.2016.05.041] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2015] [Revised: 05/18/2016] [Accepted: 05/19/2016] [Indexed: 11/30/2022]
Abstract
A series of novel symmetric and asymmetric allylated mono-carbonyl analogs of curcumin (MACs) were synthesized using an appropriate synthetic route and evaluated experimentally thru the LPS-induced expression of TNF-α and IL-6. Most of the obtained compounds exhibited improved water solubility as a hydrochloride salt compared to lead molecule 8f. The most active compound 7a was effective in reducing the Wet/Dry ratio in the lungs and protein concentration in bronchoalveolar lavage fluid. Meanwhile, 7a also inhibited mRNA expression of several inflammatory cytokines, including TNF-α, IL-6, IL-1β, and VCAM-1, in Beas-2B cells after Lipopolysaccharide (LPS) challenge. These results suggest that 7a could be therapeutically beneficial for use as an anti-inflammatory agent in the clinical treatment of acute lung injury (ALI).
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Affiliation(s)
- Heping Zhu
- Chemical Biology Research Center at School of Pharmaceutical Sciences, Wenzhou Medical University, 1210 University Town, Wenzhou, Zhejiang, 325035, China
| | - Tingting Xu
- Chemical Biology Research Center at School of Pharmaceutical Sciences, Wenzhou Medical University, 1210 University Town, Wenzhou, Zhejiang, 325035, China; The Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Chenyu Qiu
- Chemical Biology Research Center at School of Pharmaceutical Sciences, Wenzhou Medical University, 1210 University Town, Wenzhou, Zhejiang, 325035, China
| | - Beibei Wu
- Chemical Biology Research Center at School of Pharmaceutical Sciences, Wenzhou Medical University, 1210 University Town, Wenzhou, Zhejiang, 325035, China; The Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Yali Zhang
- Chemical Biology Research Center at School of Pharmaceutical Sciences, Wenzhou Medical University, 1210 University Town, Wenzhou, Zhejiang, 325035, China
| | - Lingfeng Chen
- Chemical Biology Research Center at School of Pharmaceutical Sciences, Wenzhou Medical University, 1210 University Town, Wenzhou, Zhejiang, 325035, China
| | - Qinqin Xia
- Chemical Biology Research Center at School of Pharmaceutical Sciences, Wenzhou Medical University, 1210 University Town, Wenzhou, Zhejiang, 325035, China
| | - Chenglong Li
- Chemical Biology Research Center at School of Pharmaceutical Sciences, Wenzhou Medical University, 1210 University Town, Wenzhou, Zhejiang, 325035, China
| | - Bin Zhou
- The Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
| | - Zhiguo Liu
- Chemical Biology Research Center at School of Pharmaceutical Sciences, Wenzhou Medical University, 1210 University Town, Wenzhou, Zhejiang, 325035, China.
| | - Guang Liang
- Chemical Biology Research Center at School of Pharmaceutical Sciences, Wenzhou Medical University, 1210 University Town, Wenzhou, Zhejiang, 325035, China
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Xue T, Liu P, Zhou Y, Liu K, Yang L, Moritz RL, Yan W, Xu LX. Interleukin-6 Induced "Acute" Phenotypic Microenvironment Promotes Th1 Anti-Tumor Immunity in Cryo-Thermal Therapy Revealed By Shotgun and Parallel Reaction Monitoring Proteomics. Am J Cancer Res 2016; 6:773-94. [PMID: 27162549 PMCID: PMC4860887 DOI: 10.7150/thno.14394] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2015] [Accepted: 02/08/2016] [Indexed: 12/14/2022] Open
Abstract
Cryo-thermal therapy has been emerged as a promising novel therapeutic strategy for advanced breast cancer, triggering higher incidence of tumor regression and enhanced remission of metastasis than routine treatments. To better understand its anti-tumor mechanism, we utilized a spontaneous metastatic mouse model and quantitative proteomics to compare N-glycoproteome changes in 94 serum samples with and without treatment. We quantified 231 highly confident N-glycosylated proteins using iTRAQ shotgun proteomics. Among them, 53 showed significantly discriminated regulatory patterns over the time course, in which the acute phase response emerged as the most enhanced pathway. The anti-tumor feature of the acute response was further investigated using parallel reaction monitoring target proteomics and flow cytometry on 23 of the 53 significant proteins. We found that cryo-thermal therapy reset the tumor chronic inflammation to an “acute” phenotype, with up-regulation of acute phase proteins including IL-6 as a key regulator. The IL-6 mediated “acute” phenotype transformed IL-4 and Treg-promoting ICOSL expression to Th1-promoting IFN-γ and IL-12 production, augmented complement system activation and CD86+MHCII+ dendritic cells maturation and enhanced the proliferation of Th1 memory cells. In addition, we found an increased production of tumor progression and metastatic inhibitory proteins under such “acute” environment, favoring the anti-metastatic effect. Moreover, cryo-thermal on tumors induced the strongest “acute” response compared to cryo/hyperthermia alone or cryo-thermal on healthy tissues, accompanying by the most pronounced anti-tumor immunological effect. In summary, we demonstrated that cryo-thermal therapy induced, IL-6 mediated “acute” microenvironment shifted the tumor chronic microenvironment from Th2 immunosuppressive and pro-tumorigenic to Th1 immunostimulatory and tumoricidal state. Moreover, the magnitude of “acute” and “danger” signals play a key role in determining the efficacy of anti-tumor activity.
