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Gulberk Ozcebe S, Tristan M, Zorlutuna P. Adult human heart extracellular matrix improves human iPSC-CM function via mitochondrial and metabolic maturation. Stem Cells 2025; 43:sxaf005. [PMID: 39862185 PMCID: PMC12080356 DOI: 10.1093/stmcls/sxaf005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Accepted: 01/06/2025] [Indexed: 01/27/2025]
Abstract
Myocardial infarction can lead to the loss of billions of cardiomyocytes, and while cell-based therapies are an option, immature nature of in vitro-generated human induced pluripotent stem cell (iPSC)-derived cardiomyocytes (iCMs) is a roadblock to their development. Existing iPSC differentiation protocols don't go beyond producing fetal iCMs. Recently, adult extracellular matrix (ECM) was shown to retain tissue memory and have some success driving tissue-specific differentiation in unspecified cells in various organ systems. Therefore, we focused on investigating the effect of adult human heart-derived extracellular matrix (ECM) on iPSC cardiac differentiation and subsequent maturation. By preconditioning iPSCs with ECM, we tested whether creating cardiac environments around iPSCs would drive iPSCs toward cardiac fate and which ECM components might be involved. We report novel high- and low-abundance proteomes of young, adult, and aged human hearts, with relative abundances to total proteins and each other. We found that adult ECM had extracellular galactin-1, fibronectin, fibrillins, and perlecan (HSPG2) which are implicated in normal heart development. We also showed preconditioning iPSCs with adult cardiac ECM resulted in enhanced cardiac differentiation, yielding iCMs with higher functional maturity, more developed mitochondrial network and coverage, enhanced metabolic maturity, and shift towards more energetic profile. These findings demonstrate the potential use of cardiac ECM in iCM maturation and as a promising strategy for developing iCM-based therapies, disease modeling, and drug screening studies. Upon manipulating ECM, we concluded that the beneficial effects observed were not solely due to the ECM proteins, which might be related to the decorative units attached.
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Affiliation(s)
- S Gulberk Ozcebe
- Bioengineering Graduate Program, University of Notre Dame, Notre Dame, 46556 IN, United States
- National Institute of Environmental Health Sciences (NIEHS), Durham, 27709 NC, United States
| | - Mateo Tristan
- Department of Chemical and Biomolecular Engineering, University of Notre Dame, Notre Dame, 46556 IN, United States
| | - Pinar Zorlutuna
- Bioengineering Graduate Program, University of Notre Dame, Notre Dame, 46556 IN, United States
- Department of Aerospace and Mechanical Engineering, University of Notre Dame, Notre Dame, 46556 IN, United States
- Department of Chemical and Biomolecular Engineering, University of Notre Dame, Notre Dame, 46556 IN, United States
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2
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Otsuka T, Yamagata K, Nguyen MP, Ngo UT, Sakai H, Trimova G, Anan J, Okada Y, Nakayamada S, Tanaka Y. Critical roles of IL-6 signaling in myoblast differentiation of human adipose-derived mesenchymal stem cells. Inflamm Regen 2025; 45:9. [PMID: 40211386 PMCID: PMC11983861 DOI: 10.1186/s41232-025-00373-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Accepted: 03/15/2025] [Indexed: 04/14/2025] Open
Abstract
BACKGROUND Ectopic fat is also formed in muscles as well as the liver, where adipose-derived mesenchymal stem cells (ADSCs) promote adipogenesis. On the other hand, after muscle injury, muscle satellite cells (SCs) contribute to muscle repair through myodifferentiation. Human ADSCs are multipotent stem cells, but it remains unclear whether they are involved in myoblast differentiation. The aim is to find a novel myogenic cytokine and its signaling pathway that promotes the differentiation of human ADSCs-a potential source of new muscle precursor cells-into myoblasts. METHODS An array kit was used to detect cytokines produced by ADSCs. After treating ADSCs with the DNA methyltransferase inhibitor 5-Aza-2'-deoxycytidine (5-aza-C) and different JAK inhibitors, MyHC1, a myodifferentiation marker, was detected by immunofluorescence staining and reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The expression status of signaling molecules was determined by Western blotting and the recruitment of transcription factors to the MYOG promoter by chromatin immunoprecipitation (ChIP). RESULTS IL-6 was detected at high concentrations in the culture supernatant of ADSCs. ADSCs stimulated with 5-aza-C became strongly positive for MyHC1 on day 21 post-stimulation. When co-stimulated with 5-aza-C and IL-6/sIL-6R, ADSCs became positive for MyHC1 protein and upregulated MYOG mRNA as early as day 14 post-stimulation. Co-stimulation with 5-aza-C and IL-6/sIL-6R resulted in phosphorylation of STAT1 and STAT3. The addition of a JAK2 inhibitor, but not JAK1/3 inhibitors, abolished the MyHC1 positivity and phosphorylation of STAT1 and STAT3. Co-stimulation with 5-aza-C and IL-6/sIL-6R during the myogenesis process resulted in the recruitment of STAT1, but not STAT3, to the MYOG promoter. Myoblast differentiation induced by stimulation with 5-aza-C was enhanced by activation of the IL-6/JAK2/STAT1/MYOG pathway. CONCLUSIONS Therefore, sustained IL-6/JAK2/STAT1 activation may serve as an important driver of human ADSC differentiation into myoblast, suggesting an important candidate signaling pathway for ameliorating muscle atrophy.
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Affiliation(s)
- Takashi Otsuka
- The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Kaoru Yamagata
- The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Mai-Phuong Nguyen
- The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Uyen Thi Ngo
- The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Hidenori Sakai
- The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Gulzhan Trimova
- Department of Internal Medicine, High School of Medicine, Al-Farabi Kazakh National University, Al-Farabi Avenue 71, Almaty, 050040, Kazakhstan
| | - Junpei Anan
- The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
- Oncology & Immunology Unit, Research Division, Mitsubishi Tanabe Pharma Corporation, 1000 Kamoshida, Aoba, Yokohama, Kanagawa, Japan
| | - Yosuke Okada
- The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Shingo Nakayamada
- The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Yoshiya Tanaka
- The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
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Pereira BL, Barbosa M, Granjo P, Lochmüller H, Videira PA. Beyond sialylation: Exploring the multifaceted role of GNE in GNE myopathy. Mol Genet Metab 2025; 144:109075. [PMID: 40054019 DOI: 10.1016/j.ymgme.2025.109075] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2024] [Revised: 02/25/2025] [Accepted: 02/26/2025] [Indexed: 03/09/2025]
Abstract
Defects in sialic acid metabolism disrupt the sialylation of glycoproteins and glycolipids, contributing to a spectrum of diseases, including GNE myopathy (GNEM). This rare disorder is caused by mutations in the GNE gene that encodes for a bifunctional enzyme required for sialic acid biosynthesis, resulting in progressive muscle atrophy and weakness. There is no approved treatment for GNEM, and the number of affected individuals is underestimated. Although hyposialylation is considered the hallmark of GNEM, evidence showed lack of consistent correlation with GNEM severity and unveiled additional roles of GNE that contribute to the onset and/or progression of GNEM. Recent findings indicate that these mechanisms extend beyond glycosylation, encompassing cytoskeletal dynamics, oxidative stress, and muscle regeneration pathways. Understanding how GNE mutations result in a cascade of cellular and molecular dysregulations is crucial for developing targeted therapies aimed at improving the quality of life of patients. This review comprehensively examines GNEM's pathophysiology, clinical presentation, and therapeutic strategies, highlighting key findings on non-canonical GNE functions that account to GNEM clinical outcomes and emerging therapeutic targets. We propose future research directions to explore alternative target pathways that can ultimately support clinical development.
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Affiliation(s)
- Beatriz L Pereira
- Associate Laboratory i4HB-Institute for Health and Bioeconomy, NOVA School of Science and Technology, Universidade NOVA de Lisboa, 2829-516 Caparica, Portugal; UCIBIO-Applied Molecular Biosciences Unit, Department of Life Sciences, NOVA School of Science and Technology, Universidade NOVA de Lisboa, 2829-516 Caparica, Portugal; CDG & Allies-Professionals and Patient Associations International Network (CDG & Allies-PPAIN), Department of Life Sciences, NOVA School of Science and Technology, Universidade NOVA de Lisboa, 2829-516 Caparica, Portugal
| | - Mariana Barbosa
- Associate Laboratory i4HB-Institute for Health and Bioeconomy, NOVA School of Science and Technology, Universidade NOVA de Lisboa, 2829-516 Caparica, Portugal; UCIBIO-Applied Molecular Biosciences Unit, Department of Life Sciences, NOVA School of Science and Technology, Universidade NOVA de Lisboa, 2829-516 Caparica, Portugal; CDG & Allies-Professionals and Patient Associations International Network (CDG & Allies-PPAIN), Department of Life Sciences, NOVA School of Science and Technology, Universidade NOVA de Lisboa, 2829-516 Caparica, Portugal.
| | - Pedro Granjo
- Associate Laboratory i4HB-Institute for Health and Bioeconomy, NOVA School of Science and Technology, Universidade NOVA de Lisboa, 2829-516 Caparica, Portugal; UCIBIO-Applied Molecular Biosciences Unit, Department of Life Sciences, NOVA School of Science and Technology, Universidade NOVA de Lisboa, 2829-516 Caparica, Portugal; CDG & Allies-Professionals and Patient Associations International Network (CDG & Allies-PPAIN), Department of Life Sciences, NOVA School of Science and Technology, Universidade NOVA de Lisboa, 2829-516 Caparica, Portugal
| | - Hanns Lochmüller
- Children's Hospital of Eastern Ontario Research Institute, Division of Neurology, Department of Medicine, The Ottawa Hospital, Brain and Mind Research Institute, University of Ottawa, Ottawa, Canada
| | - Paula A Videira
- Associate Laboratory i4HB-Institute for Health and Bioeconomy, NOVA School of Science and Technology, Universidade NOVA de Lisboa, 2829-516 Caparica, Portugal; UCIBIO-Applied Molecular Biosciences Unit, Department of Life Sciences, NOVA School of Science and Technology, Universidade NOVA de Lisboa, 2829-516 Caparica, Portugal; CDG & Allies-Professionals and Patient Associations International Network (CDG & Allies-PPAIN), Department of Life Sciences, NOVA School of Science and Technology, Universidade NOVA de Lisboa, 2829-516 Caparica, Portugal.
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4
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Gençer EB, Lor YK, Abomaray F, El Andaloussi S, Pernemalm M, Sharma N, Hagey DW, Görgens A, Gustafsson MO, Le Blanc K, Asad Toonsi M, Walther-Jallow L, Götherström C. Transcriptomic and proteomic profiles of fetal versus adult mesenchymal stromal cells and mesenchymal stromal cell-derived extracellular vesicles. Stem Cell Res Ther 2024; 15:77. [PMID: 38475970 DOI: 10.1186/s13287-024-03683-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Accepted: 02/23/2024] [Indexed: 03/14/2024] Open
Abstract
BACKGROUND Mesenchymal stem/stromal cells (MSCs) can regenerate tissues through engraftment and differentiation but also via paracrine signalling via extracellular vesicles (EVs). Fetal-derived MSCs (fMSCs) have been shown, both in vitro and in animal studies, to be more efficient than adult MSC (aMSCs) in generating bone and muscle but the underlying reason for this difference has not yet been clearly elucidated. In this study, we aimed to systematically investigate the differences between fetal and adult MSCs and MSC-derived EVs at the phenotypic, RNA, and protein levels. METHODS We carried out a detailed and comparative characterization of culture-expanded fetal liver derived MSCs (fMSCs) and adult bone marrow derived MSCs (aMSCs) phenotypically, and the MSCs and MSC-derived EVs were analysed using transcriptomics and proteomics approaches with RNA Sequencing and Mass Spectrometry. RESULTS Fetal MSCs were smaller, exhibited increased proliferation and colony-forming capacity, delayed onset of senescence, and demonstrated superior osteoblast differentiation capability compared to their adult counterparts. Gene Ontology analysis revealed that fMSCs displayed upregulated gene sets such as "Positive regulation of stem cell populations", "Maintenance of stemness" and "Muscle cell development/contraction/Myogenesis" in comparison to aMSCs. Conversely, aMSCs displayed upregulated gene sets such as "Complement cascade", "Adipogenesis", "Extracellular matrix glycoproteins" and "Cellular metabolism", and on the protein level, "Epithelial cell differentiation" pathways. Signalling entropy analysis suggested that fMSCs exhibit higher signalling promiscuity and hence, higher potency than aMSCs. Gene ontology comparisons revealed that fetal MSC-derived EVs (fEVs) were enriched for "Collagen fibril organization", "Protein folding", and "Response to transforming growth factor beta" compared to adult MSC-derived EVs (aEVs), whereas no significant difference in protein expression in aEVs compared to fEVs could be detected. CONCLUSIONS This study provides detailed and systematic insight into the differences between fMSCs and aMSCs, and MSC-derived EVs. The key finding across phenotypic, transcriptomic and proteomic levels is that fMSCs exhibit higher potency than aMSCs, meaning they are in a more undifferentiated state. Additionally, fMSCs and fMSC-derived EVs may possess greater bone forming capacity compared to aMSCs. Therefore, using fMSCs may lead to better treatment efficacy, especially in musculoskeletal diseases.
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Affiliation(s)
- Emine Begüm Gençer
- Division of Obstetrics and Gynecology, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
| | - Yuk Kit Lor
- Division of Obstetrics and Gynecology, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
| | - Fawaz Abomaray
- Division of Obstetrics and Gynecology, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
| | - Samir El Andaloussi
- Biomolecular Medicine, Clinical Research Center, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
- Department of Cellular Therapy and Allogeneic Stem Cell Transplantation (CAST), Karolinska University Hospital Huddinge and Karolinska Comprehensive Cancer Center, Stockholm, Sweden
| | - Maria Pernemalm
- Cancer Proteomics Mass Spectrometry, Science for Life Laboratory, Department of Oncology- Pathology, Karolinska Institutet, Stockholm, Sweden
| | - Nidhi Sharma
- Cancer Proteomics Mass Spectrometry, Science for Life Laboratory, Department of Oncology- Pathology, Karolinska Institutet, Stockholm, Sweden
| | - Daniel W Hagey
- Biomolecular Medicine, Clinical Research Center, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
- Department of Cellular Therapy and Allogeneic Stem Cell Transplantation (CAST), Karolinska University Hospital Huddinge and Karolinska Comprehensive Cancer Center, Stockholm, Sweden
| | - André Görgens
- Biomolecular Medicine, Clinical Research Center, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
- Department of Cellular Therapy and Allogeneic Stem Cell Transplantation (CAST), Karolinska University Hospital Huddinge and Karolinska Comprehensive Cancer Center, Stockholm, Sweden
- Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Manuela O Gustafsson
- Biomolecular Medicine, Clinical Research Center, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
- Department of Cellular Therapy and Allogeneic Stem Cell Transplantation (CAST), Karolinska University Hospital Huddinge and Karolinska Comprehensive Cancer Center, Stockholm, Sweden
| | - Katarina Le Blanc
- Department of Cellular Therapy and Allogeneic Stem Cell Transplantation (CAST), Karolinska University Hospital Huddinge and Karolinska Comprehensive Cancer Center, Stockholm, Sweden
- Division of Clinical Immunology and Transfusion Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Mawaddah Asad Toonsi
- Division of Obstetrics and Gynecology, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
- Department of Pediatrics, College of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Lilian Walther-Jallow
- Division of Obstetrics and Gynecology, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
| | - Cecilia Götherström
- Division of Obstetrics and Gynecology, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.
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5
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Stearns-Reider KM, Hicks MR, Hammond KG, Reynolds JC, Maity A, Kurmangaliyev YZ, Chin J, Stieg AZ, Geisse NA, Hohlbauch S, Kaemmer S, Schmitt LR, Pham TT, Yamauchi K, Novitch BG, Wollman R, Hansen KC, Pyle AD, Crosbie RH. Myoscaffolds reveal laminin scarring is detrimental for stem cell function while sarcospan induces compensatory fibrosis. NPJ Regen Med 2023; 8:16. [PMID: 36922514 PMCID: PMC10017766 DOI: 10.1038/s41536-023-00287-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Accepted: 02/22/2023] [Indexed: 03/18/2023] Open
Abstract
We developed an on-slide decellularization approach to generate acellular extracellular matrix (ECM) myoscaffolds that can be repopulated with various cell types to interrogate cell-ECM interactions. Using this platform, we investigated whether fibrotic ECM scarring affected human skeletal muscle progenitor cell (SMPC) functions that are essential for myoregeneration. SMPCs exhibited robust adhesion, motility, and differentiation on healthy muscle-derived myoscaffolds. All SPMC interactions with fibrotic myoscaffolds from dystrophic muscle were severely blunted including reduced motility rate and migration. Furthermore, SMPCs were unable to remodel laminin dense fibrotic scars within diseased myoscaffolds. Proteomics and structural analysis revealed that excessive collagen deposition alone is not pathological, and can be compensatory, as revealed by overexpression of sarcospan and its associated ECM receptors in dystrophic muscle. Our in vivo data also supported that ECM remodeling is important for SMPC engraftment and that fibrotic scars may represent one barrier to efficient cell therapy.
