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1
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Saunders AAE, Thomson RE, Goodman CA, Anderson RL, Gregorevic P. Striated muscle: an inadequate soil for cancers. Cancer Metastasis Rev 2024; 43:1511-1527. [PMID: 38995522 PMCID: PMC11554797 DOI: 10.1007/s10555-024-10199-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Accepted: 07/01/2024] [Indexed: 07/13/2024]
Abstract
Many organs of the body are susceptible to cancer development. However, striated muscles-which include skeletal and cardiac muscles-are rarely the sites of primary cancers. Most deaths from cancer arise due to complications associated with the development of secondary metastatic tumours, for which there are few effective therapies. However, as with primary cancers, the establishment of metastatic tumours in striated muscle accounts for a disproportionately small fraction of secondary tumours, relative to the proportion of body composition. Examining why primary and metastatic cancers are comparatively rare in striated muscle presents an opportunity to better understand mechanisms that can influence cancer cell biology. To gain insights into the incidence and distribution of muscle metastases, this review presents a definitive summary of the 210 case studies of metastasis in muscle published since 2010. To examine why metastases rarely form in muscles, this review considers the mechanisms currently proposed to render muscle an inhospitable environment for cancers. The "seed and soil" hypothesis proposes that tissues' differences in susceptibility to metastatic colonization are due to differing host microenvironments that promote or suppress metastatic growth to varying degrees. As such, the "soil" within muscle may not be conducive to cancer growth. Gaining a greater understanding of the mechanisms that underpin the resistance of muscles to cancer may provide new insights into mechanisms of tumour growth and progression, and offer opportunities to leverage insights into the development of interventions with the potential to inhibit metastasis in susceptible tissues.
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Affiliation(s)
- Alastair A E Saunders
- Centre for Muscle Research, and Department of Anatomy and Physiology, The University of Melbourne, Parkville, Victoria, 3010, Australia
| | - Rachel E Thomson
- Centre for Muscle Research, and Department of Anatomy and Physiology, The University of Melbourne, Parkville, Victoria, 3010, Australia
| | - Craig A Goodman
- Centre for Muscle Research, and Department of Anatomy and Physiology, The University of Melbourne, Parkville, Victoria, 3010, Australia
| | - Robin L Anderson
- Metastasis Research Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia
- School of Cancer Medicine, La Trobe University, Bundoora, Victoria, Australia
- Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria, Australia
- Peter MacCallum Cancer Centre, Parkville, Victoria, Australia
| | - Paul Gregorevic
- Centre for Muscle Research, and Department of Anatomy and Physiology, The University of Melbourne, Parkville, Victoria, 3010, Australia.
- Department of Neurology, The University of Washington School of Medicine, Seattle, WA, USA.
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2
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Chen L, Zhang J, Zhang C. Case Report: Lung cancer with rare cardiac and other multiple metastases. Front Cardiovasc Med 2024; 11:1417906. [PMID: 39328239 PMCID: PMC11424542 DOI: 10.3389/fcvm.2024.1417906] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Accepted: 08/30/2024] [Indexed: 09/28/2024] Open
Abstract
Metastasis to the left atrium is exceptionally uncommon, occurring at a rate of only 3.1%. The clinical manifestations of lung cancer metastasizing to the heart can vary widely. They range from paraneoplastic syndrome, dyspnea, and ST-segment elevation on an electrocardiogram to no clinically significant symptoms. Diverging from typical metastatic patterns observed in lung cancer, this case report presents a detailed description, from the perspective of the microenvironment, of a rare instance where lung cancer metastasized to the mediastinal lymph nodes, adrenal glands, brain, and notably, the left atrium, in a non-smoking female patient.
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Affiliation(s)
- Li Chen
- Department of Ultrasound, The Second Affiliated Hospital of Nanchang University, Nanchang, China
- Jiangxi Medical College of Nanchang University, Nanchang, China
| | - Jing Zhang
- Department of Ultrasound, The Second Affiliated Hospital of Nanchang University, Nanchang, China
- Jiangxi Medical College of Nanchang University, Nanchang, China
| | - Chunquan Zhang
- Department of Ultrasound, The Second Affiliated Hospital of Nanchang University, Nanchang, China
- Jiangxi Medical College of Nanchang University, Nanchang, China
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3
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Bruno S, Herrera Sanchez MB, Chiabotto G, Fonsato V, Navarro-Tableros V, Pasquino C, Tapparo M, Camussi G. Human Liver Stem Cells: A Liver-Derived Mesenchymal Stromal Cell-Like Population With Pro-regenerative Properties. Front Cell Dev Biol 2021; 9:644088. [PMID: 33981703 PMCID: PMC8107725 DOI: 10.3389/fcell.2021.644088] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Accepted: 04/06/2021] [Indexed: 12/16/2022] Open
Abstract
Human liver stem cells (HLSCs) were described for the first time in 2006 as a new stem cell population derived from healthy human livers. Like mesenchymal stromal cells, HLSCs exhibit multipotent and immunomodulatory properties. HLSCs can differentiate into several lineages under defined in vitro conditions, such as mature hepatocytes, osteocytes, endothelial cells, and islet-like cell organoids. Over the years, HLSCs have been shown to contribute to tissue repair and regeneration in different in vivo models, leading to more than five granted patents and over 15 peer reviewed scientific articles elucidating their potential therapeutic role in various experimental pathologies. In addition, HLSCs have recently completed a Phase 1 study evaluating their safety post intrahepatic injection in infants with inherited neonatal onset hyperammonemia. Even though a lot of progress has been made in understanding HLSCs over the past years, some important questions regarding the mechanisms of action remain to be elucidated. Among the mechanisms of interaction of HLSCs with their environment, a paracrine interface has emerged involving extracellular vesicles (EVs) as vehicles for transferring active biological materials. In our group, the EVs derived from HLSCs have been studied in vitro as well as in vivo. Our attention has mainly been focused on understanding the in vivo ability of HLSC–derived EVs as modulators of tissue regeneration, inflammation, fibrosis, and tumor growth. This review article aims to discuss in detail the role of HLSCs and HLSC-EVs in these processes and their possible future therapeutic applications.