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Transplantation of Immortalized CD34+ and CD34- Adipose-Derived Stem Cells Improve Cardiac Function and Mitigate Systemic Pro-Inflammatory Responses. PLoS One 2016; 11:e0147853. [PMID: 26840069 PMCID: PMC4740491 DOI: 10.1371/journal.pone.0147853] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2015] [Accepted: 01/08/2016] [Indexed: 01/18/2023] Open
Abstract
Adipose-derived stem cells (ADSCs) have the potential to differentiate into various cell lineages and they are easily obtainable from patients, which makes them a promising candidate for cell therapy. However, a drawback is their limited life span during in vitro culture. Therefore, hTERT-immortalized CD34+ and CD34- mouse ADSC lines (mADSCshTERT) tagged with GFP were established. We evaluated the proliferation capacity, multi-differentiation potential, and secretory profiles of CD34+ and CD34- mADSCshTERTin vitro, as well as their effects on cardiac function and systemic inflammation following transplantation into a rat model of acute myocardial infarction (AMI) to assess whether these cells could be used as a novel cell source for regeneration therapy in the cardiovascular field. CD34+ and CD34- mADSCshTERT demonstrated phenotypic characteristics and multi-differentiation potentials similar to those of primary mADSCs. CD34+ mADSCshTERT exhibited a higher proliferation ability compared to CD34- mADSCshTERT, whereas CD34- mADSCshTERT showed a higher osteogenic differentiation potential compared to CD34+ mADSCshTERT. Primary mADSCs, CD34+, and CD34- mADSCshTERT primarily secreted EGF, TGF-β1, IGF-1, IGF-2, MCP-1, and HGFR. CD34+ mADSCshTERT had higher secretion of VEGF and SDF-1 compared to CD34- mADSCshTERT. IL-6 secretion was severely reduced in both CD34+ and CD34- mADSCshTERT compared to primary mADSCs. Transplantation of CD34+ and CD34- mADSCshTERT significantly improved the left ventricular ejection fraction and reduced infarct size compared to AMI-induced rats after 28 days. At 28 days after transplantation, engraftment of CD34+ and CD34- mADSCshTERT was confirmed by positive Y chromosome staining, and differentiation of CD34+ and CD34- mADSCshTERT into endothelial cells was found in the infarcted myocardium. Significant decreases were observed in circulating IL-6 levels in CD34+ and CD34- mADSCshTERT groups compared to the AMI-induced control group. Transplantation of CD34- mADSCshTERT significantly reduced circulating MCP-1 levels compared to the AMI control and CD34+ mADSCshTERT groups. GFP-tagged CD34+ and CD34- mADSCshTERT are valuable resources for cell differentiation studies in vitro as well as for regeneration therapy in vivo.