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Affiliation(s)
- Kristen M Stearns-Reider
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, 90095, USA
- Department of Orthopaedic Surgery, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, 90095, USA
| | - Michael R Hicks
- Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, 90095, USA
- Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA, 90095, USA
- Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA, 92697, USA
| | - Katherine G Hammond
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, 90095, USA
| | - Joseph C Reynolds
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, 90095, USA
| | - Alok Maity
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, 90095, USA
- Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA, 90095, USA
- Institute for Quantitative and Computational Biology, University of California, Los Angeles, Los Angeles, CA, 90095, USA
| | - Yerbol Z Kurmangaliyev
- Institute for Quantitative and Computational Biology, University of California, Los Angeles, Los Angeles, CA, 90095, USA
- Department of Biological Chemistry, HHMI, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, 90095, USA
| | - Jesse Chin
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, 90095, USA
| | - Adam Z Stieg
- California NanoSystems Institute, University of California, Los Angeles, Los Angeles, CA, 90095, USA
| | | | - Sophia Hohlbauch
- Asylum Research, An Oxford Instruments Company, Santa Barbara, CA, 93117, USA
| | - Stefan Kaemmer
- Park Systems, 3040 Olcott St, Santa Clara, CA, 95054, USA
| | - Lauren R Schmitt
- Department of Biochemistry and Molecular Genetics, University of Colorado, Denver, Aurora, CO, 80045, USA
| | - Thanh T Pham
- Department of Biochemistry and Molecular Genetics, University of Colorado, Denver, Aurora, CO, 80045, USA
| | - Ken Yamauchi
- Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA, 90095, USA
- Department of Neurobiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, 90095, USA
| | - Bennett G Novitch
- Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA, 90095, USA
- Department of Neurobiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, 90095, USA
- Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, 90095, USA
- Intellectual and Developmental Disabilities Research Center, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095, USA
| | - Roy Wollman
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, 90095, USA
- Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA, 90095, USA
- Institute for Quantitative and Computational Biology, University of California, Los Angeles, Los Angeles, CA, 90095, USA
| | - Kirk C Hansen
- Department of Biochemistry and Molecular Genetics, University of Colorado, Denver, Aurora, CO, 80045, USA
| | - April D Pyle
- Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, 90095, USA
- Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA, 90095, USA
- Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, 90095, USA
| | - Rachelle H Crosbie
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
- Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
- Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
- Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
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Ying J, You Q, Wang Z, Hu Z. Hypoxic preconditioning promotes the immunosuppressive effects of mesenchymal stem cells in mice with colitis. Res Vet Sci 2022; 144:157-163. [PMID: 34802776 DOI: 10.1016/j.rvsc.2021.11.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Revised: 09/25/2021] [Accepted: 11/02/2021] [Indexed: 01/06/2023]
Abstract
Mesenchymal stem cells are promising candidates for stem cell therapy in many diseases, especially in immune-associated diseases. Inflammatory bowel disease is a chronic autoimmune disease that can lead to colorectal cancer if it is not controlled. Mesenchymal stem cells are always under a hypoxic environment in vivo, whether in bone marrow or adipose tissue, whereas researchers always culture MSCs (mesenchymal stem cells) under normoxic conditions (21%). In this study, we aimed to investigate whether hypoxia (1%) affects the therapeutic effect of MSCs. We hypothesize that hypoxia may benefit the treatment efficacy of MSCs. We used DSS to induce IBD (inflammatory bowel disease) in mice and then injected MSCs that had been preconditioned under normoxic conditions (21%) and hypoxic conditions (1%). We found that compared with normoxic-preconditioned MSCs (n-MSCs), hypoxic-preconditioned MSCs (h-MSCs) could alleviate colon inflammation to a large extent, as determined by inflammatory cytokines and CD3+ T cell activation. Mechanistic studies showed that hypoxia could promote iNOS expression in MSCs. Therefore, our data suggest that hypoxia may be more appropriate than normoxia for facilitating MSCs exertion of therapeutic functions.
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Affiliation(s)
- Jun Ying
- Department of Surgery, Changzheng Hospital, The second military medical university, Shanghai, China
| | - Qing You
- Department of Surgery, Changzheng Hospital, The second military medical university, Shanghai, China
| | - Zhiguo Wang
- Department of Surgery, Changzheng Hospital, The second military medical university, Shanghai, China
| | - Zhiqian Hu
- Department of Surgery, Changzheng Hospital, The second military medical university, Shanghai, China.
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7
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Therapeutic Potential of Human Fetal Mesenchymal Stem Cells in Musculoskeletal Disorders: A Narrative Review. Int J Mol Sci 2022; 23:ijms23031439. [PMID: 35163361 PMCID: PMC8835918 DOI: 10.3390/ijms23031439] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 01/24/2022] [Accepted: 01/24/2022] [Indexed: 01/15/2023] Open
Abstract
Mesenchymal stem cells (MSCs) have emerged as a promising therapeutic approach for diverse diseases and injuries. The biological and clinical advantages of human fetal MSCs (hfMSCs) have recently been reported. In terms of promising therapeutic approaches for diverse diseases and injuries, hfMSCs have gained prominence as healing tools for clinical therapies. Therefore, this review assesses not the only biological advantages of hfMSCs for healing human diseases and regeneration, but also the research evidence for the engraftment and immunomodulation of hfMSCs based on their sources and biological components. Of particular clinical relevance, the present review also suggests the potential therapeutic feasibilities of hfMSCs for musculoskeletal disorders, including osteoporosis, osteoarthritis, and osteogenesis imperfecta.
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8
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Vilen Z, Joeh E, Critcher M, Parker CG, Huang ML. Proximity Tagging Identifies the Glycan-Mediated Glycoprotein Interactors of Galectin-1 in Muscle Stem Cells. ACS Chem Biol 2021; 16:1994-2003. [PMID: 34181849 DOI: 10.1021/acschembio.1c00313] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Myogenic differentiation, the irreversible developmental process where precursor myoblast muscle stem cells become contractile myotubes, is heavily regulated by glycosylation and glycan-protein interactions at the cell surface and the extracellular matrix. The glycan-binding protein galectin-1 has been found to be a potent activator of myogenic differentiation. While it is being explored as a potential therapeutic for muscle repair, a precise understanding of its glycoprotein interactors is lacking. These gaps are due in part to the difficulties of capturing glycan-protein interactions in live cells. Here, we demonstrate the use of a proximity tagging strategy coupled with quantitative mass-spectrometry-based proteomics to capture, enrich, and identify the glycan-mediated glycoprotein interactors of galectin-1 in cultured live mouse myoblasts. Our interactome dataset can serve as a resource to aid the determination of mechanisms through which galectin-1 promotes myogenic differentiation. Moreover, it can also facilitate the determination of the physiological glycoprotein counter-receptors of galectin-1. Indeed, we identify several known and novel glycan-mediated ligands of galectin-1 as well as validate that galectin-1 binds the native CD44 glycoprotein in a glycan-mediated manner.
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Affiliation(s)
- Zak Vilen
- Department of Molecular Medicine, Scripps Research, 120 Scripps Way, Jupiter, Florida 33458-5284, United States
| | - Eugene Joeh
- Department of Molecular Medicine, Scripps Research, 120 Scripps Way, Jupiter, Florida 33458-5284, United States
| | - Meg Critcher
- Department of Molecular Medicine, Scripps Research, 120 Scripps Way, Jupiter, Florida 33458-5284, United States
| | - Christopher G. Parker
- Department of Chemistry, Scripps Research, 120 Scripps Way, Jupiter, Florida 33458-5284, United States
| | - Mia L. Huang
- Department of Molecular Medicine, Scripps Research, 120 Scripps Way, Jupiter, Florida 33458-5284, United States
- Department of Chemistry, Scripps Research, 120 Scripps Way, Jupiter, Florida 33458-5284, United States
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9
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Jeethy Ram T, Lekshmi A, Somanathan T, Sujathan K. Galectin-3: A factotum in carcinogenesis bestowing an archery for prevention. Tumour Biol 2021; 43:77-96. [PMID: 33998569 DOI: 10.3233/tub-200051] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Cancer metastasis and therapy resistance are the foremost hurdles in oncology at the moment. This review aims to pinpoint the functional aspects of a unique multifaceted glycosylated molecule in both intracellular and extracellular compartments of a cell namely galectin-3 along with its metastatic potential in different types of cancer. All materials reviewed here were collected through the search engines PubMed, Scopus, and Google scholar. Among the 15 galectins identified, the chimeric gal-3 plays an indispensable role in the differentiation, transformation, and multi-step process of tumor metastasis. It has been implicated in the molecular mechanisms that allow the cancer cells to survive in the intravascular milieu and promote tumor cell extravasation, ultimately leading to metastasis. Gal-3 has also been found to have a pivotal role in immune surveillance and pro-angiogenesis and several studies have pointed out the importance of gal-3 in establishing a resistant phenotype, particularly through the epithelial-mesenchymal transition process. Additionally, some recent findings suggest the use of gal-3 inhibitors in overcoming therapeutic resistance. All these reports suggest that the deregulation of these specific lectins at the cellular level could inhibit cancer progression and metastasis. A more systematic study of glycosylation in clinical samples along with the development of selective gal-3 antagonists inhibiting the activity of these molecules at the cellular level offers an innovative strategy for primary cancer prevention.
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Affiliation(s)
- T Jeethy Ram
- Division of Cancer Research, Regional Cancer Centre, Medical College, Trivandrum, Kerala, India
| | - Asha Lekshmi
- Division of Cancer Research, Regional Cancer Centre, Medical College, Trivandrum, Kerala, India
| | - Thara Somanathan
- Division of Pathology, Regional Cancer Centre, Medical College, Trivandrum, Kerala, India
| | - K Sujathan
- Regional Cancer Centre, Thiruvananthapuram, Kerala, India
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Dubey SK, Alexander A, Sivaram M, Agrawal M, Singhvi G, Sharma S, Dayaramani R. Uncovering the Diversification of Tissue Engineering on the Emergent Areas of Stem Cells, Nanotechnology and Biomaterials. Curr Stem Cell Res Ther 2020; 15:187-201. [PMID: 31957615 DOI: 10.2174/1574888x15666200103124821] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2019] [Revised: 11/11/2019] [Accepted: 11/12/2019] [Indexed: 12/23/2022]
Abstract
Damaged or disabled tissue is life-threatening due to the lack of proper treatment. Many conventional transplantation methods like autograft, iso-graft and allograft are in existence for ages, but they are not sufficient to treat all types of tissue or organ damages. Stem cells, with their unique capabilities like self-renewal and differentiate into various cell types, can be a potential strategy for tissue regeneration. However, the challenges like reproducibility, uncontrolled propagation and differentiation, isolation of specific kinds of cell and tumorigenic nature made these stem cells away from clinical application. Today, various types of stem cells like embryonic, fetal or gestational tissue, mesenchymal and induced-pluripotent stem cells are under investigation for their clinical application. Tissue engineering helps in configuring the stem cells to develop into a desired viable tissue, to use them clinically as a substitute for the conventional method. The use of stem cell-derived Extracellular Vesicles (EVs) is being studied to replace the stem cells, which decreases the immunological complications associated with the direct administration of stem cells. Tissue engineering also investigates various biomaterials to use clinically, either to replace the bones or as a scaffold to support the growth of stemcells/ tissue. Depending upon the need, there are various biomaterials like bio-ceramics, natural and synthetic biodegradable polymers to support replacement or regeneration of tissue. Like the other fields of science, tissue engineering is also incorporating the nanotechnology to develop nano-scaffolds to provide and support the growth of stem cells with an environment mimicking the Extracellular matrix (ECM) of the desired tissue. Tissue engineering is also used in the modulation of the immune system by using patient-specific Mesenchymal Stem Cells (MSCs) and by modifying the physical features of scaffolds that may provoke the immune system. This review describes the use of various stem cells, biomaterials and the impact of nanotechnology in regenerative medicine.
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Affiliation(s)
- Sunil K Dubey
- Department of Pharmacy, Birla Institute of Technology and Science, Pilani (BITS-PILANI), Pilani Campus, Rajasthan 333031, India
| | - Amit Alexander
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER GUWAHATI), Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Govt. of India, NH 37, NITS Mirza, Kamrup-781125, Guwahati (Assam), India
| | - Munnangi Sivaram
- Department of Pharmacy, Birla Institute of Technology and Science, Pilani (BITS-PILANI), Pilani Campus, Rajasthan 333031, India
| | - Mukta Agrawal
- Rungta College of Pharmaceutical Sciences and Research, Kohka- Kurud Road, Bhilai, Chhattisgarh 490024, India
| | - Gautam Singhvi
- Department of Pharmacy, Birla Institute of Technology and Science, Pilani (BITS-PILANI), Pilani Campus, Rajasthan 333031, India
| | - Swapnil Sharma
- Department of Pharmacy, Banastahli Vidyapith, Tonk, Rajasthan 304022, India
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Vallecillo-Zúniga ML, Rathgeber MF, Poulson PD, Hayes S, Luddington JS, Gill HN, Teynor M, Kartchner BC, Valdoz J, Stowell C, Markham AR, Arthur C, Stowell S, Van Ry PM. Treatment with galectin-1 improves myogenic potential and membrane repair in dysferlin-deficient models. PLoS One 2020; 15:e0238441. [PMID: 32881965 PMCID: PMC7470338 DOI: 10.1371/journal.pone.0238441] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Accepted: 08/17/2020] [Indexed: 11/18/2022] Open
Abstract
Limb-girdle muscular dystrophy type 2B (LGMD2B) is caused by mutations in the dysferlin gene, resulting in non-functional dysferlin, a key protein found in muscle membrane. Treatment options available for patients are chiefly palliative in nature and focus on maintaining ambulation. Our hypothesis is that galectin-1 (Gal-1), a soluble carbohydrate binding protein, increases membrane repair capacity and myogenic potential of dysferlin-deficient muscle cells and muscle fibers. To test this hypothesis, we used recombinant human galectin-1 (rHsGal-1) to treat dysferlin-deficient models. We show that rHsGal-1 treatments of 48 h-72 h promotes myogenic maturation as indicated through improvements in size, myotube alignment, myoblast migration, and membrane repair capacity in dysferlin-deficient myotubes and myofibers. Furthermore, increased membrane repair capacity of dysferlin-deficient myotubes, independent of increased myogenic maturation is apparent and co-localizes on the membrane of myotubes after a brief 10min treatment with labeled rHsGal-1. We show the carbohydrate recognition domain of Gal-1 is necessary for observed membrane repair. Improvements in membrane repair after only a 10 min rHsGal-1treatment suggest mechanical stabilization of the membrane due to interaction with glycosylated membrane bound, ECM or yet to be identified ligands through the CDR domain of Gal-1. rHsGal-1 shows calcium-independent membrane repair in dysferlin-deficient and wild-type myotubes and myofibers. Together our novel results reveal Gal-1 mediates disease pathologies through both changes in integral myogenic protein expression and mechanical membrane stabilization.