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Affiliation(s)
- Stefania Bruno
- Department of Medical Sciences, University of Torino, Turin, Italy.,Molecular Biotechnology Center, University of Torino, Turin, Italy
| | - Maria Beatriz Herrera Sanchez
- Molecular Biotechnology Center, University of Torino, Turin, Italy.,2i3T, Società per la Gestione dell'incubatore di Imprese e per il Trasferimento Tecnologico, University of Torino, Turin, Italy
| | - Giulia Chiabotto
- Department of Medical Sciences, University of Torino, Turin, Italy.,Molecular Biotechnology Center, University of Torino, Turin, Italy
| | - Valentina Fonsato
- Molecular Biotechnology Center, University of Torino, Turin, Italy.,2i3T, Società per la Gestione dell'incubatore di Imprese e per il Trasferimento Tecnologico, University of Torino, Turin, Italy
| | - Victor Navarro-Tableros
- Molecular Biotechnology Center, University of Torino, Turin, Italy.,2i3T, Società per la Gestione dell'incubatore di Imprese e per il Trasferimento Tecnologico, University of Torino, Turin, Italy
| | - Chiara Pasquino
- Department of Medical Sciences, University of Torino, Turin, Italy.,Molecular Biotechnology Center, University of Torino, Turin, Italy
| | - Marta Tapparo
- Department of Medical Sciences, University of Torino, Turin, Italy.,Molecular Biotechnology Center, University of Torino, Turin, Italy
| | - Giovanni Camussi
- Department of Medical Sciences, University of Torino, Turin, Italy.,Molecular Biotechnology Center, University of Torino, Turin, Italy
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4
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Microenvironment in Cardiac Tumor Development: What Lies Beyond the Event Horizon? ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1226:51-56. [PMID: 32030675 DOI: 10.1007/978-3-030-36214-0_4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Cardiac tumors are found in less than 1% of adult and pediatric autopsies. More than three-fourths of primary cardiac neoplasms are benign, with myxomas and rhabdomyomas being the most common cardiac tumors seen in adults and children, respectively. Primary malignant cardiac tumors are extremely rare, whereas metastatic lesions can be seen in approximately 8% of patients dying from cancer. Attempting to understand why the heart is so resistant to carcinogenesis and which fail-safe mechanisms malfunction when cardiac tumors do develop is particularly challenging considering the rarity of these tumors and the fact that when relevant clinical studies are published, they rarely focus on molecular pathogenesis. Apart from cancer cells, solid tumors are comprised of a concoction of noncancerous cells, and extracellular matrix constituents, which along with pH and oxygen levels jointly constitute the so-called tumor microenvironment (TME). In the present chapter, we explore mechanisms through which TME may influence cardiac carcinogenesis.
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5
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Rotondo F, Ho-Palma AC, Romero MDM, Remesar X, Fernández-López JA, Alemany M. Higher lactate production from glucose in cultured adipose nucleated stromal cells than for rat adipocytes. Adipocyte 2019; 8:61-76. [PMID: 30676233 PMCID: PMC6768231 DOI: 10.1080/21623945.2019.1569448] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
White adipose tissue (WAT) nucleated stromal cells (NSC) play important roles in regulation, defense, regeneration and metabolic control. In WAT sites, the proportions and functions of NSC change under diverse physiological or pathologic conditions. We had previously observed the massive anaerobic wasting of glucose to lactate and glycerol in rat epididymal adipocytes. To test site variability, and whether the adipocyte extensive anaerobic metabolism of glucose was found in NSC, we analyzed, in parallel, subcutaneous, mesenteric and epididymal WAT of male adult Wistar rats. Adipocytes and NSC fractions, were isolated, counted and incubated (as well as red blood cells: RBC) with glucose, and their ability to use glucose and produce lactate, glycerol, and free fatty acids was measured. Results were computed taking into account the number of cells present in WAT samples. Cell numbers were found in proportions close to 1:13:100 (respectively, for adipocytes, NSC and RBC) but their volumes followed a reversed pattern: 7,500:10:1. When counting only non-fat cell volumes, the ratios changed dramatically to 100:10:1. RBC contribution to lactate production was practically insignificant. In most samples, NSC produced more lactate than adipocytes did, but only adipocytes secreted glycerol (and fatty acids in smaller amounts). Glucose consumption was also highest in NSC, especially in mesenteric WAT. The heterogeneous NSC showed a practically anaerobic metabolism (like that already observed in adipocytes). Thus, NSC quantitative production of lactate markedly contributed (i.e. more than adipocytes) to WAT global use (wasting) of glucose. We also confirmed that glucose-derived glycerol is exclusively produced by adipocytes.