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Zwezdaryk KJ, Ferris MB, Strong AL, Morris CA, Bunnell BA, Dhurandhar NV, Gimble JM, Sullivan DE. Human cytomegalovirus infection of human adipose-derived stromal/stem cells restricts differentiation along the adipogenic lineage. Adipocyte 2016; 5:53-64. [PMID: 27144097 DOI: 10.1080/21623945.2015.1119957] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2015] [Revised: 11/03/2015] [Accepted: 11/05/2015] [Indexed: 12/27/2022] Open
Abstract
Human adipose-derived stromal/stem cells (ASCs) display potential to be used in regenerative stem cell therapies and as treatments for inflammatory and autoimmune disorders. Despite promising use of ASCs as therapeutics, little is known about their susceptibility to infectious agents. In this study, we demonstrate that ASCs are highly susceptible to human cytomegalovirus (HCMV) infection and permissive for replication leading to release of infectious virions. Additionally, many basic ASC functions are inhibited during HCMV infection, such as differentiation and immunomodulatory potential. To our knowledge this is the first study examining potential adverse effects of HCMV infection on ASC biology. Our results suggest, that an active HCMV infection during ASC therapy may result in a poor clinical outcome due to interference by the virus.
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Morrison T, McAuley DF, Krasnodembskaya A. Mesenchymal stromal cells for treatment of the acute respiratory distress syndrome: The beginning of the story. J Intensive Care Soc 2015; 16:320-329. [PMID: 28979439 PMCID: PMC5606462 DOI: 10.1177/1751143715586420] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
In spite of decades of research, the acute respiratory distress syndrome (ARDS) continues to have an unacceptably high mortality and morbidity. Mesenchymal stromal cells (MSCs) present a promising candidate for the treatment of this condition and have demonstrated benefit in preclinical models. MSCs, which are a topic of growing interest in many inflammatory disorders, have already progressed to early phase clinical trials in ARDS. While a number of their mechanisms of effect have been elucidated, a better understanding of the complex actions of these cells may pave the way for MSC modifications, which might enable more effective translation into clinical practice.
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Razvi SS, Richards JB, Malik F, Cromar KR, Price RE, Bell CS, Weng T, Atkins CL, Spencer CY, Cockerill KJ, Alexander AL, Blackburn MR, Alcorn JL, Haque IU, Johnston RA. Resistin deficiency in mice has no effect on pulmonary responses induced by acute ozone exposure. Am J Physiol Lung Cell Mol Physiol 2015; 309:L1174-85. [PMID: 26386120 DOI: 10.1152/ajplung.00270.2015] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2015] [Accepted: 09/14/2015] [Indexed: 01/10/2023] Open
Abstract
Acute exposure to ozone (O3), an air pollutant, causes pulmonary inflammation, airway epithelial desquamation, and airway hyperresponsiveness (AHR). Pro-inflammatory cytokines-including IL-6 and ligands of chemokine (C-X-C motif) receptor 2 [keratinocyte chemoattractant (KC) and macrophage inflammatory protein (MIP)-2], TNF receptor 1 and 2 (TNF), and type I IL-1 receptor (IL-1α and IL-1β)-promote these sequelae. Human resistin, a pleiotropic hormone and cytokine, induces expression of IL-1α, IL-1β, IL-6, IL-8 (the human ortholog of murine KC and MIP-2), and TNF. Functional differences exist between human and murine resistin; yet given the aforementioned observations, we hypothesized that murine resistin promotes O3-induced lung pathology by inducing expression of the same inflammatory cytokines as human resistin. Consequently, we examined indexes of O3-induced lung pathology in wild-type and resistin-deficient mice following acute exposure to either filtered room air or O3. In wild-type mice, O3 increased bronchoalveolar lavage fluid (BALF) resistin. Furthermore, O3 increased lung tissue or BALF IL-1α, IL-6, KC, TNF, macrophages, neutrophils, and epithelial cells in wild-type and resistin-deficient mice. With the exception of KC, which was significantly greater in resistin-deficient compared with wild-type mice, no genotype-related differences in the other indexes existed following O3 exposure. O3 caused AHR to acetyl-β-methylcholine chloride (methacholine) in wild-type and resistin-deficient mice. However, genotype-related differences in airway responsiveness to methacholine were nonexistent subsequent to O3 exposure. Taken together, these data demonstrate that murine resistin is increased in the lungs of wild-type mice following acute O3 exposure but does not promote O3-induced lung pathology.