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Affiliation(s)
- Mary L. Vallecillo-Zúniga
- Department of Chemistry & Biochemistry, Brigham Young University, Provo, UT, United States of America
| | - Matthew F. Rathgeber
- Department of Chemistry & Biochemistry, Brigham Young University, Provo, UT, United States of America
| | - P. Daniel Poulson
- Department of Chemistry & Biochemistry, Brigham Young University, Provo, UT, United States of America
| | - Spencer Hayes
- Department of Chemistry & Biochemistry, Brigham Young University, Provo, UT, United States of America
| | - Jacob S. Luddington
- Department of Chemistry & Biochemistry, Brigham Young University, Provo, UT, United States of America
| | - Hailie N. Gill
- Department of Chemistry & Biochemistry, Brigham Young University, Provo, UT, United States of America
| | - Matthew Teynor
- Department of Chemistry & Biochemistry, Brigham Young University, Provo, UT, United States of America
| | - Braden C. Kartchner
- Department of Chemistry & Biochemistry, Brigham Young University, Provo, UT, United States of America
| | - Jonard Valdoz
- Department of Chemistry & Biochemistry, Brigham Young University, Provo, UT, United States of America
| | - Caleb Stowell
- Department of Chemistry & Biochemistry, Brigham Young University, Provo, UT, United States of America
| | - Ashley R. Markham
- Department of Chemistry & Biochemistry, Brigham Young University, Provo, UT, United States of America
| | - Connie Arthur
- Center for Apheresis, Emory Hospital, Laboratory and Blood Bank, Emory Orthopaedics and Spine Hospital, Center for Transfusion and Cellular Therapies, School of Medicine, Emory University, Atlanta, GA, United States of America
| | - Sean Stowell
- Center for Apheresis, Emory Hospital, Laboratory and Blood Bank, Emory Orthopaedics and Spine Hospital, Center for Transfusion and Cellular Therapies, School of Medicine, Emory University, Atlanta, GA, United States of America
| | - Pam M. Van Ry
- Department of Chemistry & Biochemistry, Brigham Young University, Provo, UT, United States of America
- * E-mail:
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Sheveleva ON, Payushina OV, Butorina NN, Domaratskaya EI. The Myogenic Potential of Mesenchymal Stromal Cells and Their Effect on Skeletal Muscle Regeneration. BIOL BULL+ 2020. [DOI: 10.1134/s106235902005009x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
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Abstract
PURPOSE OF REVIEW Osteogenesis imperfecta (OI) is a chronic disease with few treatment options available. The purpose of this review is to provide an overview on treating OI with mesenchymal stem cells (MSC). RECENT FINDINGS Off-the-shelf MSC have a good safety profile and exhibit multilineage differentiation potential and a low immunogenic profile and are easy to manufacture. Their ability to migrate, engraft, and differentiate into bone cells, and also to act via paracrine effects on the recipient's tissues, makes MSC candidates as a clinical therapy for OI. Due to their high osteogenic potency, fetal MSC offer an even higher therapeutic potential in OI compared with MSC derived from adult sources. Preclinical and initial clinical data support the use of MSC in treating OI. The characteristics of MSC make them of great interest in treating OI. MSC may be safely transplanted via intravenous administration and show potential positive clinical effects.
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Affiliation(s)
- Cecilia Götherström
- Department of Clinical Science, Intervention and Technology, Division of Obstetrics and Gynecology, Karolinska Institutet, ANA Futura, floor 8, Alfred Nobels Allé 8, 141 52 Huddinge, Stockholm, Sweden.
| | - Lilian Walther-Jallow
- Department of Clinical Science, Intervention and Technology, Division of Obstetrics and Gynecology, Karolinska Institutet, ANA Futura, floor 8, Alfred Nobels Allé 8, 141 52 Huddinge, Stockholm, Sweden
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Tazhitdinova R, Timoshenko AV. The Emerging Role of Galectins and O-GlcNAc Homeostasis in Processes of Cellular Differentiation. Cells 2020; 9:cells9081792. [PMID: 32731422 PMCID: PMC7465113 DOI: 10.3390/cells9081792] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 07/24/2020] [Accepted: 07/24/2020] [Indexed: 02/07/2023] Open
Abstract
Galectins are a family of soluble β-galactoside-binding proteins with diverse glycan-dependent and glycan-independent functions outside and inside the cell. Human cells express twelve out of sixteen recognized mammalian galectin genes and their expression profiles are very different between cell types and tissues. In this review, we summarize the current knowledge on the changes in the expression of individual galectins at mRNA and protein levels in different types of differentiating cells and the effects of recombinant galectins on cellular differentiation. A new model of galectin regulation is proposed considering the change in O-GlcNAc homeostasis between progenitor/stem cells and mature differentiated cells. The recognition of galectins as regulatory factors controlling cell differentiation and self-renewal is essential for developmental and cancer biology to develop innovative strategies for prevention and targeted treatment of proliferative diseases, tissue regeneration, and stem-cell therapy.
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15
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Liu S, Liu F, Zhou Y, Jin B, Sun Q, Guo S. Immunosuppressive Property of MSCs Mediated by Cell Surface Receptors. Front Immunol 2020; 11:1076. [PMID: 32849489 PMCID: PMC7399134 DOI: 10.3389/fimmu.2020.01076] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Accepted: 05/04/2020] [Indexed: 12/16/2022] Open
Abstract
In the past decade, mesenchymal stem cells (MSCs) tend to exhibit inherent tropism for refractory inflammatory diseases and engineered MSCs have appeared on the market as therapeutic agents. Recently, engineered MSCs target to cell surface molecules on immune cells has been a new strategy to improve MSC applications. In this review, we discuss the roles of multiple receptors (ICAM-1, Gal-9, PD-L1, TIGIT, CD200, and CXCR4) in the process of MSCs' immunosuppressive properties. Furthermore, we discuss the principles and strategies for developing receptor-regulated MSCs and their mechanisms of action and the challenges of using MSCs as immunosuppressive therapies.
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Affiliation(s)
- Siyu Liu
- Department of Plastic Surgery, The First Hospital of China Medical University, Shenyang, China
| | - Fei Liu
- Department of Breast Surgery, Shengjing Hospital of China Medical University, Shenyang, China
| | - You Zhou
- Department of Plastic Surgery, The First Hospital of China Medical University, Shenyang, China
| | - Baeku Jin
- Department of Plastic Surgery, The First Hospital of China Medical University, Shenyang, China
| | - Qiang Sun
- Department of Plastic Surgery, The First Hospital of China Medical University, Shenyang, China
| | - Shu Guo
- Department of Plastic Surgery, The First Hospital of China Medical University, Shenyang, China
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16
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Wienke J, Pachman LM, Morgan GA, Yeo JG, Amoruso MC, Hans V, Kamphuis SSM, Hoppenreijs EPAH, Armbrust W, van den Berg JM, Hissink Muller PCE, Gelderman KA, Arkachaisri T, van Wijk F, van Royen-Kerkhof A. Endothelial and Inflammation Biomarker Profiles at Diagnosis Reflecting Clinical Heterogeneity and Serving as a Prognostic Tool for Treatment Response in Two Independent Cohorts of Patients With Juvenile Dermatomyositis. Arthritis Rheumatol 2020; 72:1214-1226. [PMID: 32103637 PMCID: PMC7329617 DOI: 10.1002/art.41236] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Accepted: 02/06/2020] [Indexed: 12/22/2022]
Abstract
Objective Juvenile dermatomyositis (DM) is a heterogeneous systemic immune‐mediated vasculopathy. This study was undertaken to 1) identify inflammation/endothelial dysfunction–related biomarker profiles reflecting disease severity at diagnosis, and 2) establish whether such biomarker profiles could be used for predicting the response to treatment in patients with juvenile DM. Methods In total, 39 biomarkers related to activation of endothelial cells, endothelial dysfunction, and inflammation were measured using multiplex technology in serum samples from treatment‐naive patients with juvenile DM from 2 independent cohorts (n = 30 and n = 29). Data were analyzed by unsupervised hierarchical clustering, nonparametric tests with correction for multiple comparisons, and Kaplan‐Meier tests with Cox proportional hazards models for analysis of treatment duration. Myositis‐specific antibodies (MSAs) were measured in the patients’ serum using line blot assays. Results Severe vasculopathy in patients with juvenile DM was associated with low serum levels of intercellular adhesion molecule 1 (Spearman's rho [rs] = 0.465, P = 0.0111) and high serum levels of endoglin (rs = −0.67, P < 0.0001). In the discovery cohort, unsupervised hierarchical clustering analysis of the biomarker profiles yielded 2 distinct patient clusters, of which the smaller cluster (cluster 1; n = 8) exhibited high serum levels of CXCL13, CCL19, galectin‐9, CXCL10, tumor necrosis factor receptor type II (TNFRII), and galectin‐1 (false discovery rate <0.0001), and this cluster had greater severity of muscle disease and global disease activity (each P < 0.05 versus cluster 2). In the validation cohort, correlations between the serum levels of galectin‐9, CXCL10, TNFRII, and galectin‐1 and the severity of global disease activity were confirmed (rs = 0.40–0.52, P < 0.05). Stratification of patients according to the 4 confirmed biomarkers identified a cluster of patients with severe symptoms (comprising 64.7% of patients) who were considered at high risk of requiring more intensive treatment in the first 3 months after diagnosis (P = 0.0437 versus other cluster). Moreover, high serum levels of galectin‐9, CXCL10, and TNFRII were predictive of a longer total treatment duration (P < 0.05). The biomarker‐based clusters were not evidently correlated with patients’ MSA serotypes. Conclusion Results of this study confirm the heterogeneity of new‐onset juvenile DM based on serum biomarker profiles. Patients with high serum levels of galectin‐9, CXCL10, TNFRII, and galectin‐1 may respond suboptimally to conventional treatment, and may therefore benefit from more intensive monitoring and/or treatment.
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Affiliation(s)
- Judith Wienke
- University Medical Center Utrecht and Utrecht University, Utrecht, The Netherlands
| | - Lauren M Pachman
- Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, and the Cure JM Center of Excellence, Chicago, Illinois
| | - Gabrielle A Morgan
- Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, and the Cure JM Center of Excellence, Chicago, Illinois
| | - Joo Guan Yeo
- KK Women's and Children's Hospital, and Duke-NUS Medical School, Singapore, Singapore
| | - Maria C Amoruso
- Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, and the Cure JM Center of Excellence, Chicago, Illinois
| | - Victoria Hans
- Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, and the Cure JM Center of Excellence, Chicago, Illinois
| | - Sylvia S M Kamphuis
- Sophia Children's Hospital and Erasmus University Medical Centre, Rotterdam, The Netherlands
| | | | - Wineke Armbrust
- Beatrix Children's Hospital and University Medical Centre Groningen, Groningen, The Netherlands
| | - J Merlijn van den Berg
- Emma Children's Hospital and Amsterdam University Medical Center, Amsterdam, The Netherlands
| | - Petra C E Hissink Muller
- Sophia Children's Hospital and Erasmus University Medical Centre, Rotterdam, The Netherlands, and Leiden University Medical Centre, Leiden, The Netherlands
| | | | | | - Femke van Wijk
- University Medical Center Utrecht and Utrecht University, Utrecht, The Netherlands
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17
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Ye Z, Lu W, Liang L, Tang M, Wang Y, Li Z, Zeng H, Wang A, Lin M, Huang L, Wang H, Hu H. Mesenchymal stem cells overexpressing hepatocyte nuclear factor-4 alpha alleviate liver injury by modulating anti-inflammatory functions in mice. Stem Cell Res Ther 2019; 10:149. [PMID: 31133062 PMCID: PMC6537220 DOI: 10.1186/s13287-019-1260-7] [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: 12/03/2018] [Revised: 05/03/2019] [Accepted: 05/10/2019] [Indexed: 01/20/2023] Open
Abstract
Background Mesenchymal stem cells (MSCs) can migrate to tissue injury sites where they can induce multipotential differentiation and anti-inflammation effects to treat tissue injury. When traditional therapeutic methods do not work, MSCs are considered to be one of the best candidates for cell therapy. MSCs have been used for treating several injury- and inflammation-associated diseases, including liver cirrhosis. However, the therapeutic effect of MSCs is limited. In some cases, the anti-inflammatory function of naïve MSCs is not enough to rescue tissue injury. Methods Carbon tetrachloride (CCl4) was used to establish a mouse liver cirrhosis model. Enhanced green fluorescence protein (EGFP) and hepatocyte nuclear factor-4α (HNF-4α) overexpression adenoviruses were used to modify MSCs. Three weeks after liver injury induction, mice were injected with bone marrow MSCs via their tail vein. The mice were then sacrificed 3 weeks after MSC injection. Liver injury was evaluated by measuring glutamic-pyruvic transaminase (ALT) and glutamic oxalacetic transaminase (AST) levels. Histological and molecular evaluations were performed to study the mechanisms. Results We found that HNF-4α-overexpressing MSCs had a better treatment effect than unmodified MSCs on liver cirrhosis. In the CCl4-induced mouse liver injury model, we found that HNF-4α-MSCs reduced inflammation in the liver and alleviated liver injury. In addition, we found that HNF-4α promoted the anti-inflammatory effect of MSCs by enhancing nitric oxide synthase (iNOS) expression, which was dependent on the nuclear factor kappa B (NF-κB) signalling pathway. Conclusions MSCs overexpressing HNF-4α exerted good therapeutic effects against mouse liver cirrhosis due to an enhanced anti-inflammatory effect. Gene modification is likely a promising method for improving the effects of cell therapy. Electronic supplementary material The online version of this article (10.1186/s13287-019-1260-7) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Zhenxiong Ye
- Department of General Surgery, Yangpu Hospital, Tongji University School of Medicine, 450 Teng Yue Road, Shanghai, 200090, China
| | - Wenfeng Lu
- Department of General Surgery, Yangpu Hospital, Tongji University School of Medicine, 450 Teng Yue Road, Shanghai, 200090, China.,Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China
| | - Lei Liang
- Department of General Surgery, Yangpu Hospital, Tongji University School of Medicine, 450 Teng Yue Road, Shanghai, 200090, China.,Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China
| | - Min Tang
- Department of General Surgery, Yangpu Hospital, Tongji University School of Medicine, 450 Teng Yue Road, Shanghai, 200090, China
| | - Yunfeng Wang
- Department of General Surgery, Yangpu Hospital, Tongji University School of Medicine, 450 Teng Yue Road, Shanghai, 200090, China
| | - Zhen Li
- Department of General Surgery, Yangpu Hospital, Tongji University School of Medicine, 450 Teng Yue Road, Shanghai, 200090, China
| | - Heping Zeng
- Department of General Surgery, Yangpu Hospital, Tongji University School of Medicine, 450 Teng Yue Road, Shanghai, 200090, China
| | - Aili Wang
- Department of General Surgery, Yangpu Hospital, Tongji University School of Medicine, 450 Teng Yue Road, Shanghai, 200090, China
| | - Moubin Lin
- Department of General Surgery, Yangpu Hospital, Tongji University School of Medicine, 450 Teng Yue Road, Shanghai, 200090, China
| | - Lei Huang
- Department of General Surgery, Yangpu Hospital, Tongji University School of Medicine, 450 Teng Yue Road, Shanghai, 200090, China
| | - Hui Wang
- Department of General Surgery, Yangpu Hospital, Tongji University School of Medicine, 450 Teng Yue Road, Shanghai, 200090, China
| | - Hai Hu
- Center of Gallbladder Disease, Shanghai East Hospital, Tongji University School of Medicine, 150 Ji Mo Road, Shanghai, 201200, China.
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18
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Han LG, Zhao QL, Yoshida T, Okabe M, Soko C, Rehman MU, Kondo T, Nikaido T. Differential response of immortalized human amnion mesenchymal and epithelial cells against oxidative stress. Free Radic Biol Med 2019; 135:79-86. [PMID: 30807827 DOI: 10.1016/j.freeradbiomed.2019.02.017] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Revised: 02/14/2019] [Accepted: 02/15/2019] [Indexed: 12/21/2022]
Abstract
Cells are equipped with various antioxidant defense factors to antagonize insults from reactive oxygen species (ROS), thus the antioxidant capacity has been characterized by a variety of cellular responses during the pathophysiological processes. Amniotic cells have been extensively applied in clinical practice for burn treatment, corneal repair, and tissue regeneration. However, the antioxidative properties of amniotic cells have not yet been fully understood. Therefore, the current study was aimed to observe the response of amniotic cells against ROS stimuli, and to investigate the underlying molecular mechanisms. The immortalized human amniotic mesenchymal cells (iHAMs) and immortalized human amniotic epithelial cells (iHAEs) were used. The human skin fibroblast (HSF) was used as a control cell line. Changes in intracellular ROS generation, cell viability, and cellular morphology were investigated to reveal the response of amniotic cells against oxidative stresses induced by x-rays and hydrogen peroxide. In addition, expression of apoptosis-related proteins and response to antioxidative stress was also examined. The intracellular ROS level and cell apoptosis in iHAMs was remarkably increased. iHAEs showed relatively high resistance to ROS stimulation, which can be attributed to the high SOD2 expression and up-regulation of Nrf2, HO-1 after x-rays exposure. In contrast, iHAMs were found sensitive to oxidative damage. Expression of caspase-3, caspase-8 and BAX was increased, whereas down-regulation of Bcl-xL, Nrf2, HO-1, and TrxR-1. Taken together, findings have highlighted the characterization of response of amniotic derived epithelial and mesenchymal cells to oxidative stress. In physiological processes, iHAMs may play an important role to maintain the homeostasis of the pregnancy environment. However, under oxidative stimulations, iHAEs provides protection against oxidative damage in amnion tissue.