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Affiliation(s)
- Floriana Rotondo
- Department of Biochemistry and Molecular Biomedicine, Faculty of Biology University of Barcelona, Barcelona, Spain
| | - Ana-Cecilia Ho-Palma
- Department of Biochemistry and Molecular Biomedicine, Faculty of Biology University of Barcelona, Barcelona, Spain
| | - María del Mar Romero
- Department of Biochemistry and Molecular Biomedicine, Faculty of Biology University of Barcelona, Barcelona, Spain
- Institute of Biomedicine, University of Barcelona, Barcelona, Spain
- CIBER-OBN Research Web, Barcelona, Spain
| | - Xavier Remesar
- Department of Biochemistry and Molecular Biomedicine, Faculty of Biology University of Barcelona, Barcelona, Spain
- Institute of Biomedicine, University of Barcelona, Barcelona, Spain
- CIBER-OBN Research Web, Barcelona, Spain
| | - José Antonio Fernández-López
- Department of Biochemistry and Molecular Biomedicine, Faculty of Biology University of Barcelona, Barcelona, Spain
- Institute of Biomedicine, University of Barcelona, Barcelona, Spain
- CIBER-OBN Research Web, Barcelona, Spain
| | - Marià Alemany
- Department of Biochemistry and Molecular Biomedicine, Faculty of Biology University of Barcelona, Barcelona, Spain
- Institute of Biomedicine, University of Barcelona, Barcelona, Spain
- CIBER-OBN Research Web, Barcelona, Spain
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6
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Mesenchymal Stem Cells in the Adult Human Liver: Hype or Hope? Cells 2019; 8:cells8101127. [PMID: 31546729 PMCID: PMC6830330 DOI: 10.3390/cells8101127] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Revised: 09/18/2019] [Accepted: 09/21/2019] [Indexed: 02/06/2023] Open
Abstract
Chronic liver diseases constitute a significant economic, social, and biomedical burden. Among commonly adopted approaches, only organ transplantation can radically help patients with end-stage liver pathologies. Cell therapy with hepatocytes as a treatment for chronic liver disease has demonstrated promising results. However, quality human hepatocytes are in short supply. Stem/progenitor cells capable of differentiating into functionally active hepatocytes provide an attractive alternative approach to cell therapy for liver diseases, as well as to liver-tissue engineering, drug screening, and basic research. The application of methods generally used to isolate mesenchymal stem cells (MSCs) and maintain them in culture to human liver tissue provides cells, designated here as liver MSCs. They have much in common with MSCs from other tissues, but differ in two aspects-expression of a range of hepatocyte-specific genes and, possibly, inherent commitment to hepatogenic differentiation. The aim of this review is to analyze data regarding liver MSCs, probably another type of liver stem/progenitor cells different from hepatic stellate cells or so-called hepatic progenitor cells. The review presents an analysis of the phenotypic characteristics of liver MSCs, their differentiation and therapeutic potential, methods for isolating these cells from human liver, and discusses issues of their origin and heterogeneity. Human liver MSCs are a fascinating object of fundamental research with a potential for important practical applications.
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7
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Manufacturing mesenchymal stromal cells for clinical applications: A survey of Good Manufacturing Practices at U.S. academic centers. Cytotherapy 2019; 21:782-792. [DOI: 10.1016/j.jcyt.2019.04.003] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2019] [Revised: 03/26/2019] [Accepted: 04/03/2019] [Indexed: 12/28/2022]
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8
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Tan L, Zhang Y, Huang Y, Luo Y, Liu Y. Preservation of alveolar ridge after tooth extraction with hypoxia-inducible factor-1α protein in a dog model. Exp Ther Med 2019; 17:2913-2920. [PMID: 30936961 PMCID: PMC6434234 DOI: 10.3892/etm.2019.7301] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2018] [Accepted: 10/26/2018] [Indexed: 12/12/2022] Open
Abstract
Hypoxia-inducible factor (HIF)-1α protein, which is upregulated by hypoxia, serves an important role in angiogenesis during osteogenesis. The aim of the present study was to investigate the effect of HIF-1α on alveolar ridge preservation in a dog tooth extraction model. Six beagle dogs were used in the present study. The second and fourth premolar teeth of the lower jaws on both sides were extracted. Two unilateral extraction sockets were randomly selected and filled with Bio-Oss and Bio-Oss + HIF-1α. The contralateral sockets remained unfilled and served as the negative control. Micro-computed tomography examination and histological staining were performed to examine the difference of new bone formation among the three groups. Western blotting and reverse transcription-quantitative polymerase chain reaction analysis were used to detect the expression levels of osteogenesis- and angiogenesis-associated genes in the bone tissues of the three groups. Twelve weeks post-surgery, trabecular bone formation in the Bio-Oss + HIF-1α group was significantly increased compared with the other groups. The expression levels of osteogenesis-associated genes (runt-related transcription factor 2, osteoblast-specific transcription factor osterix and osteocalcin) and angiogenesis-associated genes (HIF-1α and vascular endothelial growth factor) were all significantly increased in the Bio-Oss + HIF-1α group compared with the other two groups (P<0.05). The present results indicated that Bio-Oss with HIF-1α can promote osteogenesis and angiogenesis in vivo and may be used as an effective treatment for the preservation of the alveolar ridge.