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Affiliation(s)
- Shehla S Razvi
- Division of Critical Care Medicine, Department of Pediatrics, The University of Texas Medical School at Houston, Houston, Texas
| | - Jeremy B Richards
- Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina
| | - Farhan Malik
- Division of Critical Care Medicine, Department of Pediatrics, The University of Texas Medical School at Houston, Houston, Texas
| | - Kevin R Cromar
- Department of Environmental Medicine, New York University School of Medicine, Tuxedo, New York
| | - Roger E Price
- Comparative Pathology Laboratory, Center for Comparative Medicine, Baylor College of Medicine, Houston, Texas
| | - Cynthia S Bell
- Division of Nephrology, Department of Pediatrics, The University of Texas Medical School at Houston, Houston, Texas
| | - Tingting Weng
- Department of Biochemistry and Molecular Biology, The University of Texas Medical School at Houston, Houston, Texas
| | - Constance L Atkins
- Division of Pulmonary Medicine, Department of Pediatrics, The University of Texas Medical School at Houston, Houston, Texas
| | - Chantal Y Spencer
- Pediatric Pulmonary Section, Department of Pediatrics, Baylor College of Medicine, Houston, Texas
| | - Katherine J Cockerill
- Pediatric Research Center, Department of Pediatrics, The University of Texas Medical School at Houston, Houston, Texas
| | - Amy L Alexander
- Pediatric Research Center, Department of Pediatrics, The University of Texas Medical School at Houston, Houston, Texas
| | - Michael R Blackburn
- Department of Biochemistry and Molecular Biology, The University of Texas Medical School at Houston, Houston, Texas
| | - Joseph L Alcorn
- Department of Biochemistry and Molecular Biology, The University of Texas Medical School at Houston, Houston, Texas; Pediatric Research Center, Department of Pediatrics, The University of Texas Medical School at Houston, Houston, Texas; Division of Neonatal-Perinatal Medicine, Department of Pediatrics, The University of Texas Medical School at Houston, Houston, Texas; and
| | - Ikram U Haque
- Division of Critical Care Medicine, Department of Pediatrics, The University of Texas Medical School at Houston, Houston, Texas
| | - Richard A Johnston
- Division of Critical Care Medicine, Department of Pediatrics, The University of Texas Medical School at Houston, Houston, Texas; Pediatric Research Center, Department of Pediatrics, The University of Texas Medical School at Houston, Houston, Texas; Department of Integrative Biology and Pharmacology, The University of Texas Medical School at Houston, Houston, Texas
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Strong AL, Burow ME, Gimble JM, Bunnell BA. Concise review: The obesity cancer paradigm: exploration of the interactions and crosstalk with adipose stem cells. Stem Cells 2015; 33:318-26. [PMID: 25267443 DOI: 10.1002/stem.1857] [Citation(s) in RCA: 72] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2014] [Revised: 07/28/2014] [Accepted: 08/06/2014] [Indexed: 01/04/2023]
Abstract
With the recognition of obesity as a global health crisis, researchers have devoted greater effort to defining and understanding the pathophysiological molecular pathways regulating the biology of adipose tissue and obesity. Obesity, the excessive accumulation of adipose tissue due to hyperplasia and hypertrophy, has been linked to an increased incidence and aggressiveness of colon, hematological, prostate, and postmenopausal breast cancers. The increased morbidity and mortality of obesity-associated cancers have been attributed to higher levels of hormones, adipokines, and cytokines secreted by the adipose tissue. The increased amount of adipose tissue also results in higher numbers of adipose stromal/stem cells (ASCs). These ASCs have been shown to impact cancer progression directly through several mechanisms, including the increased recruitment of ASCs to the tumor site and increased production of cytokines and growth factors by ASCs and other cells within the tumor stroma. Emerging evidence indicates that obesity induces alterations in the biologic properties of ASCs, subsequently leading to enhanced tumorigenesis and metastasis of cancer cells. This review will discuss the links between obesity and cancer tumor progression, including obesity-associated changes in adipose tissue, inflammation, adipokines, and chemokines. Novel topics will include a discussion of the contribution of ASCs to this complex system with an emphasis on their role in the tumor stroma. The reciprocal and circular feedback loop between obesity and ASCs as well as the mechanisms by which ASCs from obese patients alter the biology of cancer cells and enhance tumorigenesis will be discussed.