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Affiliation(s)
- Lu Guang Han
- Department of Regenerative Medicine, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, 930-0194, Japan; Department of CT, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, China
| | - Qing-Li Zhao
- Department of Radiology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, 930-0194, Japan
| | - Toshiko Yoshida
- Department of Regenerative Medicine, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, 930-0194, Japan
| | - Motonori Okabe
- Department of Regenerative Medicine, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, 930-0194, Japan
| | - Chika Soko
- Department of Regenerative Medicine, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, 930-0194, Japan
| | - Mati Ur Rehman
- Department of Radiology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, 930-0194, Japan
| | - Takashi Kondo
- Department of Radiology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, 930-0194, Japan
| | - Toshio Nikaido
- Department of Regenerative Medicine, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, 930-0194, Japan.
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Xie ZY, Wang P, Wu YF, Shen HY. Long non-coding RNA: The functional regulator of mesenchymal stem cells. World J Stem Cells 2019; 11:167-179. [PMID: 30949295 PMCID: PMC6441937 DOI: 10.4252/wjsc.v11.i3.167] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2019] [Revised: 02/07/2019] [Accepted: 02/28/2019] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are a subset of multipotent stroma cells residing in various tissues of the body. Apart from supporting the hematopoietic stem cell niche, MSCs possess strong immunoregulatory ability and multiple differentiation potentials. These powerful capacities allow the extensive application of MSCs in clinical practice as an effective treatment for diseases. Therefore, illuminating the functional mechanism of MSCs will help to improve their curative effect and promote their clinical use. Long noncoding RNA (LncRNA) is a novel class of noncoding RNA longer than 200 nt. Recently, multiple studies have demonstrated that LncRNA is widely involved in growth and development through controlling the fate of cells, including MSCs. In this review, we highlight the role of LncRNA in regulating the functions of MSCs and discuss their participation in the pathogenesis of diseases and clinical use in diagnosis and treatment.
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Affiliation(s)
- Zhong-Yu Xie
- Department of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen 518033, Guangdong Province, China
| | - Peng Wang
- Department of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen 518033, Guangdong Province, China
| | - Yan-Feng Wu
- Center for Biotherapy, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, Guangdong Province, China
| | - Hui-Yong Shen
- Department of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen 518033, Guangdong Province, China
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Wuebbles RD, Cruz V, Van Ry P, Barraza-Flores P, Brewer PD, Jones P, Burkin DJ. Human Galectin-1 Improves Sarcolemma Stability and Muscle Vascularization in the mdx Mouse Model of Duchenne Muscular Dystrophy. MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT 2019; 13:145-153. [PMID: 30788383 PMCID: PMC6369265 DOI: 10.1016/j.omtm.2019.01.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/23/2018] [Accepted: 01/11/2019] [Indexed: 01/29/2023]
Abstract
Duchenne muscular dystrophy (DMD) is a devastating disease caused by mutations in the dystrophin gene that result in the complete absence of dystrophin protein. We have shown previously that recombinant mouse Galectin-1 treatment improves physiological and histological outcome measures in the mdx mouse model of DMD. Because recombinant human Galectin-1 (rHsGal1) will be used to treat DMD patients, we performed a dose-ranging study and intraperitoneal or intravenous delivery to determine the efficacy of rHsGal1 to improve preclinical outcome measures in mdx mice. Our studies showed that the optimal dose of rHsGal1 delivered intraperitoneally was 20 mg/kg and that this treatment improved muscle strength, sarcolemma stability, and capillary density in skeletal muscle. We next examined the efficacy of intravenous delivery and found that a dose of 2.5 mg/kg rHsGal1 was well tolerated and improved outcome measures in the mdx mouse model. Our studies identified that intravenous doses of rHsGal1 exceeding 2.5 mg/kg resulted in toxicity, indicating that dosing using this delivery mechanism will need to be carefully monitored. Our results support the idea that rHsGal1 treatment can improve outcome measures in the mdx mouse model and support further development as a potential therapeutic agent for DMD.
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Affiliation(s)
- Ryan D Wuebbles
- Department of Pharmacology, Center for Molecular Medicine, University of Nevada, Reno School of Medicine, Reno, NV 89557, USA.,StrykaGen Corporation, Reno, NV 89557, USA
| | | | - Pam Van Ry
- Department of Pharmacology, Center for Molecular Medicine, University of Nevada, Reno School of Medicine, Reno, NV 89557, USA.,StrykaGen Corporation, Reno, NV 89557, USA
| | - Pamela Barraza-Flores
- Department of Pharmacology, Center for Molecular Medicine, University of Nevada, Reno School of Medicine, Reno, NV 89557, USA
| | | | - Peter Jones
- Department of Pharmacology, Center for Molecular Medicine, University of Nevada, Reno School of Medicine, Reno, NV 89557, USA
| | - Dean J Burkin
- Department of Pharmacology, Center for Molecular Medicine, University of Nevada, Reno School of Medicine, Reno, NV 89557, USA.,StrykaGen Corporation, Reno, NV 89557, USA
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21
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Rufaihah AJ, Cheyyatraivendran S, Mazlan MDM, Lim K, Chong MSK, Mattar CNZ, Chan JKY, Kofidis T, Seliktar D. The Effect of Scaffold Modulus on the Morphology and Remodeling of Fetal Mesenchymal Stem Cells. Front Physiol 2018; 9:1555. [PMID: 30622472 PMCID: PMC6308149 DOI: 10.3389/fphys.2018.01555] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2018] [Accepted: 10/17/2018] [Indexed: 12/17/2022] Open
Abstract
Hydrogel materials have been successfully used as matrices to explore the role of biophysical and biochemical stimuli in directing stem cell behavior. Here, we present our findings on the role of modulus in guiding bone marrow fetal mesenchymal stem cell (BMfMSC) fate determination using semi-synthetic hydrogels made from PEG-fibrinogen (PF). The BMfMSCs were cultivated in the PF for up to 2 weeks to study the influence of matrix modulus (i.e., cross-linking density of the PF) on BMfMSC survival, morphology and integrin expression. Both two-dimensional (2D) and three-dimensional (3D) culture conditions were employed to examine the BMfMSCs as single cells or as cell spheroids. The hydrogel modulus affected the rate of BMfMSC metabolic activity, the integrin expression levels and the cell morphology, both as single cells and as spheroids. The cell seeding density was also found to be an important parameter of the system in that high densities were favorable in facilitating more cell-to-cell contacts that favored higher metabolic activity. Our findings provide important insight about design of a hydrogel scaffold that can be used to optimize the biological response of BMfMSCs for various tissue engineering applications.
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Affiliation(s)
- Abdul Jalil Rufaihah
- Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Suganya Cheyyatraivendran
- Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Muhammad Danial Mohd Mazlan
- Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Kenrich Lim
- Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Mark Seow Khoon Chong
- Division of Bioengineering, School of Chemical and Biomedical Engineering, Nanyang Technological University, Singapore, Singapore
| | | | - Jerry Kok Yen Chan
- Department of Obstretics and Gynaecology, National University of Singapore, Singapore, Singapore
| | - Theodoros Kofidis
- Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.,Department of Cardiac, Thoracic and Vascular Surgery, National University Heart Centre Singapore, National University Health System, Singapore, Singapore
| | - Dror Seliktar
- Nanoscience and Nanotechnology Initiative, National University of Singapore, Singapore, Singapore.,Faculty of Biomedical Engineering, Technion - Israel Institute of Technology, Haifa, Israel
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22
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Fan SMY, Tsai CF, Yen CM, Lin MH, Wang WH, Chan CC, Chen CL, Phua KKL, Pan SH, Plikus MV, Yu SL, Chen YJ, Lin SJ. Inducing hair follicle neogenesis with secreted proteins enriched in embryonic skin. Biomaterials 2018; 167:121-131. [PMID: 29567388 PMCID: PMC6050066 DOI: 10.1016/j.biomaterials.2018.03.003] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2017] [Revised: 02/22/2018] [Accepted: 03/02/2018] [Indexed: 12/17/2022]
Abstract
Organ development is a sophisticated process of self-organization. However, despite growing understanding of the developmental mechanisms, little is known about how to reactivate them postnatally for regeneration. We found that treatment of adult non-hair fibroblasts with cell-free extract from embryonic skin conferred upon them the competency to regenerate hair follicles. Proteomics analysis identified three secreted proteins enriched in the embryonic skin, apolipoprotein-A1, galectin-1 and lumican that together were essential and sufficient to induce new hair follicles. These 3 proteins show a stage-specific co-enrichment in the perifolliculogenetic embryonic dermis. Mechanistically, exposure to embryonic skin extract or to the combination of the 3 proteins altered the gene expression to an inductive hair follicle dermal papilla fibroblast-like profile and activated Igf and Wnt signaling, which are crucial for the regeneration process. Therefore, a cocktail of organ-specific extracellular proteins from the embryonic environment can render adult cells competent to re-engage in developmental interactions for organ neogenesis. Identification of factors that recreate the extracellular context of respective developing tissues can become an important strategy to promote regeneration in adult organs.
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Affiliation(s)
- Sabrina Mai-Yi Fan
- Institute of Biomedical Engineering, College of Medicine and College of Engineering, National Taiwan University, Taipei, Taiwan
| | - Chia-Feng Tsai
- Institute of Chemistry, Academia Sinica, Taipei, Taiwan; Department of Chemistry, National Taiwan University, Taipei, Taiwan
| | - Chien-Mei Yen
- Institute of Biomedical Engineering, College of Medicine and College of Engineering, National Taiwan University, Taipei, Taiwan; Department of Dermatology, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan
| | - Miao-Hsia Lin
- Institute of Chemistry, Academia Sinica, Taipei, Taiwan
| | - Wei-Hung Wang
- Institute of Biomedical Engineering, College of Medicine and College of Engineering, National Taiwan University, Taipei, Taiwan
| | - Chih-Chieh Chan
- Institute of Biomedical Engineering, College of Medicine and College of Engineering, National Taiwan University, Taipei, Taiwan; Department of Dermatology, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan
| | - Chih-Lung Chen
- Institute of Biomedical Engineering, College of Medicine and College of Engineering, National Taiwan University, Taipei, Taiwan; Department of Dermatology, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan
| | - Kyle K L Phua
- Department of Chemical and Biomolecular Engineering, National University of Singapore, Singapore
| | - Szu-Hua Pan
- Graduate Institute of Medical Genomics and Proteomics, College of Medicine, National Taiwan University, Taipei, Taiwan; Doctoral Degree Program of Translational Medicine, National Taiwan University, Taipei, Taiwan; Genome and Systems Biology Degree Program, National Taiwan University and Academia Sinica, Taipei, Taiwan
| | - Maksim V Plikus
- Department of Developmental and Cell Biology, Sue and Bill Gross Stem Cell Research Center, Center for Complex Biological Systems, University of California, Irvine, Irvine, CA, USA
| | - Sung-Liang Yu
- Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Yu-Ju Chen
- Institute of Chemistry, Academia Sinica, Taipei, Taiwan; Department of Chemistry, National Taiwan University, Taipei, Taiwan.
| | - Sung-Jan Lin
- Institute of Biomedical Engineering, College of Medicine and College of Engineering, National Taiwan University, Taipei, Taiwan; Department of Dermatology, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan; Genome and Systems Biology Degree Program, National Taiwan University and Academia Sinica, Taipei, Taiwan; Research Center for Developmental Biology and Regenerative Medicine, National Taiwan University, Taipei, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
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23
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Han X, Chen H, Huang D, Chen H, Fei L, Cheng C, Huang H, Yuan GC, Guo G. Mapping human pluripotent stem cell differentiation pathways using high throughput single-cell RNA-sequencing. Genome Biol 2018; 19:47. [PMID: 29622030 PMCID: PMC5887227 DOI: 10.1186/s13059-018-1426-0] [Citation(s) in RCA: 65] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2017] [Accepted: 03/21/2018] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Human pluripotent stem cells (hPSCs) provide powerful models for studying cellular differentiations and unlimited sources of cells for regenerative medicine. However, a comprehensive single-cell level differentiation roadmap for hPSCs has not been achieved. RESULTS We use high throughput single-cell RNA-sequencing (scRNA-seq), based on optimized microfluidic circuits, to profile early differentiation lineages in the human embryoid body system. We present a cellular-state landscape for hPSC early differentiation that covers multiple cellular lineages, including neural, muscle, endothelial, stromal, liver, and epithelial cells. Through pseudotime analysis, we construct the developmental trajectories of these progenitor cells and reveal the gene expression dynamics in the process of cell differentiation. We further reprogram primed H9 cells into naïve-like H9 cells to study the cellular-state transition process. We find that genes related to hemogenic endothelium development are enriched in naïve-like H9. Functionally, naïve-like H9 show higher potency for differentiation into hematopoietic lineages than primed cells. CONCLUSIONS Our single-cell analysis reveals the cellular-state landscape of hPSC early differentiation, offering new insights that can be harnessed for optimization of differentiation protocols.
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Affiliation(s)
- Xiaoping Han
- Center for Stem Cell and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, 310058, China.,Institute of Hematology, The 1st Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.,Stem Cell Institute, Zhejiang University, Hangzhou, 310058, China
| | - Haide Chen
- Center for Stem Cell and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, 310058, China. .,Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Zhejiang Provincial Key Lab for Tissue Engineering and Regenerative Medicine, Hangzhou, 310058, China. .,College of Animal Science, Zhejiang University, Hangzhou, 310058, China.
| | - Daosheng Huang
- Center for Stem Cell and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, 310058, China.,Stem Cell Institute, Zhejiang University, Hangzhou, 310058, China
| | - Huidong Chen
- Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard Chan School of Public Health, Boston, MA, 02115, USA.,Department of Computer Science and Technology, Tongji University, Shanghai, 201804, China
| | - Lijiang Fei
- Center for Stem Cell and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, 310058, China.,Stem Cell Institute, Zhejiang University, Hangzhou, 310058, China
| | - Chen Cheng
- College of Life Sciences, Zhejiang University, Hangzhou, 310058, China
| | - He Huang
- Institute of Hematology, The 1st Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.,Stem Cell Institute, Zhejiang University, Hangzhou, 310058, China
| | - Guo-Cheng Yuan
- Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard Chan School of Public Health, Boston, MA, 02115, USA.
| | - Guoji Guo
- Center for Stem Cell and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, 310058, China. .,Institute of Hematology, The 1st Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China. .,Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Zhejiang Provincial Key Lab for Tissue Engineering and Regenerative Medicine, Hangzhou, 310058, China. .,Stem Cell Institute, Zhejiang University, Hangzhou, 310058, China.
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24
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Abstract
Purpose of Review The aim of the study is to provide an overview on the possibility of treating congenital disorders prenatally with mesenchymal stromal cells (MSCs). Recent Findings MSCs have multilineage potential and a low immunogenic profile and are immunomodulatory and more easy to expand in culture. Their ability to migrate, engraft and differentiate, or act via a paracrine effect on target tissues makes MSCs candidates for clinical therapies. Fetal and extra-fetal MSCs offer higher therapeutic potential compared to MSCs derived from adult sources. Summary MSCs may be safely transplanted prenatally via ultrasound-guided injection into the umbilical cord. Due to these characteristics, fetal MSCs are of great interest in the field of in utero stem cell transplantation for treatment of congenital disease.
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25
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Regenerative Medicine Applications of Mesenchymal Stem Cells. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 1089:115-141. [PMID: 29767289 DOI: 10.1007/5584_2018_213] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
A major research challenge is to develop therapeutics that assist with healing damaged tissues and organs because the human body has limited ability to restore the majority of these tissues and organs to their original state. Tissue engineering (TE) and regenerative medicine (RM) promises to offer efficient therapeutic biological strategies that use mesenchymal stem cells (MSCs). MSCs possess the capability for self-renewal, multilineage differentiation, and immunomodulatory properties that make them attractive for clinical applications. They have been extensively investigated in numerous preclinical and clinical settings in an attempt to overcome their challenges and promote tissue regeneration and repair. This review explores the exciting opportunities afforded by MSCs, their desirable properties as cellular therapeutics in RM, and implicates their potential use in clinical practice. Here, we attempt to identify challenges and issues that determine the clinical efficacy of MSCs as treatment for skeletal and non-skeletal tissues.
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26
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Koo JH, Cho JY. Erratum to: Treadmill Exercise Attenuates α-Synuclein Levels by Promoting Mitochondrial Function and Autophagy Possibly via SIRT1 in the Chronic MPTP/P-Induced Mouse Model of Parkinson's Disease. Neurotox Res 2017; 32:532-533. [PMID: 28741160 DOI: 10.1007/s12640-017-9779-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Affiliation(s)
- Jung-Hoon Koo
- Department of Exercise Biochemistry, Korea National Sport University, Seoul, 138-763, Republic of Korea
- Institute of Sport Science, Korea National Sport University, Seoul, 138-763, Republic of Korea
| | - Joon-Yong Cho
- Department of Exercise Biochemistry, Korea National Sport University, Seoul, 138-763, Republic of Korea.