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Affiliation(s)
- Luanjun Tan
- Department of Stomatology, Shanghai East Hospital Affiliated with Tongji University, Shanghai 200120, P.R. China
| | - Yingdi Zhang
- Department of Stomatology, Shanghai East Hospital Affiliated with Tongji University, Shanghai 200120, P.R. China
| | - Yuanliang Huang
- Department of Stomatology, Shanghai East Hospital Affiliated with Tongji University, Shanghai 200120, P.R. China
| | - Yuan Luo
- Oral Biomedical Engineering Laboratory, Shanghai Stomatological Hospital, Fudan University, Shanghai 200031, P.R. China.,Department of Oral Surgery, Shanghai Stomatological Hospital, Fudan University, Shanghai 200031, P.R. China
| | - Yuehua Liu
- Department of Orthodontics, Shanghai Stomatological Hospital, Fudan University, Shanghai 200031, P.R. China.,Oral Biomedical Engineering Laboratory, Shanghai Stomatological Hospital, Fudan University, Shanghai 200031, P.R. China
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9
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Zollino I, Campioni D, Sibilla MG, Tessari M, Malagoni AM, Zamboni P. A phase II randomized clinical trial for the treatment of recalcitrant chronic leg ulcers using centrifuged adipose tissue containing progenitor cells. Cytotherapy 2018; 21:200-211. [PMID: 30583949 DOI: 10.1016/j.jcyt.2018.10.012] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2018] [Revised: 10/17/2018] [Accepted: 10/24/2018] [Indexed: 12/15/2022]
Abstract
BACKGROUND AIMS Preclinical and observational reports indicate that adipose tissue (AT) is a safe and promising tool to treat non-healing venous leg ulcers (VLUs). METHODS From an initial cohort of 38 patients, 16 patients affected by non-healing VLUs were randomly allocated to the experimental arm (5 men and 3 women) and control arm (5 men and 3 women). In the experimental arm, wounds were treated by debridement, centrifuged adipose tissue (CAT), advanced dressings and compression. No experimental treatment (CAT) was administered to the control arm. We investigated the functional and the immunophenotypical features of the harvested CAT-derived stem cells. The primary outcome measures were healing time and safety of the cell treatment. Secondary outcomes were pain evaluated by numeric rating scale (NRS), complete wound healing at 24 weeks by Margolis Index and wound-healing process expressed in square centimeters per week. The various immunophenotypic and functional characteristics of CAT-derived stem cells were then correlated with the clinical outcomes. RESULTS No major adverse events were recorded. The healing time was significantly faster by applying CAT, 17.5 ± 7.0 weeks versus 24.5 ± 4.9 weeks recorded in the control arm (P < 0.036). NRS dropped after the first week to 2.7 ± 2.0 in the experimental arm versus 6.6 ± 3.0 in the control group (P < 0.01). The rate of healing at the 24th week was not significantly different between arms. Interestingly, we found a strong reverse correlation between the percent of CD34+/CD45- non-hematopoietic cells, respectively, with the healing time (r = -0.894, P < 0.041) and NRS (r = -0.934, P < 0.020). CONCLUSIONS CAT is safe and may accelerate healing time in VLUs as well as reduce wound pain. The percentage of CD34+/CD45- cells in stromal vascular fraction (SVF) seems to be a predictive biomarker of successful CAT treatment in these patients.
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Affiliation(s)
- Ilaria Zollino
- Department of Morphology, Surgery and Experimental Medicine, Section of Translational of Medicine and Surgery, University of Ferrara, Ferrara, Italy.