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Affiliation(s)
- Amy L Strong
- Center for Stem Cell Research and Regenerative Medicine
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Nolta JA. New advances in understanding stem cell fate and function. Stem Cells 2015; 33:313-5. [PMID: 25446041 DOI: 10.1002/stem.1905] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2014] [Indexed: 01/01/2023]
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Li J, Zhou J, Zhang D, Song Y, She J, Bai C. Bone marrow-derived mesenchymal stem cells enhance autophagy via PI3K/AKT signalling to reduce the severity of ischaemia/reperfusion-induced lung injury. J Cell Mol Med 2015; 19:2341-51. [PMID: 26177266 PMCID: PMC4594676 DOI: 10.1111/jcmm.12638] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2015] [Accepted: 05/20/2015] [Indexed: 12/22/2022] Open
Abstract
Autophagy, a type II programmed cell death, is essential for cell survival under stress, e.g. lung injury, and bone marrow-derived mesenchymal stem cells (BM-MSCs) have great potential for cell therapy. However, the mechanisms underlying the BM-MSC activation of autophagy to provide a therapeutic effect in ischaemia/reperfusion-induced lung injury (IRI) remain unclear. Thus, we investigate the activation of autophagy in IRI following transplantation with BM-MSCs. Seventy mice were pre-treated with BM-MSCs before they underwent lung IRI surgery in vivo. Human pulmonary micro-vascular endothelial cells (HPMVECs) were pre-conditioned with BM-MSCs by oxygen-glucose deprivation/reoxygenation (OGD) in vitro. Expression markers for autophagy and the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) signalling pathway were analysed. In IRI-treated mice, administration of BM-MSCs significantly attenuated lung injury and inflammation, and increased the level of autophagy. In OGD-treated HPMVECs, co-culture with BM-MSCs attenuated endothelial permeability by decreasing the level of cell death and enhanced autophagic activation. Moreover, administration of BM-MSCs decreased the level of PI3K class I and p-Akt while the expression of PI3K class III was increased. Finally, BM-MSCs-induced autophagic activity was prevented using the inhibitor LY294002. Administration of BM-MSCs attenuated lung injury by improving the autophagy level via the PI3K/Akt signalling pathway. These findings provide further understanding of the mechanisms related to BM-MSCs and will help to develop new cell-based therapeutic strategies in lung injury.
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Affiliation(s)
- Jing Li
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai Respiratory Research Institute, Shanghai, China
| | - Jian Zhou
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai Respiratory Research Institute, Shanghai, China
| | - Dan Zhang
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai Respiratory Research Institute, Shanghai, China
| | - Yuanlin Song
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai Respiratory Research Institute, Shanghai, China
| | - Jun She
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai Respiratory Research Institute, Shanghai, China
| | - Chunxue Bai
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai Respiratory Research Institute, Shanghai, China
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Kavanagh DPJ, Suresh S, Newsome PN, Frampton J, Kalia N. Pretreatment of Mesenchymal Stem Cells Manipulates Their Vasculoprotective Potential While Not Altering Their Homing Within the Injured Gut. Stem Cells 2015; 33:2785-97. [PMID: 26124062 PMCID: PMC4737111 DOI: 10.1002/stem.2061] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2014] [Accepted: 04/20/2015] [Indexed: 12/15/2022]
Abstract
Mesenchymal stem cells (MSCs) have shown therapeutic promise in many experimental and clinical models of inflammation. However, a commonly reported feature of MSC transplantation is poor homing to injured tissues. Previously, we have shown that pretreatment with cytokines/chemical factors enhances hematopoietic SC adhesion within intestinal microvasculature following ischemia-reperfusion (IR) injury. Using intravital microscopy, the ability of similar pretreatment strategies to enhance the recruitment of murine MSCs to murine intestinal microvasculature following IR injury was investigated. Primary MSCs were isolated from bone marrow and selected on the basis of platelet-derived growth factor receptor-α and SC antigen-1 positivity (PDGFRα(+) /Sca-1(+) ). MSC recruitment was similar in IR injured gut mucosa when compared with sham operated controls, with limited cell adhesion observed. MSCs appeared contorted in microvessels, suggesting physical entrapment. Although not recruited specifically by injury, MSC administration significantly reduced neutrophil recruitment and improved tissue perfusion in the severely injured jejunum. Vasculoprotective effects were not demonstrated in the lesser injured ileum. Pretreatment of MSCs with tumor necrosis factor (TNF)-α, CXCL12, interferon (IFN)-γ, or hydrogen peroxide did not enhance their intestinal recruitment. In fact, TNFα and IFNγ removed the previous therapeutic ability of transplanted MSCs to reduce neutrophil infiltration and improve perfusion in the jejunum. We provide direct evidence that MSCs can rapidly limit leukocyte recruitment and improve tissue perfusion following intestinal IR injury. However, this study also highlights complexities associated with strategies to improve MSC therapeutic efficacy. Future studies using cytokine/chemical pretreatments to enhance MSC recruitment/function require careful consideration and validation to ensure therapeutic function is not impeded.