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27
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Abebayehu D, Spence A, Boyan BD, Schwartz Z, Ryan JJ, McClure MJ. Galectin-1 promotes an M2 macrophage response to polydioxanone scaffolds. J Biomed Mater Res A 2017; 105:2562-2571. [PMID: 28544348 DOI: 10.1002/jbm.a.36113] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2017] [Revised: 04/27/2017] [Accepted: 05/15/2017] [Indexed: 12/20/2022]
Abstract
Regulating soft tissue repair to prevent fibrosis and promote regeneration is central to creating a microenvironment conducive to soft tissue development. Macrophages play an important role in this process. The macrophage response can be modulated using biomaterials, altering cytokine and growth factor secretion to promote regeneration. Electrospun polydioxanone (PDO) fiber scaffolds promoted an M2 phenotype when macrophages were cultured on large diameter, highly porous scaffolds, but an M1 phenotype on smaller diameter fibers. In this study, we investigated whether incorporation of galectin-1, an immunosuppressive protein that enhances muscle regeneration, could promote the M2 response. Galectin-1 was incorporated into large and small fiber PDO scaffolds during electrospinning. Galectin-1 incorporation increased arginase-1 and reduced iNOS and IL-6 production in mouse bone-marrow derived macrophages compared with PDO alone for both scaffold types. Inhibition of ERK mitogen-activated protein kinase did not alter galectin-1 effects on arginase-1 and iNOS expression, but reversed IL-6 suppression, indicating that IL-6 is mediated by a different mechanism. Our results suggest that galectin-1 can be used to modulate macrophage commitment to a pro-regenerative M2 phenotype, which may positively impact tissue regeneration when using small diameter PDO scaffolds. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 2562-2571, 2017.
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Affiliation(s)
- Daniel Abebayehu
- Department of Biology, Virginia Commonwealth University, Richmond, Virginia.,Department of Biomedical Engineering, School of Engineering, Virginia Commonwealth University, Richmond, Virginia
| | - Andrew Spence
- Department of Biology, Virginia Commonwealth University, Richmond, Virginia
| | - Barbara D Boyan
- Department of Biomedical Engineering, School of Engineering, Virginia Commonwealth University, Richmond, Virginia.,Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia
| | - Zvi Schwartz
- Department of Biomedical Engineering, School of Engineering, Virginia Commonwealth University, Richmond, Virginia.,Department of Periodontics, University of Texas Health Sciences Center at San Antonio, San Antonio, Texas
| | - John J Ryan
- Department of Biology, Virginia Commonwealth University, Richmond, Virginia
| | - Michael J McClure
- Department of Biomedical Engineering, School of Engineering, Virginia Commonwealth University, Richmond, Virginia.,Physical Medicine and Rehabilitation Service, Hunter Holmes McGuire VA Medical Center, Richmond, Virginia
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28
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Seasonal and flight-related variation of galectin expression in heart, liver and flight muscles of yellow-rumped warblers (Setophaga coronata). Glycoconj J 2017; 34:603-611. [DOI: 10.1007/s10719-017-9779-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2017] [Revised: 05/25/2017] [Accepted: 05/28/2017] [Indexed: 10/19/2022]
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29
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Pham ND, Pang PC, Krishnamurthy S, Wands AM, Grassi P, Dell A, Haslam SM, Kohler JJ. Effects of altered sialic acid biosynthesis on N-linked glycan branching and cell surface interactions. J Biol Chem 2017; 292:9637-9651. [PMID: 28424265 PMCID: PMC5465488 DOI: 10.1074/jbc.m116.764597] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2016] [Revised: 04/17/2017] [Indexed: 12/22/2022] Open
Abstract
GNE (UDP-GlcNAc 2-epimerase/ManNAc kinase) myopathy is a rare muscle disorder associated with aging and is related to sporadic inclusion body myositis, the most common acquired muscle disease of aging. Although the cause of sporadic inclusion body myositis is unknown, GNE myopathy is associated with mutations in GNE. GNE harbors two enzymatic activities required for biosynthesis of sialic acid in mammalian cells. Mutations to both GNE domains are linked to GNE myopathy. However, correlation between mutation-associated reductions in sialic acid production and disease severity is imperfect. To investigate other potential effects of GNE mutations, we compared sialic acid production in cell lines expressing wild type or mutant forms of GNE. Although we did not detect any differences attributable to disease-associated mutations, lectin binding and mass spectrometry analysis revealed that GNE deficiency is associated with unanticipated effects on the structure of cell-surface glycans. In addition to exhibiting low levels of sialylation, GNE-deficient cells produced distinct N-linked glycan structures with increased branching and extended poly-N-acetyllactosamine. GNE deficiency may affect levels of UDP-GlcNAc, a key metabolite in the nutrient-sensing hexosamine biosynthetic pathway, but this modest effect did not fully account for the change in N-linked glycan structure. Furthermore, GNE deficiency and glucose supplementation acted independently and additively to increase N-linked glycan branching. Notably, N-linked glycans produced by GNE-deficient cells displayed enhanced binding to galectin-1, indicating that changes in GNE activity can alter affinity of cell-surface glycoproteins for the galectin lattice. These findings suggest an unanticipated mechanism by which GNE activity might affect signaling through cell-surface receptors.
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Affiliation(s)
- Nam D Pham
- From the Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9038 and
| | - Poh-Choo Pang
- the Department of Life Sciences, Imperial College London, South Kensington Campus, London SW7 2AZ, United Kingdom
| | - Soumya Krishnamurthy
- From the Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9038 and
| | - Amberlyn M Wands
- From the Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9038 and
| | - Paola Grassi
- the Department of Life Sciences, Imperial College London, South Kensington Campus, London SW7 2AZ, United Kingdom
| | - Anne Dell
- the Department of Life Sciences, Imperial College London, South Kensington Campus, London SW7 2AZ, United Kingdom
| | - Stuart M Haslam
- the Department of Life Sciences, Imperial College London, South Kensington Campus, London SW7 2AZ, United Kingdom
| | - Jennifer J Kohler
- From the Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9038 and
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30
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Okamura LH, Cordero P, Palomino J, Parraguez VH, Torres CG, Peralta OA. Myogenic Differentiation Potential of Mesenchymal Stem Cells Derived from Fetal Bovine Bone Marrow. Anim Biotechnol 2017; 29:1-11. [DOI: 10.1080/10495398.2016.1276926] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Affiliation(s)
- Lucas Hidenori Okamura
- Departamento de Apoio, Produção e Saúde Animal, Faculdade de Medicina Veterinária, Universidade Estadual Paulista “Júlio de Mesquita Filho”, Araçatuba, São Paulo, Brasil
- Departamento de Fomento de la Producción Animal, Facultad de Ciencias Veterinarias y Pecuarias, Universidad de Chile, Santiago, Chile
| | - Paloma Cordero
- Departamento de Fomento de la Producción Animal, Facultad de Ciencias Veterinarias y Pecuarias, Universidad de Chile, Santiago, Chile
| | - Jaime Palomino
- Departamento de Fomento de la Producción Animal, Facultad de Ciencias Veterinarias y Pecuarias, Universidad de Chile, Santiago, Chile
| | - Victor Hugo Parraguez
- Departamento de Ciencias Biológicas, Facultad de Ciencias Veterinarias y Pecuarias, Universidad de Chile, Santiago, Chile
| | - Cristian Gabriel Torres
- Departamento de Ciencias Clínicas, Facultad de Ciencias Veterinarias y Pecuarias, Universidad de Chile, Santiago, Chile
| | - Oscar Alejandro Peralta
- Departamento de Fomento de la Producción Animal, Facultad de Ciencias Veterinarias y Pecuarias, Universidad de Chile, Santiago, Chile
- Department of Biomedical Sciences and Pathobiology, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Tech, Blacksburg, Virginia, USA
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31
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de Souza LEB, Malta TM, Kashima Haddad S, Covas DT. Mesenchymal Stem Cells and Pericytes: To What Extent Are They Related? Stem Cells Dev 2016; 25:1843-1852. [PMID: 27702398 DOI: 10.1089/scd.2016.0109] [Citation(s) in RCA: 78] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Mesenchymal stem cells (MSCs) were initially identified as progenitors of skeletal tissues within mammalian bone marrow and cells with similar properties were also obtained from other tissues such as adipose and dental pulp. Although MSCs have been extensively investigated, their native behavior and in vivo identity remain poorly defined. Uncovering the in vivo identity of MSCs has been challenging due to the lack of exclusive cell markers, cellular alterations caused by culture methods, and extensive focus on in vitro properties for characterization. Although MSC site of origin influences their functional properties, these mesenchymal progenitors can be found in the perivascular space in virtually all organs from where they were obtained. However, the precise identity of MSCs within the vascular wall is highly controversial. The recurrent concept that MSCs correspond to pericytes in vivo has been supported mainly by their perivascular localization and expression of some molecular markers. However, this view has been a subject of controversy, in part, due to the application of loose criteria to define pericytes and due to the lack of a marker able to unequivocally identify these cells. Furthermore, recent evidences indicate that subpopulations of MSCs can be found at extravascular sites such as the endosteum. In this opinion review, we bring together the advances and pitfalls on the search for the in vivo identity of MSCs and highlight the recent evidences that suggest that perivascular MSCs are adventitial cells, acting as precursors of pericytes and other stromal cells during tissue homeostasis.
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Affiliation(s)
- Lucas Eduardo Botelho de Souza
- 1 Department of Clinical Medicine, Ribeirão Preto Medical School, University of São Paulo , Ribeirão Preto, Brazil .,2 National Institute of Science and Technology for Stem Cell and Cell Therapy , Ribeirão Preto, Brazil
| | - Tathiane Maistro Malta
- 2 National Institute of Science and Technology for Stem Cell and Cell Therapy , Ribeirão Preto, Brazil .,3 Department of Genetics, Ribeirão Preto Medical School, University of São Paulo , Ribeirão Preto, Brazil
| | - Simone Kashima Haddad
- 2 National Institute of Science and Technology for Stem Cell and Cell Therapy , Ribeirão Preto, Brazil
| | - Dimas Tadeu Covas
- 1 Department of Clinical Medicine, Ribeirão Preto Medical School, University of São Paulo , Ribeirão Preto, Brazil .,2 National Institute of Science and Technology for Stem Cell and Cell Therapy , Ribeirão Preto, Brazil
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32
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Huda F, Fan Y, Suzuki M, Konno A, Matsuzaki Y, Takahashi N, Chan JKY, Hirai H. Fusion of Human Fetal Mesenchymal Stem Cells with "Degenerating" Cerebellar Neurons in Spinocerebellar Ataxia Type 1 Model Mice. PLoS One 2016; 11:e0164202. [PMID: 27802273 PMCID: PMC5089746 DOI: 10.1371/journal.pone.0164202] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2016] [Accepted: 09/21/2016] [Indexed: 12/11/2022] Open
Abstract
Mesenchymal stem cells (MSCs) migrate to damaged tissues, where they participate in tissue repair. Human fetal MSCs (hfMSCs), compared with adult MSCs, have higher proliferation rates, a greater differentiation capacity and longer telomeres with reduced senescence. Therefore, transplantation of quality controlled hfMSCs is a promising therapeutic intervention. Previous studies have shown that intravenous or intracortical injections of MSCs result in the emergence of binucleated cerebellar Purkinje cells (PCs) containing an MSC-derived marker protein in mice, thus suggesting a fusion event. However, transdifferentiation of MSCs into PCs or transfer of a marker protein from an MSC to a PC cannot be ruled out. In this study, we unequivocally demonstrated the fusion of hfMSCs with murine PCs through a tetracycline-regulated (Tet-off) system with or without a Cre-dependent genetic inversion switch (flip-excision; FLEx). In the FLEx-Tet system, we performed intra-cerebellar injection of viral vectors expressing tetracycline transactivator (tTA) and Cre recombinase into either non-symptomatic (4-week-old) or clearly symptomatic (6–8-month-old) spinocerebellar ataxia type 1 (SCA1) mice. Then, the mice received an injection of 50,000 genetically engineered hfMSCs that expressed GFP only in the presence of Cre recombinase and tTA. We observed a significant emergence of GFP-expressing PCs and interneurons in symptomatic, but not non-symptomatic, SCA1 mice 2 weeks after the MSC injection. These results, together with the results obtained using age-matched wild-type mice, led us to conclude that hfMSCs have the potential to preferentially fuse with degenerating PCs and interneurons but not with healthy neurons.
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Affiliation(s)
- Fathul Huda
- Department of Neurophysiology & Neural Repair, Gunma University Graduate School of Medicine, Maebashi, Gunma 371–8511, Japan
- Physiology Division, Department of Anatomy Physiology and Cell Biology, Faculty of Medicine Universitas Padjadjaran, Bandung, 40161, Indonesia
| | - Yiping Fan
- Department of Reproductive Medicine, KK Women's and Children's Hospital, 229899, Singapore
- Experimental Fetal Medicine Group, Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University Health System, 119228, Singapore
| | - Mamiko Suzuki
- Department of Neurophysiology & Neural Repair, Gunma University Graduate School of Medicine, Maebashi, Gunma 371–8511, Japan
| | - Ayumu Konno
- Department of Neurophysiology & Neural Repair, Gunma University Graduate School of Medicine, Maebashi, Gunma 371–8511, Japan
| | - Yasunori Matsuzaki
- Department of Neurophysiology & Neural Repair, Gunma University Graduate School of Medicine, Maebashi, Gunma 371–8511, Japan
| | - Nobutaka Takahashi
- Department of Neurophysiology & Neural Repair, Gunma University Graduate School of Medicine, Maebashi, Gunma 371–8511, Japan
| | - Jerry K. Y. Chan
- Department of Reproductive Medicine, KK Women's and Children's Hospital, 229899, Singapore
- Experimental Fetal Medicine Group, Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University Health System, 119228, Singapore
- Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, 169857, Singapore
| | - Hirokazu Hirai
- Department of Neurophysiology & Neural Repair, Gunma University Graduate School of Medicine, Maebashi, Gunma 371–8511, Japan
- * E-mail:
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Locke M, Davies LC, Stephens P. Oral mucosal progenitor cell clones resist in vitro myogenic differentiation. Arch Oral Biol 2016; 70:100-110. [PMID: 27343692 DOI: 10.1016/j.archoralbio.2016.06.013] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2015] [Revised: 12/23/2015] [Accepted: 06/09/2016] [Indexed: 10/21/2022]
Abstract
Progenitor cells derived from the oral mucosa lamina propria (OMLP-PCs) demonstrate an ability to differentiate into tissue lineages removed from their anatomical origin. This clonally derived population of neural-crest cells have demonstrated potential to differentiate along mesenchymal and neuronal cell lineages. OBJECTIVE Significant efforts are being made to generate functioning muscle constructs for use in research and clinical tissue engineering. In this study we aimed to determine the myogenic properties of clonal populations of expanded OMLP-PCs. DESIGN PCs were subject to several in vitro culture conditions in an attempt to drive myogenic conversion. Methodologies include use of demethylation gene-modifying reagents, mechanical conditioning of tissue culture substrates, tuneable polyacrylamide gels and a 3-dimensional construct as well as published myogenic media compositions. PCR and immunostaining for the muscle cell markers Desmin and MyoD1 were used to assess muscle differentiation. RESULTS The clones tested did not intrinsically express myogenic lineage markers. Despite use of two and 3-dimensional pre-published in vitro culture protocols OMLP clones could not be differentiated down a myogenic lineage. CONCLUSIONS Within the confines of these experimental parameters it was not possible to generate identifiable muscle using the clonal populations. When reviewing the previously successful reports of myogenic conversion, cells utilised have either been derived from tissues that are already 'primed' with the requisite myogenic genetic potential or have undergone specific genetic reprogramming to enhance the myogenic conversion rate. This, along with as yet unidentified stromal interplay, may therefore be required for positive myogenic differentiation to be realised.
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Affiliation(s)
- Matthew Locke
- Wound Biology Group, Cardiff Institute of Tissue Engineering and Repair, Tissue Engineering and Reparative Dentistry, School of Dentistry, College of Biomedical and Life Sciences, Cardiff University, Cardiff, CF14 4XY, United Kingdom.
| | - Lindsay C Davies
- Wound Biology Group, Cardiff Institute of Tissue Engineering and Repair, Tissue Engineering and Reparative Dentistry, School of Dentistry, College of Biomedical and Life Sciences, Cardiff University, Cardiff, CF14 4XY, United Kingdom.
| | - Phil Stephens
- Wound Biology Group, Cardiff Institute of Tissue Engineering and Repair, Tissue Engineering and Reparative Dentistry, School of Dentistry, College of Biomedical and Life Sciences, Cardiff University, Cardiff, CF14 4XY, United Kingdom.