| | - Diana Campioni
- Center of Hemostasis & Thrombosis, Department of Biomedical and Surgical Science, Section of Medical Biochemistry, Molecular Biology & Genetics, University of Ferrara, Ferrara, Italy
| | - Maria Grazia Sibilla
- Sant'Anna University Hospital, Unit of Translational Surgery and Vascular Diseases Center, Ferrara, Italy
| | - Mirko Tessari
- Department of Morphology, Surgery and Experimental Medicine, Section of Translational of Medicine and Surgery, University of Ferrara, Ferrara, Italy; Sant'Anna University Hospital, Unit of Translational Surgery and Vascular Diseases Center, Ferrara, Italy
| | - Anna Maria Malagoni
- Sant'Anna University Hospital, Unit of Translational Surgery and Vascular Diseases Center, Ferrara, Italy
| | - Paolo Zamboni
- Department of Morphology, Surgery and Experimental Medicine, Section of Translational of Medicine and Surgery, University of Ferrara, Ferrara, Italy; Sant'Anna University Hospital, Unit of Translational Surgery and Vascular Diseases Center, Ferrara, Italy
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10
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Srinivasan A, Chang SY, Zhang S, Toh WS, Toh YC. Substrate stiffness modulates the multipotency of human neural crest derived ectomesenchymal stem cells via CD44 mediated PDGFR signaling. Biomaterials 2018; 167:153-167. [PMID: 29571051 DOI: 10.1016/j.biomaterials.2018.03.022] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2017] [Revised: 02/26/2018] [Accepted: 03/12/2018] [Indexed: 12/12/2022]
Abstract
Mesenchymal stem cells (MSCs) have been isolated from various mesodermal and ectodermal tissues. While the phenotypic and functional heterogeneity of MSCs stemming from their developmental origins has been acknowledged, the genetic and environmental factors underpinning these differences are not well-understood. Here, we investigated whether substrate stiffness mediated mechanical cues can directly modulate the development of ectodermal MSCs (eMSCs) from a precursor human neural crest stem cell (NCSC) population. We showed that NCSC-derived eMSCs were transcriptionally and functionally distinct from mesodermal bone marrow MSCs. eMSCs derived on lower substrate stiffness specifically increased their expression of the MSC marker, CD44 in a Rho-ROCK signaling dependent manner, which resulted in a concomitant increase in the eMSCs' adipogenic and chondrogenic differentiation potential. This mechanically-induced effect can only be maintained for short-term upon switching back to a stiff substrate but can be sustained for longer-term when the eMSCs were exclusively maintained on soft substrates. We also discovered that CD44 expression modulated eMSC self-renewal and multipotency via the downregulation of downstream platelet-derived growth factor receptor beta (PDGFRβ) signaling. This is the first instance demonstrating that substrate stiffness not only influences the differentiation trajectories of MSCs but also their derivation from upstream progenitors, such as NCSCs.
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Affiliation(s)
- Akshaya Srinivasan
- Department of Biomedical Engineering, National University of Singapore, 4 Engineering Drive 3, #04-10, Singapore 117583
| | - Shu-Yung Chang
- Department of Biomedical Engineering, National University of Singapore, 4 Engineering Drive 3, #04-10, Singapore 117583
| | - Shipin Zhang
- Faculty of Dentistry, National University of Singapore, 11 Lower Kent Ridge Road, Singapore 119083
| | - Wei Seong Toh
- NUS Tissue Engineering Program (NUSTEP), National University of Singapore, DSO (Kent Ridge), 27 Medical Drive, #04-01, Singapore 117510; Faculty of Dentistry, National University of Singapore, 11 Lower Kent Ridge Road, Singapore 119083
| | - Yi-Chin Toh
- Department of Biomedical Engineering, National University of Singapore, 4 Engineering Drive 3, #04-10, Singapore 117583; Singapore Institute for Neurotechnology (SINAPSE), National University of Singapore, Centre for Life Sciences, 28 Medical Drive, #05-COR, Singapore 117456; NUS Tissue Engineering Program (NUSTEP), National University of Singapore, DSO (Kent Ridge), 27 Medical Drive, #04-01, Singapore 117510; Biomedical Institute for Global Health, Research and Technology (BIGHEART), MD6, 14 Medical Drive, #14-01, Singapore 117599.
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11
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Qadan MA, Piuzzi NS, Boehm C, Bova W, Moos M, Midura RJ, Hascall VC, Malcuit C, Muschler GF. Variation in primary and culture-expanded cells derived from connective tissue progenitors in human bone marrow space, bone trabecular surface and adipose tissue. Cytotherapy 2018; 20:343-360. [PMID: 29396254 DOI: 10.1016/j.jcyt.2017.11.013] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2017] [Revised: 11/27/2017] [Accepted: 11/29/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND AIMS Connective tissue progenitors (CTPs) embody the heterogeneous stem and progenitor cell populations present in native tissue. CTPs are essential to the formation and remodeling of connective tissue and represent key targets for tissue-engineering and cell-based therapies. To better understand and characterize CTPs, we aimed to compare the (i) concentration and prevalence, (ii) early in vitro biological behavior and (iii) expression of surface-markers and transcription factors among cells derived from marrow space (MS), trabecular surface (TS), and adipose tissues (AT). METHODS Cancellous-bone and subcutaneous-adipose tissues were collected from 8 patients. Cells were isolated and cultured. Colony formation was assayed using Colonyze software based on ASTM standards. Cell concentration ([Cell]), CTP concentration ([CTP]) and CTP prevalence (PCTP) were determined. Attributes of culture-expanded cells were compared based on (i) effective proliferation rate and (ii) expression of surface-markers CD73, CD90, CD105, SSEA-4, SSEA-3, SSEA-1/CD15, Cripto-1, E-Cadherin/CD324, Ep-CAM/CD326, CD146, hyaluronan and transcription factors Oct3/4, Sox-2 and Nanog using flow cytometry. RESULTS Mean [Cell], [CTP] and PCTP were significantly different between MS and TS samples (P = 0.03, P = 0.008 and P= 0.0003), respectively. AT-derived cells generated the highest mean total cell yield at day 6 of culture-4-fold greater than TS and more than 40-fold greater than MS per million cells plated. TS colonies grew with higher mean density than MS colonies (290 ± 11 versus 150 ± 11 cell per mm2; P = 0.0002). Expression of classical-mesenchymal stromal cell (MSC) markers was consistently recorded (>95%) from all tissue sources, whereas all the other markers were highly variable. CONCLUSIONS The prevalence and biological potential of CTPs are different between patients and tissue sources and lack variation in classical MSC markers. Other markers are more likely to discriminate differences between cell populations in biological performance. Understanding the underlying reasons for variation in the concentration, prevalence, marker expression and biological potential of CTPs between patients and source tissues and determining the means of managing this variation will contribute to the rational development of cell-based clinical diagnostics and targeted cell-based therapies.