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Affiliation(s)
- Dean P J Kavanagh
- Centre for Cardiovascular Sciences, University of Birmingham, Edgbaston, Birmingham, United Kingdom
| | - Shankar Suresh
- NIHR Centre for Liver Research and Biomedical Research Unit, University of Birmingham, Edgbaston, Birmingham, United Kingdom
| | - Philip N Newsome
- NIHR Centre for Liver Research and Biomedical Research Unit, University of Birmingham, Edgbaston, Birmingham, United Kingdom
| | - Jon Frampton
- School of Immunity and Infection, University of Birmingham, Edgbaston, Birmingham, United Kingdom
| | - Neena Kalia
- Centre for Cardiovascular Sciences, University of Birmingham, Edgbaston, Birmingham, United Kingdom
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Elimination of reperfusion-induced microcirculatory alterations in vivo by adipose-derived stem cell supernatant without adipose-derived stem cells. Plast Reconstr Surg 2015; 135:1056-1064. [PMID: 25811572 DOI: 10.1097/prs.0000000000001097] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
BACKGROUND In the present study, the authors hypothesized that adipose-derived stem cells in cell culture may secrete multiple cytokines in the supernatant, which might have a significant impact in vivo on the reperfusion-induced microcirculatory alterations and endothelial dysfunction. METHODS Fat tissue was surgically harvested from rat flanks and processed for adipose-derived stem cell isolation; cells (1 × 10(6)) were subcultured for 3, 6, 9, and 12 days without passage. The postcultivated medium was harvested with medium change every 3 days. After centrifugation, the supernatant was collected and stored at -20°C. Supernatant collected on day 9 was analyzed for eight oxidative stress cytokines by an enzyme-linked immunosorbent assay strip. The effect of the supernatant on the reperfusion-induced microcirculatory alterations was examined in the vascular pedicle of isolated rat cremaster muscles subjected to 4 hours of ischemia followed by 2 hours of reperfusion. RESULTS Enzyme-linked immunosorbent assay results demonstrated that adipose-derived stem cells produced several highly expressed cytokines in the supernatant. The average concentration of interleukin-6, in particular, was 5-fold higher compared with control. The reperfusion-induced vasospasm, arteriole stagnation, and the capillary no-reflow that often appear in the early phase of reperfusion were eliminated by adipose-derived stem cell supernatant. CONCLUSIONS Adipose-derived stem cells in cell culture display cytokine secretory properties that enable the cells to act through paracrine signaling. The supernatant even without cells could be used as a paracrine agent to interfere with the reperfusion-induced microcirculatory alterations and endothelial dysfunction.
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Design, synthesis and biological activity of novel asymmetric C66 analogs as anti-inflammatory agents for the treatment of acute lung injury. Eur J Med Chem 2015; 94:436-46. [DOI: 10.1016/j.ejmech.2014.11.054] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2014] [Revised: 11/24/2014] [Accepted: 11/26/2014] [Indexed: 11/19/2022]
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Lu H, Poirier C, Cook T, Traktuev DO, Merfeld-Clauss S, Lease B, Petrache I, March KL, Bogatcheva NV. Conditioned media from adipose stromal cells limit lipopolysaccharide-induced lung injury, endothelial hyperpermeability and apoptosis. J Transl Med 2015; 13:67. [PMID: 25889857 PMCID: PMC4358867 DOI: 10.1186/s12967-015-0422-3] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2014] [Accepted: 01/28/2015] [Indexed: 01/08/2023] Open
Abstract