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Götherström C. Human Foetal Mesenchymal Stem Cells. Best Pract Res Clin Obstet Gynaecol 2015; 31:82-7. [PMID: 26725704 DOI: 10.1016/j.bpobgyn.2015.11.010] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2015] [Accepted: 11/17/2015] [Indexed: 01/07/2023]
Abstract
Finding suitable cell sources is one of the main challenges in regenerative medicine. In addition to improving the dysfunctional tissue requiring reconstruction, low immunogenicity is beneficial. Mesenchymal stem cells (MSCs) are immune-privileged multipotent stromal cells that can easily multiply and differentiate along many lineages with a minimal oncogenic risk. MSCs derived from foetal tissues present characteristics that suggest an even stronger cell therapeutic potential in comparison to adult MSCs. Due to these characteristics, they have been and are currently being tested in clinical trials for a diverse variety of disorders.
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Affiliation(s)
- Cecilia Götherström
- Division of Obstetrics and Gynaecology and Centre for Haematology and Regenerative Medicine, Karolinska Institutet, Stockholm, Sweden.
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Kaltner H, Singh T, Manning JC, Raschta AS, André S, Sinowatz F, Gabius HJ. Network monitoring of adhesion/growth-regulatory galectins: localization of the five canonical chicken proteins in embryonic and maturing bone and cartilage and their introduction as histochemical tools. Anat Rec (Hoboken) 2015; 298:2051-70. [PMID: 26340709 DOI: 10.1002/ar.23265] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2015] [Revised: 06/26/2015] [Accepted: 07/08/2015] [Indexed: 01/15/2023]
Abstract
Divergence from an ancestral gene leads to a family of homologous proteins. Whether they are physiologically distinct, similar, or even redundant is an open question in each case. Defining profiles of tissue localization is a step toward giving diversity a functional meaning. Due to the significance of endogenous sugar receptors (lectins) as effectors for a wide range of cellular activities we have focused on galectins. The comparatively low level of network complexity constituted by only five canonical proteins makes chicken galectins (CGs) an attractive choice to perform comprehensive analysis, here studied on bone/cartilage as organ system. Galectin expression was monitored by Western blotting and immunohistochemistry using non-cross-reactive antibodies. Overall, three galectins (CG-1B, CG-3, CG-8) were present with individual expression patterns, one was found exclusively in the mesenchyme (CG-1A), the fifth (CG-2) not being detectable. The documented extents of separation are a sign for functional divergence; in cases with overlapping stainings, as for example in the osteoprogenitor layer or periosteum, cooperation may also be possible. Recombinant production enabled the introduction of the endogenous lectins as tools for binding-site localization. Their testing revealed developmental regulation and cell-type-specific staining. Of relevance for research on mammalian galectins, this study illustrates that certain cell types can express more than one galectin, letting functional interrelationships appear likely. Thus, complete network analysis irrespective of its degree of complexity is mandatory.
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Affiliation(s)
- Herbert Kaltner
- Faculty of Veterinary Medicine, Institute of Physiological Chemistry, Ludwig-Maximilians-University Munich, 80539, Munich, Germany
| | - Tanuja Singh
- Faculty of Veterinary Medicine, Institute of Physiological Chemistry, Ludwig-Maximilians-University Munich, 80539, Munich, Germany
| | - Joachim C Manning
- Faculty of Veterinary Medicine, Institute of Physiological Chemistry, Ludwig-Maximilians-University Munich, 80539, Munich, Germany
| | - Anne-Sarah Raschta
- Faculty of Veterinary Medicine, Institute of Physiological Chemistry, Ludwig-Maximilians-University Munich, 80539, Munich, Germany
| | - Sabine André
- Faculty of Veterinary Medicine, Institute of Physiological Chemistry, Ludwig-Maximilians-University Munich, 80539, Munich, Germany
| | - Fred Sinowatz
- Faculty of Veterinary Medicine, Institute of Anatomy, Histology and Embryology, Ludwig-Maximilians-University Munich, 80539, Munich, Germany
| | - Hans-Joachim Gabius
- Faculty of Veterinary Medicine, Institute of Physiological Chemistry, Ludwig-Maximilians-University Munich, 80539, Munich, Germany
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Redox state influence on human galectin-1 function. Biochimie 2015; 116:8-16. [DOI: 10.1016/j.biochi.2015.06.013] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2014] [Accepted: 06/19/2015] [Indexed: 11/22/2022]
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Simonson OE, Mougiakakos D, Heldring N, Bassi G, Johansson HJ, Dalén M, Jitschin R, Rodin S, Corbascio M, El Andaloussi S, Wiklander OPB, Nordin JZ, Skog J, Romain C, Koestler T, Hellgren-Johansson L, Schiller P, Joachimsson PO, Hägglund H, Mattsson M, Lehtiö J, Faridani OR, Sandberg R, Korsgren O, Krampera M, Weiss DJ, Grinnemo KH, Le Blanc K. In Vivo Effects of Mesenchymal Stromal Cells in Two Patients With Severe Acute Respiratory Distress Syndrome. Stem Cells Transl Med 2015; 4:1199-213. [PMID: 26285659 DOI: 10.5966/sctm.2015-0021] [Citation(s) in RCA: 109] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2015] [Accepted: 04/13/2015] [Indexed: 12/17/2022] Open
Abstract
UNLABELLED Mesenchymal stromal cells (MSCs) have been investigated as a treatment for various inflammatory diseases because of their immunomodulatory and reparative properties. However, many basic questions concerning their mechanisms of action after systemic infusion remain unanswered. We performed a detailed analysis of the immunomodulatory properties and proteomic profile of MSCs systemically administered to two patients with severe refractory acute respiratory distress syndrome (ARDS) on a compassionate use basis and attempted to correlate these with in vivo anti-inflammatory actions. Both patients received 2×10(6) cells per kilogram, and each subsequently improved with resolution of respiratory, hemodynamic, and multiorgan failure. In parallel, a decrease was seen in multiple pulmonary and systemic markers of inflammation, including epithelial apoptosis, alveolar-capillary fluid leakage, and proinflammatory cytokines, microRNAs, and chemokines. In vitro studies of the MSCs demonstrated a broad anti-inflammatory capacity, including suppression of T-cell responses and induction of regulatory phenotypes in T cells, monocytes, and neutrophils. Some of these in vitro potency assessments correlated with, and were relevant to, the observed in vivo actions. These experiences highlight both the mechanistic information that can be gained from clinical experience and the value of correlating in vitro potency assessments with clinical effects. The findings also suggest, but do not prove, a beneficial effect of lung protective strategies using adoptively transferred MSCs in ARDS. Appropriate randomized clinical trials are required to further assess any potential clinical efficacy and investigate the effects on in vivo inflammation. SIGNIFICANCE This article describes the cases of two patients with severe refractory adult respiratory syndrome (ARDS) who failed to improve after both standard life support measures, including mechanical ventilation, and additional measures, including extracorporeal ventilation (i.e., in a heart-lung machine). Unlike acute forms of ARDS (such in the current NIH-sponsored study of mesenchymal stromal cells in ARDS), recovery does not generally occur in such patients.
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Affiliation(s)
- Oscar E Simonson
- Departments of Molecular Medicine and Surgery, Cardiothoracic Surgery and Anesthesia, and Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; Department of Internal Medicine, Hematology and Oncology, University of Erlangen-Nuremberg, Erlangen, Germany; Stem Cell Research Laboratory, Section of Hematology, Department of Medicine, University of Verona, Verona, Italy; Cancer Proteomics Mass Spectrometry, Science for Life Laboratory, Department of Oncology-Pathology, Department of Medical Biochemistry and Biophysics, and Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden; Center for Diseases of Aging, Vaccine and Gene Therapy Institute Florida, Port St. Lucie, Florida, USA; Exosome Diagnostics Inc., New York, New York, USA; Departments of Cardiothoracic Surgery, Hematology, and Immunology, Genetics and Pathology, Uppsala University Hospital, Uppsala, Sweden; Ludwig Institute for Cancer Research, Stockholm, Sweden; Health Sciences Research Facility, Department of Medicine, University of Vermont, Burlington, Vermont, USA
| | - Dimitrios Mougiakakos
- Departments of Molecular Medicine and Surgery, Cardiothoracic Surgery and Anesthesia, and Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; Department of Internal Medicine, Hematology and Oncology, University of Erlangen-Nuremberg, Erlangen, Germany; Stem Cell Research Laboratory, Section of Hematology, Department of Medicine, University of Verona, Verona, Italy; Cancer Proteomics Mass Spectrometry, Science for Life Laboratory, Department of Oncology-Pathology, Department of Medical Biochemistry and Biophysics, and Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden; Center for Diseases of Aging, Vaccine and Gene Therapy Institute Florida, Port St. Lucie, Florida, USA; Exosome Diagnostics Inc., New York, New York, USA; Departments of Cardiothoracic Surgery, Hematology, and Immunology, Genetics and Pathology, Uppsala University Hospital, Uppsala, Sweden; Ludwig Institute for Cancer Research, Stockholm, Sweden; Health Sciences Research Facility, Department of Medicine, University of Vermont, Burlington, Vermont, USA
| | - Nina Heldring
- Departments of Molecular Medicine and Surgery, Cardiothoracic Surgery and Anesthesia, and Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; Department of Internal Medicine, Hematology and Oncology, University of Erlangen-Nuremberg, Erlangen, Germany; Stem Cell Research Laboratory, Section of Hematology, Department of Medicine, University of Verona, Verona, Italy; Cancer Proteomics Mass Spectrometry, Science for Life Laboratory, Department of Oncology-Pathology, Department of Medical Biochemistry and Biophysics, and Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden; Center for Diseases of Aging, Vaccine and Gene Therapy Institute Florida, Port St. Lucie, Florida, USA; Exosome Diagnostics Inc., New York, New York, USA; Departments of Cardiothoracic Surgery, Hematology, and Immunology, Genetics and Pathology, Uppsala University Hospital, Uppsala, Sweden; Ludwig Institute for Cancer Research, Stockholm, Sweden; Health Sciences Research Facility, Department of Medicine, University of Vermont, Burlington, Vermont, USA
| | - Giulio Bassi
- Departments of Molecular Medicine and Surgery, Cardiothoracic Surgery and Anesthesia, and Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; Department of Internal Medicine, Hematology and Oncology, University of Erlangen-Nuremberg, Erlangen, Germany; Stem Cell Research Laboratory, Section of Hematology, Department of Medicine, University of Verona, Verona, Italy; Cancer Proteomics Mass Spectrometry, Science for Life Laboratory, Department of Oncology-Pathology, Department of Medical Biochemistry and Biophysics, and Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden; Center for Diseases of Aging, Vaccine and Gene Therapy Institute Florida, Port St. Lucie, Florida, USA; Exosome Diagnostics Inc., New York, New York, USA; Departments of Cardiothoracic Surgery, Hematology, and Immunology, Genetics and Pathology, Uppsala University Hospital, Uppsala, Sweden; Ludwig Institute for Cancer Research, Stockholm, Sweden; Health Sciences Research Facility, Department of Medicine, University of Vermont, Burlington, Vermont, USA
| | - Henrik J Johansson
- Departments of Molecular Medicine and Surgery, Cardiothoracic Surgery and Anesthesia, and Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; Department of Internal Medicine, Hematology and Oncology, University of Erlangen-Nuremberg, Erlangen, Germany; Stem Cell Research Laboratory, Section of Hematology, Department of Medicine, University of Verona, Verona, Italy; Cancer Proteomics Mass Spectrometry, Science for Life Laboratory, Department of Oncology-Pathology, Department of Medical Biochemistry and Biophysics, and Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden; Center for Diseases of Aging, Vaccine and Gene Therapy Institute Florida, Port St. Lucie, Florida, USA; Exosome Diagnostics Inc., New York, New York, USA; Departments of Cardiothoracic Surgery, Hematology, and Immunology, Genetics and Pathology, Uppsala University Hospital, Uppsala, Sweden; Ludwig Institute for Cancer Research, Stockholm, Sweden; Health Sciences Research Facility, Department of Medicine, University of Vermont, Burlington, Vermont, USA
| | - Magnus Dalén
- Departments of Molecular Medicine and Surgery, Cardiothoracic Surgery and Anesthesia, and Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; Department of Internal Medicine, Hematology and Oncology, University of Erlangen-Nuremberg, Erlangen, Germany; Stem Cell Research Laboratory, Section of Hematology, Department of Medicine, University of Verona, Verona, Italy; Cancer Proteomics Mass Spectrometry, Science for Life Laboratory, Department of Oncology-Pathology, Department of Medical Biochemistry and Biophysics, and Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden; Center for Diseases of Aging, Vaccine and Gene Therapy Institute Florida, Port St. Lucie, Florida, USA; Exosome Diagnostics Inc., New York, New York, USA; Departments of Cardiothoracic Surgery, Hematology, and Immunology, Genetics and Pathology, Uppsala University Hospital, Uppsala, Sweden; Ludwig Institute for Cancer Research, Stockholm, Sweden; Health Sciences Research Facility, Department of Medicine, University of Vermont, Burlington, Vermont, USA
| | - Regina Jitschin
- Departments of Molecular Medicine and Surgery, Cardiothoracic Surgery and Anesthesia, and Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; Department of Internal Medicine, Hematology and Oncology, University of Erlangen-Nuremberg, Erlangen, Germany; Stem Cell Research Laboratory, Section of Hematology, Department of Medicine, University of Verona, Verona, Italy; Cancer Proteomics Mass Spectrometry, Science for Life Laboratory, Department of Oncology-Pathology, Department of Medical Biochemistry and Biophysics, and Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden; Center for Diseases of Aging, Vaccine and Gene Therapy Institute Florida, Port St. Lucie, Florida, USA; Exosome Diagnostics Inc., New York, New York, USA; Departments of Cardiothoracic Surgery, Hematology, and Immunology, Genetics and Pathology, Uppsala University Hospital, Uppsala, Sweden; Ludwig Institute for Cancer Research, Stockholm, Sweden; Health Sciences Research Facility, Department of Medicine, University of Vermont, Burlington, Vermont, USA
| | - Sergey Rodin
- Departments of Molecular Medicine and Surgery, Cardiothoracic Surgery and Anesthesia, and Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; Department of Internal Medicine, Hematology and Oncology, University of Erlangen-Nuremberg, Erlangen, Germany; Stem Cell Research Laboratory, Section of Hematology, Department of Medicine, University of Verona, Verona, Italy; Cancer Proteomics Mass Spectrometry, Science for Life Laboratory, Department of Oncology-Pathology, Department of Medical Biochemistry and Biophysics, and Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden; Center for Diseases of Aging, Vaccine and Gene Therapy Institute Florida, Port St. Lucie, Florida, USA; Exosome Diagnostics Inc., New York, New York, USA; Departments of Cardiothoracic Surgery, Hematology, and Immunology, Genetics and Pathology, Uppsala University Hospital, Uppsala, Sweden; Ludwig Institute for Cancer Research, Stockholm, Sweden; Health Sciences Research Facility, Department of Medicine, University of Vermont, Burlington, Vermont, USA
| | - Matthias Corbascio
- Departments of Molecular Medicine and Surgery, Cardiothoracic Surgery and Anesthesia, and Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; Department of Internal Medicine, Hematology and Oncology, University of Erlangen-Nuremberg, Erlangen, Germany; Stem Cell Research Laboratory, Section of Hematology, Department of Medicine, University of Verona, Verona, Italy; Cancer Proteomics Mass Spectrometry, Science for Life Laboratory, Department of Oncology-Pathology, Department of Medical Biochemistry and Biophysics, and Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden; Center for Diseases of Aging, Vaccine and Gene Therapy Institute Florida, Port St. Lucie, Florida, USA; Exosome Diagnostics Inc., New York, New York, USA; Departments of Cardiothoracic Surgery, Hematology, and Immunology, Genetics and Pathology, Uppsala University Hospital, Uppsala, Sweden; Ludwig Institute for Cancer Research, Stockholm, Sweden; Health Sciences Research Facility, Department of Medicine, University of Vermont, Burlington, Vermont, USA
| | - Samir El Andaloussi
- Departments of Molecular Medicine and Surgery, Cardiothoracic Surgery and Anesthesia, and Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; Department of Internal Medicine, Hematology and Oncology, University of Erlangen-Nuremberg, Erlangen, Germany; Stem Cell Research Laboratory, Section of Hematology, Department of Medicine, University of Verona, Verona, Italy; Cancer Proteomics Mass Spectrometry, Science for Life Laboratory, Department of Oncology-Pathology, Department of Medical Biochemistry and Biophysics, and Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden; Center for Diseases of Aging, Vaccine and Gene Therapy Institute Florida, Port St. Lucie, Florida, USA; Exosome Diagnostics Inc., New York, New York, USA; Departments of Cardiothoracic Surgery, Hematology, and Immunology, Genetics and Pathology, Uppsala University Hospital, Uppsala, Sweden; Ludwig Institute for Cancer Research, Stockholm, Sweden; Health Sciences Research Facility, Department of Medicine, University of Vermont, Burlington, Vermont, USA
| | - Oscar P B Wiklander
- Departments of Molecular Medicine and Surgery, Cardiothoracic Surgery and Anesthesia, and Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; Department of Internal Medicine, Hematology and Oncology, University of Erlangen-Nuremberg, Erlangen, Germany; Stem Cell Research Laboratory, Section of Hematology, Department of Medicine, University of Verona, Verona, Italy; Cancer Proteomics Mass Spectrometry, Science for Life Laboratory, Department of Oncology-Pathology, Department of Medical Biochemistry and Biophysics, and Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden; Center for Diseases of Aging, Vaccine and Gene Therapy Institute Florida, Port St. Lucie, Florida, USA; Exosome Diagnostics Inc., New York, New York, USA; Departments of Cardiothoracic Surgery, Hematology, and Immunology, Genetics and Pathology, Uppsala University Hospital, Uppsala, Sweden; Ludwig Institute for Cancer Research, Stockholm, Sweden; Health Sciences Research Facility, Department of Medicine, University of Vermont, Burlington, Vermont, USA
| | - Joel Z Nordin