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Affiliation(s)
- Maha A Qadan
- Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA; School of Biomedical Sciences, Kent State University, Kent, Ohio, USA; Department of Biotechnology and Genetic Engineering, Philadelphia University, Amman, Jordan
| | - Nicolas S Piuzzi
- Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA; Department of Orthopaedic Surgery, Cleveland Clinic Foundation, Cleveland, Ohio, USA; Instituto Universitario del Hospital Italiano de Buenos Aires, Buenos Aires, Argentina
| | - Cynthia Boehm
- Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Wesley Bova
- Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Malcolm Moos
- FDA/Center for Biologics Evaluation and Research, Division of Cellular and Gene Therapies, Office of Cellular, Tissue, and Gene Therapies, Silver Spring, Maryland, USA
| | - Ronald J Midura
- Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Vincent C Hascall
- Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | | | - George F Muschler
- Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA; Department of Orthopaedic Surgery, Cleveland Clinic Foundation, Cleveland, Ohio, USA.
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12
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Timari H, Shamsasenjan K, Movassaghpour A, Akbarzadehlaleh P, Pashoutan Sarvar D, Aqmasheh S. The Effect of Mesenchymal Stem Cell-Derived Extracellular Vesicles on Hematopoietic Stem Cells Fate. Adv Pharm Bull 2017; 7:531-546. [PMID: 29399543 PMCID: PMC5788208 DOI: 10.15171/apb.2017.065] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2017] [Revised: 11/25/2017] [Accepted: 11/28/2017] [Indexed: 12/16/2022] Open
Abstract
Hematopoietic stem cells (HSCs) are multipotent stem cells, with self-renewal ability as well as ability to generate all blood cells. Mesenchymal stem cells (MSCs) are multipotent stem cells, with self-renewal ability, and capable of differentiating into a variety of cell types. MSCs have supporting effects on hematopoiesis; through direct intercellular communications as well as secreting cytokines, chemokines, and extracellular vesicles (EVs). Recent investigations demonstrated that some biological functions and effects of MSCs are mediated by their EVs. MSC-EVs are the cell membrane and endosomal membrane compartments, which are important mediators in the intercellular communications. MSC-EVs contain some of the molecules such as proteins, mRNA, siRNA, and miRNA from their parental cells. MSC-EVs are able to inhibit tumor, repair damaged tissue, and modulate immune system responses. MSC-EVs compared to their parental cells, may have the specific safety advantages such as the lower potential to trigger immune system responses and limited side effects. Recently some studies demonstrated the effect of MSC-EVs on the expansion, differentiation, and clinical applications of HSCs such as improvement of hematopoietic stem cell transplantation (HSCT) and inhibition of graft versus host disease (GVHD). HSCT may be the only therapeutic choice for patients who suffer from malignant and non-malignant hematological disorders. However, there are several severe side effects such GVHD that restricts the successfulness of HSCT. In this review, we will discuss the most important effects of MSCs and MSC-EVs on the improvement of HSCT, inhibition and treatment of GVHD, as well as, on the expansion of HSCs.
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Affiliation(s)
- Hamze Timari
- Stem Cell Research Centre, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Karim Shamsasenjan
- Stem Cell Research Centre, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Aliakbar Movassaghpour
- Hematology Oncology Research Centre, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Parvin Akbarzadehlaleh
- Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Sara Aqmasheh
- Stem Cell Research Centre, Tabriz University of Medical Sciences, Tabriz, Iran
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Eslani M, Putra I, Shen X, Hamouie J, Afsharkhamseh N, Besharat S, Rosenblatt MI, Dana R, Hematti P, Djalilian AR. Corneal Mesenchymal Stromal Cells Are Directly Antiangiogenic via PEDF and sFLT-1. Invest Ophthalmol Vis Sci 2017; 58:5507-5517. [PMID: 29075761 PMCID: PMC5661382 DOI: 10.1167/iovs.17-22680] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Purpose To evaluate the angiogenic properties of corneal derived mesenchymal stromal cells (Co-MSC). Methods Co-MSCs were extracted from human cadaver, and wild-type (C57BL/6J) and SERPINF1−/− mice corneas. The MSC secretome was collected in a serum-free medium. Human umbilical vein endothelial cell (HUVEC) tube formation and fibrin gel bead assay (FIBA) sprout formation were used to assess the angiogenic properties of Co-MSC secretome. Complete corneal epithelial debridement was used to induce corneal neovascularization in wild-type mice. Co-MSCs embedded in fibrin gel was applied over the debrided cornea to evaluate the angiogenic effects of Co-MSCs in vivo. Immunoprecipitation was used to remove soluble fms-like tyrosine kinase-1 (sFLT-1) and pigment epithelium-derived factor (PEDF, SERPINF1 gene) from the Co-MSC secretome. Results Co-MSC secretome significantly inhibited HUVECs tube and sprout formation. Co-MSCs from different donors consistently contained high levels of antiangiogenic factors including sFLT-1 and PEDF; and low levels of the angiogenic factor VEGF-A. In vivo, application of Co-MSCs to mouse corneas after injury prevented the development of corneal neovascularization. Removing PEDF or sFLT-1 from the secretome significantly diminished the antiangiogenic effects of Co-MSCs. Co-MSCs isolated from SERPINF1−/− mice had significantly reduced antiangiogenic effects compared to SERPINF1+/+ (wild-type) Co-MSCs. Conclusions These results illustrate the direct antiangiogenic properties of Co-MSCs, the importance of sFLT-1 and PEDF, and their potential clinical application for preventing pathologic corneal neovascularization.