Background Acute Respiratory Distress Syndrome (ARDS) is a condition that contributes to morbidity and mortality of critically ill patients. We investigated whether factors secreted by adipose stromal cells (ASC) into conditioned media (ASC-CM) will effectively decrease lung injury in the model of lipopolysaccharide (LPS)-induced ARDS. Methods To assess the effect of ASC-CM on ARDS indices, intravenous delivery of ASC and ASC-CM to C57Bl/6 mice was carried out 4 h after LPS oropharyngeal aspiration; Evans Blue Dye (EBD) was injected intravenously 1 h prior to animal sacrifice (48 h post-LPS). Lungs were either fixed for histopathology, or used to extract bronchoalveolar lavage fluid (BALF) or EBD. To assess the effect of ASC-CM on endothelial barrier function and apoptosis, human pulmonary artery endothelial cells were treated with ASC-CM for 48-72 h. Results ASC-CM markedly reduced LPS-induced histopathologic changes of lung, protein extravasation into BALF, and suppressed the secretion of proinflammatory cytokines TNFα and IL6. White Blood Cells (WBC) from BALF of LPS-challenged mice receiving ASC-CM had decreased reactive oxygen species (ROS) generation compared to WBC from LPS-challenged mice receiving control media injection. Treatment of pulmonary endothelial monolayers with ASC-CM significantly suppressed H2O2-induced leakage of FITC dextran and changes in transendothelial resistance, as well as gap formation in endothelial monolayer. ASC-CM exposure reduced the percentage of endothelial cells expressing ICAM-1, and suppressed TNFα-induced expression of E-selectin and cleavage of caspase-3. ASC-CM reduced the endothelial level of pro-apoptotic protein Bim, but did not affect the level of Bcl-2, Bad, or Bad phosphorylation. Conclusions Factors secreted by ASC efficiently reduce ARDS indices, endothelial barrier hyperpermeability, and activation of pro-inflammatory and pro-apoptotic pathways in endothelium.
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Affiliation(s)
- Hongyan Lu
- Division of Cardiology, Indiana University, Indianapolis, IN, USA. .,Indiana Center for Vascular Biology and Medicine and VC-CAST Signature Center, Indianapolis, IN, USA. .,Roudebush Veterans Affairs Medical Center, Indiana University, Indianapolis, IN, USA.
| | - Christophe Poirier
- Division of Pulmonary and Critical Care Medicine, Indiana University, Indianapolis, IN, USA.
| | - Todd Cook
- Division of Cardiology, Indiana University, Indianapolis, IN, USA. .,Indiana Center for Vascular Biology and Medicine and VC-CAST Signature Center, Indianapolis, IN, USA.
| | - Dmitry O Traktuev
- Division of Cardiology, Indiana University, Indianapolis, IN, USA. .,Indiana Center for Vascular Biology and Medicine and VC-CAST Signature Center, Indianapolis, IN, USA. .,Roudebush Veterans Affairs Medical Center, Indiana University, Indianapolis, IN, USA.
| | - Stephanie Merfeld-Clauss
- Division of Cardiology, Indiana University, Indianapolis, IN, USA. .,Indiana Center for Vascular Biology and Medicine and VC-CAST Signature Center, Indianapolis, IN, USA. .,Roudebush Veterans Affairs Medical Center, Indiana University, Indianapolis, IN, USA.
| | - Benjamin Lease
- Indiana Center for Vascular Biology and Medicine and VC-CAST Signature Center, Indianapolis, IN, USA.
| | - Irina Petrache
- Indiana Center for Vascular Biology and Medicine and VC-CAST Signature Center, Indianapolis, IN, USA. .,Roudebush Veterans Affairs Medical Center, Indiana University, Indianapolis, IN, USA. .,Division of Pulmonary and Critical Care Medicine, Indiana University, Indianapolis, IN, USA.
| | - Keith L March
- Division of Cardiology, Indiana University, Indianapolis, IN, USA. .,Indiana Center for Vascular Biology and Medicine and VC-CAST Signature Center, Indianapolis, IN, USA. .,Roudebush Veterans Affairs Medical Center, Indiana University, Indianapolis, IN, USA.
| | - Natalia V Bogatcheva
- Division of Cardiology, Indiana University, Indianapolis, IN, USA. .,Indiana Center for Vascular Biology and Medicine and VC-CAST Signature Center, Indianapolis, IN, USA. .,Roudebush Veterans Affairs Medical Center, Indiana University, Indianapolis, IN, USA.
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Kavanagh DPJ, Robinson J, Kalia N. Mesenchymal Stem Cell Priming: Fine-tuning Adhesion and Function. Stem Cell Rev Rep 2014; 10:587-99. [DOI: 10.1007/s12015-014-9510-7] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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