- Departments of Molecular Medicine and Surgery, Cardiothoracic Surgery and Anesthesia, and Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; Department of Internal Medicine, Hematology and Oncology, University of Erlangen-Nuremberg, Erlangen, Germany; Stem Cell Research Laboratory, Section of Hematology, Department of Medicine, University of Verona, Verona, Italy; Cancer Proteomics Mass Spectrometry, Science for Life Laboratory, Department of Oncology-Pathology, Department of Medical Biochemistry and Biophysics, and Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden; Center for Diseases of Aging, Vaccine and Gene Therapy Institute Florida, Port St. Lucie, Florida, USA; Exosome Diagnostics Inc., New York, New York, USA; Departments of Cardiothoracic Surgery, Hematology, and Immunology, Genetics and Pathology, Uppsala University Hospital, Uppsala, Sweden; Ludwig Institute for Cancer Research, Stockholm, Sweden; Health Sciences Research Facility, Department of Medicine, University of Vermont, Burlington, Vermont, USA
| | - Johan Skog
- Departments of Molecular Medicine and Surgery, Cardiothoracic Surgery and Anesthesia, and Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; Department of Internal Medicine, Hematology and Oncology, University of Erlangen-Nuremberg, Erlangen, Germany; Stem Cell Research Laboratory, Section of Hematology, Department of Medicine, University of Verona, Verona, Italy; Cancer Proteomics Mass Spectrometry, Science for Life Laboratory, Department of Oncology-Pathology, Department of Medical Biochemistry and Biophysics, and Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden; Center for Diseases of Aging, Vaccine and Gene Therapy Institute Florida, Port St. Lucie, Florida, USA; Exosome Diagnostics Inc., New York, New York, USA; Departments of Cardiothoracic Surgery, Hematology, and Immunology, Genetics and Pathology, Uppsala University Hospital, Uppsala, Sweden; Ludwig Institute for Cancer Research, Stockholm, Sweden; Health Sciences Research Facility, Department of Medicine, University of Vermont, Burlington, Vermont, USA
| | - Charlotte Romain
- Departments of Molecular Medicine and Surgery, Cardiothoracic Surgery and Anesthesia, and Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; Department of Internal Medicine, Hematology and Oncology, University of Erlangen-Nuremberg, Erlangen, Germany; Stem Cell Research Laboratory, Section of Hematology, Department of Medicine, University of Verona, Verona, Italy; Cancer Proteomics Mass Spectrometry, Science for Life Laboratory, Department of Oncology-Pathology, Department of Medical Biochemistry and Biophysics, and Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden; Center for Diseases of Aging, Vaccine and Gene Therapy Institute Florida, Port St. Lucie, Florida, USA; Exosome Diagnostics Inc., New York, New York, USA; Departments of Cardiothoracic Surgery, Hematology, and Immunology, Genetics and Pathology, Uppsala University Hospital, Uppsala, Sweden; Ludwig Institute for Cancer Research, Stockholm, Sweden; Health Sciences Research Facility, Department of Medicine, University of Vermont, Burlington, Vermont, USA
| | - Tina Koestler
- Departments of Molecular Medicine and Surgery, Cardiothoracic Surgery and Anesthesia, and Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; Department of Internal Medicine, Hematology and Oncology, University of Erlangen-Nuremberg, Erlangen, Germany; Stem Cell Research Laboratory, Section of Hematology, Department of Medicine, University of Verona, Verona, Italy; Cancer Proteomics Mass Spectrometry, Science for Life Laboratory, Department of Oncology-Pathology, Department of Medical Biochemistry and Biophysics, and Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden; Center for Diseases of Aging, Vaccine and Gene Therapy Institute Florida, Port St. Lucie, Florida, USA; Exosome Diagnostics Inc., New York, New York, USA; Departments of Cardiothoracic Surgery, Hematology, and Immunology, Genetics and Pathology, Uppsala University Hospital, Uppsala, Sweden; Ludwig Institute for Cancer Research, Stockholm, Sweden; Health Sciences Research Facility, Department of Medicine, University of Vermont, Burlington, Vermont, USA
| | - Laila Hellgren-Johansson
- Departments of Molecular Medicine and Surgery, Cardiothoracic Surgery and Anesthesia, and Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; Department of Internal Medicine, Hematology and Oncology, University of Erlangen-Nuremberg, Erlangen, Germany; Stem Cell Research Laboratory, Section of Hematology, Department of Medicine, University of Verona, Verona, Italy; Cancer Proteomics Mass Spectrometry, Science for Life Laboratory, Department of Oncology-Pathology, Department of Medical Biochemistry and Biophysics, and Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden; Center for Diseases of Aging, Vaccine and Gene Therapy Institute Florida, Port St. Lucie, Florida, USA; Exosome Diagnostics Inc., New York, New York, USA; Departments of Cardiothoracic Surgery, Hematology, and Immunology, Genetics and Pathology, Uppsala University Hospital, Uppsala, Sweden; Ludwig Institute for Cancer Research, Stockholm, Sweden; Health Sciences Research Facility, Department of Medicine, University of Vermont, Burlington, Vermont, USA
| | - Petter Schiller
- Departments of Molecular Medicine and Surgery, Cardiothoracic Surgery and Anesthesia, and Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; Department of Internal Medicine, Hematology and Oncology, University of Erlangen-Nuremberg, Erlangen, Germany; Stem Cell Research Laboratory, Section of Hematology, Department of Medicine, University of Verona, Verona, Italy; Cancer Proteomics Mass Spectrometry, Science for Life Laboratory, Department of Oncology-Pathology, Department of Medical Biochemistry and Biophysics, and Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden; Center for Diseases of Aging, Vaccine and Gene Therapy Institute Florida, Port St. Lucie, Florida, USA; Exosome Diagnostics Inc., New York, New York, USA; Departments of Cardiothoracic Surgery, Hematology, and Immunology, Genetics and Pathology, Uppsala University Hospital, Uppsala, Sweden; Ludwig Institute for Cancer Research, Stockholm, Sweden; Health Sciences Research Facility, Department of Medicine, University of Vermont, Burlington, Vermont, USA
| | - Per-Olof Joachimsson
- Departments of Molecular Medicine and Surgery, Cardiothoracic Surgery and Anesthesia, and Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; Department of Internal Medicine, Hematology and Oncology, University of Erlangen-Nuremberg, Erlangen, Germany; Stem Cell Research Laboratory, Section of Hematology, Department of Medicine, University of Verona, Verona, Italy; Cancer Proteomics Mass Spectrometry, Science for Life Laboratory, Department of Oncology-Pathology, Department of Medical Biochemistry and Biophysics, and Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden; Center for Diseases of Aging, Vaccine and Gene Therapy Institute Florida, Port St. Lucie, Florida, USA; Exosome Diagnostics Inc., New York, New York, USA; Departments of Cardiothoracic Surgery, Hematology, and Immunology, Genetics and Pathology, Uppsala University Hospital, Uppsala, Sweden; Ludwig Institute for Cancer Research, Stockholm, Sweden; Health Sciences Research Facility, Department of Medicine, University of Vermont, Burlington, Vermont, USA
| | - Hans Hägglund
- Departments of Molecular Medicine and Surgery, Cardiothoracic Surgery and Anesthesia, and Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; Department of Internal Medicine, Hematology and Oncology, University of Erlangen-Nuremberg, Erlangen, Germany; Stem Cell Research Laboratory, Section of Hematology, Department of Medicine, University of Verona, Verona, Italy; Cancer Proteomics Mass Spectrometry, Science for Life Laboratory, Department of Oncology-Pathology, Department of Medical Biochemistry and Biophysics, and Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden; Center for Diseases of Aging, Vaccine and Gene Therapy Institute Florida, Port St. Lucie, Florida, USA; Exosome Diagnostics Inc., New York, New York, USA; Departments of Cardiothoracic Surgery, Hematology, and Immunology, Genetics and Pathology, Uppsala University Hospital, Uppsala, Sweden; Ludwig Institute for Cancer Research, Stockholm, Sweden; Health Sciences Research Facility, Department of Medicine, University of Vermont, Burlington, Vermont, USA
| | - Mattias Mattsson
- Departments of Molecular Medicine and Surgery, Cardiothoracic Surgery and Anesthesia, and Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; Department of Internal Medicine, Hematology and Oncology, University of Erlangen-Nuremberg, Erlangen, Germany; Stem Cell Research Laboratory, Section of Hematology, Department of Medicine, University of Verona, Verona, Italy; Cancer Proteomics Mass Spectrometry, Science for Life Laboratory, Department of Oncology-Pathology, Department of Medical Biochemistry and Biophysics, and Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden; Center for Diseases of Aging, Vaccine and Gene Therapy Institute Florida, Port St. Lucie, Florida, USA; Exosome Diagnostics Inc., New York, New York, USA; Departments of Cardiothoracic Surgery, Hematology, and Immunology, Genetics and Pathology, Uppsala University Hospital, Uppsala, Sweden; Ludwig Institute for Cancer Research, Stockholm, Sweden; Health Sciences Research Facility, Department of Medicine, University of Vermont, Burlington, Vermont, USA
| | - Janne Lehtiö
- Departments of Molecular Medicine and Surgery, Cardiothoracic Surgery and Anesthesia, and Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; Department of Internal Medicine, Hematology and Oncology, University of Erlangen-Nuremberg, Erlangen, Germany; Stem Cell Research Laboratory, Section of Hematology, Department of Medicine, University of Verona, Verona, Italy; Cancer Proteomics Mass Spectrometry, Science for Life Laboratory, Department of Oncology-Pathology, Department of Medical Biochemistry and Biophysics, and Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden; Center for Diseases of Aging, Vaccine and Gene Therapy Institute Florida, Port St. Lucie, Florida, USA; Exosome Diagnostics Inc., New York, New York, USA; Departments of Cardiothoracic Surgery, Hematology, and Immunology, Genetics and Pathology, Uppsala University Hospital, Uppsala, Sweden; Ludwig Institute for Cancer Research, Stockholm, Sweden; Health Sciences Research Facility, Department of Medicine, University of Vermont, Burlington, Vermont, USA
| | - Omid R Faridani
- Departments of Molecular Medicine and Surgery, Cardiothoracic Surgery and Anesthesia, and Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; Department of Internal Medicine, Hematology and Oncology, University of Erlangen-Nuremberg, Erlangen, Germany; Stem Cell Research Laboratory, Section of Hematology, Department of Medicine, University of Verona, Verona, Italy; Cancer Proteomics Mass Spectrometry, Science for Life Laboratory, Department of Oncology-Pathology, Department of Medical Biochemistry and Biophysics, and Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden; Center for Diseases of Aging, Vaccine and Gene Therapy Institute Florida, Port St. Lucie, Florida, USA; Exosome Diagnostics Inc., New York, New York, USA; Departments of Cardiothoracic Surgery, Hematology, and Immunology, Genetics and Pathology, Uppsala University Hospital, Uppsala, Sweden; Ludwig Institute for Cancer Research, Stockholm, Sweden; Health Sciences Research Facility, Department of Medicine, University of Vermont, Burlington, Vermont, USA
| | - Rickard Sandberg
- Departments of Molecular Medicine and Surgery, Cardiothoracic Surgery and Anesthesia, and Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; Department of Internal Medicine, Hematology and Oncology, University of Erlangen-Nuremberg, Erlangen, Germany; Stem Cell Research Laboratory, Section of Hematology, Department of Medicine, University of Verona, Verona, Italy; Cancer Proteomics Mass Spectrometry, Science for Life Laboratory, Department of Oncology-Pathology, Department of Medical Biochemistry and Biophysics, and Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden; Center for Diseases of Aging, Vaccine and Gene Therapy Institute Florida, Port St. Lucie, Florida, USA; Exosome Diagnostics Inc., New York, New York, USA; Departments of Cardiothoracic Surgery, Hematology, and Immunology, Genetics and Pathology, Uppsala University Hospital, Uppsala, Sweden; Ludwig Institute for Cancer Research, Stockholm, Sweden; Health Sciences Research Facility, Department of Medicine, University of Vermont, Burlington, Vermont, USA
| | - Olle Korsgren
- Departments of Molecular Medicine and Surgery, Cardiothoracic Surgery and Anesthesia, and Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; Department of Internal Medicine, Hematology and Oncology, University of Erlangen-Nuremberg, Erlangen, Germany; Stem Cell Research Laboratory, Section of Hematology, Department of Medicine, University of Verona, Verona, Italy; Cancer Proteomics Mass Spectrometry, Science for Life Laboratory, Department of Oncology-Pathology, Department of Medical Biochemistry and Biophysics, and Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden; Center for Diseases of Aging, Vaccine and Gene Therapy Institute Florida, Port St. Lucie, Florida, USA; Exosome Diagnostics Inc., New York, New York, USA; Departments of Cardiothoracic Surgery, Hematology, and Immunology, Genetics and Pathology, Uppsala University Hospital, Uppsala, Sweden; Ludwig Institute for Cancer Research, Stockholm, Sweden; Health Sciences Research Facility, Department of Medicine, University of Vermont, Burlington, Vermont, USA
| | - Mauro Krampera
- Departments of Molecular Medicine and Surgery, Cardiothoracic Surgery and Anesthesia, and Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; Department of Internal Medicine, Hematology and Oncology, University of Erlangen-Nuremberg, Erlangen, Germany; Stem Cell Research Laboratory, Section of Hematology, Department of Medicine, University of Verona, Verona, Italy; Cancer Proteomics Mass Spectrometry, Science for Life Laboratory, Department of Oncology-Pathology, Department of Medical Biochemistry and Biophysics, and Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden; Center for Diseases of Aging, Vaccine and Gene Therapy Institute Florida, Port St. Lucie, Florida, USA; Exosome Diagnostics Inc., New York, New York, USA; Departments of Cardiothoracic Surgery, Hematology, and Immunology, Genetics and Pathology, Uppsala University Hospital, Uppsala, Sweden; Ludwig Institute for Cancer Research, Stockholm, Sweden; Health Sciences Research Facility, Department of Medicine, University of Vermont, Burlington, Vermont, USA
| | - Daniel J Weiss
- Departments of Molecular Medicine and Surgery, Cardiothoracic Surgery and Anesthesia, and Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; Department of Internal Medicine, Hematology and Oncology, University of Erlangen-Nuremberg, Erlangen, Germany; Stem Cell Research Laboratory, Section of Hematology, Department of Medicine, University of Verona, Verona, Italy; Cancer Proteomics Mass Spectrometry, Science for Life Laboratory, Department of Oncology-Pathology, Department of Medical Biochemistry and Biophysics, and Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden; Center for Diseases of Aging, Vaccine and Gene Therapy Institute Florida, Port St. Lucie, Florida, USA; Exosome Diagnostics Inc., New York, New York, USA; Departments of Cardiothoracic Surgery, Hematology, and Immunology, Genetics and Pathology, Uppsala University Hospital, Uppsala, Sweden; Ludwig Institute for Cancer Research, Stockholm, Sweden; Health Sciences Research Facility, Department of Medicine, University of Vermont, Burlington, Vermont, USA
| | - Karl-Henrik Grinnemo
- Departments of Molecular Medicine and Surgery, Cardiothoracic Surgery and Anesthesia, and Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; Department of Internal Medicine, Hematology and Oncology, University of Erlangen-Nuremberg, Erlangen, Germany; Stem Cell Research Laboratory, Section of Hematology, Department of Medicine, University of Verona, Verona, Italy; Cancer Proteomics Mass Spectrometry, Science for Life Laboratory, Department of Oncology-Pathology, Department of Medical Biochemistry and Biophysics, and Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden; Center for Diseases of Aging, Vaccine and Gene Therapy Institute Florida, Port St. Lucie, Florida, USA; Exosome Diagnostics Inc., New York, New York, USA; Departments of Cardiothoracic Surgery, Hematology, and Immunology, Genetics and Pathology, Uppsala University Hospital, Uppsala, Sweden; Ludwig Institute for Cancer Research, Stockholm, Sweden; Health Sciences Research Facility, Department of Medicine, University of Vermont, Burlington, Vermont, USA
| | - Katarina Le Blanc
- Departments of Molecular Medicine and Surgery, Cardiothoracic Surgery and Anesthesia, and Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; Department of Internal Medicine, Hematology and Oncology, University of Erlangen-Nuremberg, Erlangen, Germany; Stem Cell Research Laboratory, Section of Hematology, Department of Medicine, University of Verona, Verona, Italy; Cancer Proteomics Mass Spectrometry, Science for Life Laboratory, Department of Oncology-Pathology, Department of Medical Biochemistry and Biophysics, and Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden; Center for Diseases of Aging, Vaccine and Gene Therapy Institute Florida, Port St. Lucie, Florida, USA; Exosome Diagnostics Inc., New York, New York, USA; Departments of Cardiothoracic Surgery, Hematology, and Immunology, Genetics and Pathology, Uppsala University Hospital, Uppsala, Sweden; Ludwig Institute for Cancer Research, Stockholm, Sweden; Health Sciences Research Facility, Department of Medicine, University of Vermont, Burlington, Vermont, USA
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Restuccia A, Tian YF, Collier JH, Hudalla GA. Self-assembled glycopeptide nanofibers as modulators of galectin-1 bioactivity. Cell Mol Bioeng 2015; 8:471-487. [PMID: 26495044 DOI: 10.1007/s12195-015-0399-2] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Galectins are carbohydrate-binding proteins that act as extracellular signaling molecules in various normal and pathological processes. Galectin bioactivity is mediated by specific non-covalent interactions with cell-surface and extracellular matrix (ECM) glycoproteins, which can enhance or inhibit signaling events that influence various cellular behaviors, including adhesion, proliferation, differentiation, and apoptosis. Here, we developed a materials approach to modulate galectin bioactivity by mimicking natural galectin-glycoprotein interactions. Specifically, we created a variant of a peptide that self-assembles into β-sheet nanofibers under aqueous conditions, QQKFQFQFEQQ (Q11), which has an asparagine residue modified with the monosaccharide N-acetylglucosamine (GlcNAc) at its N-terminus (GlcNAc-Q11). GlcNAc-Q11 self-assembled into β-sheet nanofibers under similar conditions as Q11. Nanofibrillar GlcNAc moieties were efficiently converted to the galectin-binding disaccharide N-acetyllactosamine (LacNAc) via the enzyme β-1,4-galactosyltransferase and the sugar donor UDP-galactose, while retaining β-sheet structure and nanofiber morphology. LacNAc-Q11 nanofibers bound galectin-1 and -3 in a LacNAc concentration-dependent manner, although nanofibers bound galectin-1 with higher affinity than galectin-3. In contrast, galectin-1 bound weakly to GlcNAc-Q11 nanofibers, while no galectin-3 binding to these nanofibers was observed. Galectin-1 binding to LacNAc-Q11 nanofibers was specific because it could be inhibited by excess soluble β-lactose, a galectin-binding carbohydrate. LacNAc-Q11 nanofibers inhibited galectin-1-mediated apoptosis of Jurkat T cells in a LacNAc concentration-dependent manner, but were unable to inhibit galectin-3 activity, consistent with galectin-binding affinity of the nanofibers. We envision that glycopeptide nanofibers capable of modulating galectin-1 bioactivity will be broadly useful as biomaterials for various medical applications, including cancer therapeutics, immunotherapy, tissue regeneration, and viral prophylaxis.