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Affiliation(s)
- Medi Eslani
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, Illinois, United States
| | - Ilham Putra
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, Illinois, United States
| | - Xiang Shen
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, Illinois, United States
| | - Judy Hamouie
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, Illinois, United States
| | - Neda Afsharkhamseh
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, Illinois, United States
| | - Soroush Besharat
- Department of Medicine and University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, School of Medicine and Public Health, Madison, Wisconsin, United States
| | - Mark I Rosenblatt
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, Illinois, United States
| | - Reza Dana
- Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States
| | - Peiman Hematti
- Department of Medicine and University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, School of Medicine and Public Health, Madison, Wisconsin, United States
| | - Ali R Djalilian
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, Illinois, United States
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Xu LJ, Wang SF, Wang DQ, Ma LJ, Chen Z, Chen QQ, Wang J, Yan L. Adipose-derived stromal cells resemble bone marrow stromal cells in hepatocyte differentiation potential in vitro and in vivo. World J Gastroenterol 2017; 23:6973-6982. [PMID: 29097870 PMCID: PMC5658315 DOI: 10.3748/wjg.v23.i38.6973] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2017] [Revised: 07/20/2017] [Accepted: 09/05/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate whether mesenchymal stem cells (MSCs) from adipose-derived stromal cells (ADSCs) and bone marrow stromal cells (BMSCs) have similar hepatic differentiation potential.
METHODS Mouse ADSCs and BMSCs were isolated and cultured. Their morphological and phenotypic characteristics, as well as their multiple differentiation capacity were compared. A new culture system was established to induce ADSCs and BMSCs into functional hepatocytes. Reverse transcription polymerase chain reaction, Western blot, and immunofluorescence analyses were performed to identify the induced hepatocyte-like cells. CM-Dil-labeled ADSCs and BMSCs were then transplanted into a mouse model of CCl4-induced acute liver failure. Fluorescence microscopy was used to track the transplanted MSCs. Liver function was tested by an automatic biochemistry analyzer, and liver tissue histology was observed by hematoxylin and eosin (HE) staining.
RESULTS ADSCs and BMSCs shared a similar morphology and multiple differentiation capacity, as well as a similar phenotype (with expression of CD29 and CD90 and no expression of CD11b or CD45). Morphologically, ADSCs and BMSCs became round and epithelioid following hepatic induction. These two cell types differentiated into hepatocyte-like cells with similar expression of albumin, cytokeratin 18, cytokeratin 19, alpha fetoprotein, and cytochrome P450. Fluorescence microscopy revealed that both ADSCs and BMSCs were observed in the mouse liver at different time points. Compared to the control group, both the function of the injured livers and HE staining showed significant improvement in the ADSC- and BMSC-transplanted mice. There was no significant difference between the two MSC groups.
CONCLUSION ADSCs share a similar hepatic differentiation capacity and therapeutic effect with BMSCs in an acute liver failure model. ADSCs may represent an ideal seed cell type for cell transplantation or a bio-artificial liver support system.
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Affiliation(s)
- Li-Juan Xu
- Department of Gastroenterology, Institute of Geriatrics, Chinese PLA General Hospital, Beijing 100853, China
| | - Shu-Fang Wang
- Department of Blood Transfusion, Chinese PLA General Hospital, Beijing 100853, China
| | - De-Qing Wang
- Department of Blood Transfusion, Chinese PLA General Hospital, Beijing 100853, China
| | - Lian-Jun Ma
- Department of Endoscopics, China-Japan Union Hospital of Jilin University, Changchun 130000, Jilin Province, China
| | - Zheng Chen
- Department of Gastroenterology, Institute of Geriatrics, Chinese PLA General Hospital, Beijing 100853, China
| | - Qian-Qian Chen
- Department of Gastroenterology, Institute of Geriatrics, Chinese PLA General Hospital, Beijing 100853, China
| | - Jun Wang
- Department of Gastroenterology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing 400042, China
| | - Li Yan
- Department of Gastroenterology, Institute of Geriatrics, Chinese PLA General Hospital, Beijing 100853, China
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15
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Tsai WL, Yeh PH, Tsai CY, Ting CT, Chiu YH, Tao MH, Li WC, Hung SC. Efficient programming of human mesenchymal stem cell-derived hepatocytes by epigenetic regulations. J Gastroenterol Hepatol 2017; 32:261-269. [PMID: 27218433 DOI: 10.1111/jgh.13451] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/16/2016] [Indexed: 12/15/2022]
Abstract
BACKGROUND AND AIM In view of its unique properties of detoxification and involvement of metabolic and biochemical functions, in vitro hepatocyte culture serves as a valuable material for drug screening and mechanistic analysis for pathology of liver diseases. The restriction of rapid de-differentiation and inaccessibility of human hepatocytes from routine clinical procedure, however, limits its use. METHODS To address this issue, the effort to direct human mesenchymal stem cells (hMSCs) into hepatocytes using a modified protocol was proposed. With the additional treatment of histone deacetylase inhibitor (HDACi) and DNA methyltransferase inhibitor (DNMTi), in vitro hMSC-derived hepatocytes were cultivated and their hepatic characteristics were examined. RESULTS By using a modified protocol, it was shown that Trichostatin A and 5-aza-2-deoxycitidine protected differentiating cells from death and could sufficiently trigger a wide range of liver-specific markers as well as liver functions including albumin production, glycogen storage, and urea cycle in hMSC-derived hepatocytes. The increased mRNA expression for hepatitis C virus (HCV) entry including CD81, Occludin, LDL receptor, and scavenger receptor class B type I in hMSC-derived hepatocytes was also detected, implying its potential to be utilized as an in vitro model to analyze dynamic HCV infection. CONCLUSIONS The present study successfully established a protocol to direct hMSCs into hepatocyte-like cells suggesting the beneficial impact to apply HDACi and DNMTi as potent modulators for hMSCs to liver differentiation.
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Affiliation(s)
- Wei-Lun Tsai
- Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.,Medical School, National Yang-Ming University, Taipei, Taiwan
| | - Po-Hung Yeh
- Stem Cell Laboratory, Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei, Taiwan.,Department of Orthopaedics and Traumatology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Chia-Yun Tsai
- Institute of Oral Biology, School of Dentistry, National Yang-Ming University, Taipei, Taiwan.,Department of Dentistry, School of Dentistry, National Yang-Ming University, Taipei, Taiwan
| | - Chin-Tsung Ting
- Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.,Division of Gastrointestinal Surgery, Department of Surgery, Ren-Ai Branch, Taipei City Hospital, Taipei, Taiwan
| | - Yen-Hui Chiu
- Department of Education and Research, Taipei City Hospital, Taipei, Taiwan
| | - Mi-Hua Tao
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Wan-Chun Li
- Institute of Oral Biology, School of Dentistry, National Yang-Ming University, Taipei, Taiwan.,Department of Dentistry, School of Dentistry, National Yang-Ming University, Taipei, Taiwan.,Department of Education and Research, Taipei City Hospital, Taipei, Taiwan
| | - Shih-Chieh Hung
- Stem Cell Laboratory, Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei, Taiwan.,Department of Orthopaedics and Traumatology, Taipei Veterans General Hospital, Taipei, Taiwan.,Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.,Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.,Integrative Stem Cell Center, Department of Orthopedics, China Medical University Hospital, Taichung, Taiwan.,Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan
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16
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Pashoutan Sarvar D, Shamsasenjan K, Akbarzadehlaleh P. Mesenchymal Stem Cell-Derived Exosomes: New Opportunity in Cell-Free Therapy. Adv Pharm Bull 2016; 6:293-299. [PMID: 27766213 DOI: 10.15171/apb.2016.041] [Citation(s) in RCA: 115] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2016] [Revised: 08/15/2016] [Accepted: 08/22/2016] [Indexed: 12/15/2022] Open
Abstract
Mesenchymal stromal/stem cells (MSCs) are involved in tissue homeostasis through direct cell-to-cell interaction, as well as secretion of soluble factors. Exosomes are the sort of soluble biological mediators that obtained from MSCs cultured media in vitro. MSC-derived exosomes (MSC-DEs) which produced under physiological or pathological conditions are central mediators of intercellular communications by conveying proteins, lipids, mRNAs, siRNA, ribosomal RNAs and miRNAs to the neighbor or distant cells. MSC-DEs have been tested in various disease models, and the results have revealed that their functions are similar to those of MSCs. They have the supportive functions in organisms such as repairing tissue damages, suppressing inflammatory responses, and modulating the immune system. MSC-DEs are of great interest in the scope of regenerative medicine because of their unique capacity to the regeneration of the damaged tissues, and the present paper aims to introduce MSC-DEs as a novel hope in cell-free therapy.
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Affiliation(s)
- Davod Pashoutan Sarvar
- Umbilical Cord Stem Cell Research Centre, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Karim Shamsasenjan
- Umbilical Cord Stem Cell Research Centre, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Parvin Akbarzadehlaleh
- Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
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