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Affiliation(s)
| | - Ye F Tian
- Department of Surgery, University of Chicago. ; Department of Biomedical Engineering, Illinois Institute of Technology
| | | | - Gregory A Hudalla
- J. Crayton Pruitt Family Department of Biomedical Engineering. ; Department of Surgery, University of Chicago
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Galectin-1 Protein Therapy Prevents Pathology and Improves Muscle Function in the mdx Mouse Model of Duchenne Muscular Dystrophy. Mol Ther 2015; 23:1285-1297. [PMID: 26050991 DOI: 10.1038/mt.2015.105] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2014] [Accepted: 05/27/2015] [Indexed: 12/17/2022] Open
Abstract
Duchenne muscular dystrophy (DMD) is a fatal neuromuscular disease caused by mutations in the dystrophin gene, leading to the loss of a critical component of the sarcolemmal dystrophin glycoprotein complex. Galectin-1 is a small 14 kDa protein normally found in skeletal muscle and has been shown to be a modifier of immune response, muscle repair, and apoptosis. Galectin-1 levels are elevated in the muscle of mouse and dog models of DMD. Together, these findings led us to hypothesize that Galectin-1 may serve as a modifier of disease progression in DMD. To test this hypothesis, recombinant mouse Galectin-1 was produced and used to treat myogenic cells and the mdx mouse model of DMD. Here we show that intramuscular and intraperitoneal injections of Galectin-1 into mdx mice prevented pathology and improved muscle function in skeletal muscle. These improvements were a result of enhanced sarcolemmal stability mediated by elevated utrophin and α7β1 integrin protein levels. Together our results demonstrate for the first time that Galectin-1 may serve as an exciting new protein therapeutic for the treatment of DMD.
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Westgren M, Götherström C. Stem cell transplantation before birth - a realistic option for treatment of osteogenesis imperfecta? Prenat Diagn 2015; 35:827-32. [PMID: 25962526 DOI: 10.1002/pd.4611] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2014] [Revised: 04/28/2015] [Accepted: 04/28/2015] [Indexed: 01/17/2023]
Abstract
Osteogenesis imperfecta (OI) is characterized by severe bone deformities, growth retardation and bones that break easily, often from little or no apparent cause. OI is a genetic disorder primarily with defective type I collagen with a wide spectrum of clinical expression. In the more severe cases, it can be diagnosed before birth. Transplantation of mesenchymal stem cells (MSC) has the potential to improve the bone structure and stability, growth and fracture healing. Prenatal and postnatal cell transplantation has been investigated in preclinical and clinical studies of OI and suggests that this procedure is safe and has positive effects. Cell transplantation resulted in improved linear growth, mobility and reduced fracture incidence. However, the effect is transient and for this reason re-transplantation may be needed. So far there is limited experience in this area, and proper studies are required to accurately determine if MSC transplantation is of clinical benefit in the treatment of OI. In this review, we summarize what is currently known in this field.
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Affiliation(s)
- Magnus Westgren
- Center for Fetal Medicine, Karolinska University Hospital, Stockholm, Sweden.,Division of Obstetrics and Gynaecology, Karolinska Institutet, Stockholm, Sweden
| | - Cecilia Götherström
- Division of Obstetrics and Gynaecology, Karolinska Institutet, Stockholm, Sweden.,Center for Haematology and Regenerative Medicine, Karolinska Institutet, Stockholm, Sweden
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Systemic delivery of human bone marrow embryonic-like stem cells improves motor function of severely affected dystrophin/utrophin–deficient mice. Cytotherapy 2014; 16:1739-49. [DOI: 10.1016/j.jcyt.2014.08.013] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2014] [Revised: 08/18/2014] [Accepted: 08/24/2014] [Indexed: 01/07/2023]
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Chan JKY, Götherström C. Prenatal transplantation of mesenchymal stem cells to treat osteogenesis imperfecta. Front Pharmacol 2014; 5:223. [PMID: 25346689 PMCID: PMC4191163 DOI: 10.3389/fphar.2014.00223] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2014] [Accepted: 09/16/2014] [Indexed: 12/28/2022] Open
Abstract
Osteogenesis imperfecta (OI) can be a severe disorder that can be diagnosed before birth. Transplantation of mesenchymal stem cells (MSC) has the potential to improve the bone structure, growth, and fracture healing. In this review, we give an introduction to OI and MSC, and the basis for pre- and postnatal transplantation in OI. We also summarize the two patients with OI who have received pre- and postnatal transplantation of MSC. The findings suggest that prenatal transplantation of allogeneic MSC in OI is safe. The cell therapy is of likely clinical benefit with improved linear growth, mobility, and reduced fracture incidence. Unfortunately, the effect is transient. For this reason, postnatal booster infusions using same-donor MSC have been performed with clinical benefit, and without any adverse events. So far there is limited experience in this specific field and proper studies are required to accurately conclude on clinical benefits of MSC transplantation to treat OI.
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Affiliation(s)
- Jerry K Y Chan
- Experimental Fetal Medicine Group, Department of Obstetrics and Gynecology, Yong Loo Lin School of Medicine and National University of Singapore , Singapore, Singapore ; Department of Reproductive Medicine, KK Women's and Children's Hospital, Singapore , Singapore ; Cancer and Stem Cell Biology, Duke-National University of Singapore Graduate Medical School, Singapore , Singapore
| | - Cecilia Götherström
- Division for Obstetrics and Gynecology, Department of Clinical Science Intervention and Technology, Karolinska Institutet , Stockholm, Sweden ; Center for Hematology and Regenerative Medicine, Karolinska Institutet , Stockholm, Sweden
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Heazlewood CF, Sherrell H, Ryan J, Atkinson K, Wells CA, Fisk NM. High incidence of contaminating maternal cell overgrowth in human placental mesenchymal stem/stromal cell cultures: a systematic review. Stem Cells Transl Med 2014; 3:1305-11. [PMID: 25154781 DOI: 10.5966/sctm.2014-0051] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Abstract
Placenta is a readily accessible translationally advantageous source of mesenchymal stem/stromal cells (MSCs) currently used in cryobanking and clinical trials. MSCs cultured from human chorion have been widely assumed to be fetal in origin, despite evidence that placental MSCs may be contaminated with maternal cells, resulting in entirely maternally derived MSC cultures. To document the frequency and determinants of maternal cell contamination in chorionic MSCs, we undertook a PRISMA-compliant systematic review of publications in the PubMed, Medline, and Embase databases (January 2000 to July 2013) on placental and/or chorionic MSCs from uncomplicated pregnancies. Of 147 studies, only 26 (18%) investigated fetal and/or maternal cell origin. After excluding studies that did not satisfy minimal MSC criteria, 7 of 15 informative studies documented MSC cultures as entirely fetal, a further 7 studies reported cultured human chorionic MSC populations to be either maternal (n=6) or mixed (n=1), whereas 1 study separately cultured pure fetal and pure maternal MSC from the same placenta. Maternal cell contamination was associated with term and chorionic membrane samples and greater passage number but was still present in 30% of studies of chorionic villous MSCs. Although most studies assume fetal origin for MSCs sourced from chorion, this systematic review documents a high incidence of maternal-origin MSC populations in placental MSC cultures. Given that fetal MSCs have more primitive properties than adult MSCs, our findings have implications for clinical trials in which knowledge of donor and tissue source is pivotal. We recommend sensitive methods to quantitate the source and purity of placental MSCs.
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Affiliation(s)
- Celena F Heazlewood
- Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Brisbane, Queensland, Australia; University of Queensland Centre for Clinical Research, University of Queensland, Institute of Health and Biomedical Innovation, Queensland University of Technology at the Translational Research Institute, and Centre for Advanced Prenatal Care, Royal Brisbane & Women's Hospital, Brisbane, Queensland, Australia; Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom
| | - Helen Sherrell
- Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Brisbane, Queensland, Australia; University of Queensland Centre for Clinical Research, University of Queensland, Institute of Health and Biomedical Innovation, Queensland University of Technology at the Translational Research Institute, and Centre for Advanced Prenatal Care, Royal Brisbane & Women's Hospital, Brisbane, Queensland, Australia; Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom
| | - Jennifer Ryan
- Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Brisbane, Queensland, Australia; University of Queensland Centre for Clinical Research, University of Queensland, Institute of Health and Biomedical Innovation, Queensland University of Technology at the Translational Research Institute, and Centre for Advanced Prenatal Care, Royal Brisbane & Women's Hospital, Brisbane, Queensland, Australia; Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom
| | - Kerry Atkinson
- Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Brisbane, Queensland, Australia; University of Queensland Centre for Clinical Research, University of Queensland, Institute of Health and Biomedical Innovation, Queensland University of Technology at the Translational Research Institute, and Centre for Advanced Prenatal Care, Royal Brisbane & Women's Hospital, Brisbane, Queensland, Australia; Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom
| | - Christine A Wells
- Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Brisbane, Queensland, Australia; University of Queensland Centre for Clinical Research, University of Queensland, Institute of Health and Biomedical Innovation, Queensland University of Technology at the Translational Research Institute, and Centre for Advanced Prenatal Care, Royal Brisbane & Women's Hospital, Brisbane, Queensland, Australia; Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom
| | - Nicholas M Fisk
- Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Brisbane, Queensland, Australia; University of Queensland Centre for Clinical Research, University of Queensland, Institute of Health and Biomedical Innovation, Queensland University of Technology at the Translational Research Institute, and Centre for Advanced Prenatal Care, Royal Brisbane & Women's Hospital, Brisbane, Queensland, Australia; Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom
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Hart ML, Neumayer KMH, Vaegler M, Daum L, Amend B, Sievert KD, Di Giovanni S, Kraushaar U, Guenther E, Stenzl A, Aicher WK. Cell-based therapy for the deficient urinary sphincter. Curr Urol Rep 2014; 14:476-87. [PMID: 23824516 DOI: 10.1007/s11934-013-0352-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
When sterile culture techniques of mammalian cells first became state of the art, there was tremendous anticipation that such cells could be eventually applied for therapeutic purposes. The discovery of adult human stem or progenitor cells further motivated scientists to pursue research in cell-based therapies. Although evidence from animal studies suggests that application of cells yields measurable benefits, in urology and many other disciplines, progenitor-cell-based therapies are not yet routinely clinically available. Stress urinary incontinence (SUI) is a condition affecting a large number of patients. The etiology of SUI includes, but is not limited to, degeneration of the urinary sphincter muscle tissue and loss of innervation, as well as anatomical and biomechanical causes. Therefore, different regimens were developed to treat SUI. However, at present, a curative functional treatment is not at hand. A progenitor-cell-based therapy that can tackle the etiology of incontinence, rather than the consequences, is a promising strategy. Therefore, several research teams have intensified their efforts to develop such a therapy for incontinence. Here, we introduce candidate stem and progenitor cells suitable for SUI treatment, show how the functional homogeneity and state of maturity of differentiated cells crucial for proper tissue integration can be assessed electrophysiologically prior to their clinical application, and discuss the trophic potential of adult mesenchymal stromal (or stem) cells in regeneration of neuronal function.
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Affiliation(s)
- Melanie L Hart
- KFO273, Department of Urology, UKT, University of Tuebingen, Paul-Ehrlich-Str. 15, 72076, Tuebingen, Germany
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Ryan JM, Pettit AR, Guillot PV, Chan JKY, Fisk NM. Unravelling the pluripotency paradox in fetal and placental mesenchymal stem cells: Oct-4 expression and the case of The Emperor's New Clothes. Stem Cell Rev Rep 2014; 9:408-21. [PMID: 22161644 DOI: 10.1007/s12015-011-9336-5] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Mesenchymal stem cells (MSC) from fetal-placental tissues have translational advantages over their adult counterparts, and have variably been reported to express pluripotency markers. OCT-4 expression in fetal-placental MSC has been documented in some studies, paradoxically without tumourogenicity in vivo. It is possible that OCT-4 expression is insufficient to induce true "stemness", but this issue is important for the translational safety of fetal-derived MSC. To clarify this, we undertook a systematic literature review on OCT-4 in fetal or adnexal MSC to show that most studies report OCT-4 message or protein expression, but no study provides definitive evidence of true OCT-4A expression. Discrepant findings were attributable not to different culture conditions, tissue sources, or gestational ages but instead to techniques used. In assessing OCT-4 as a pluripotency marker, we highlight the challenges in detecting the correct OCT-4 isoform (OCT-4A) associated with pluripotency. Although specific detection of OCT-4A mRNA is achievable, it appears unlikely that any antibody can reliably distinguish between OCT-4A and the pseudogene OCT-4B. Finally, using five robust techniques we demonstrate that fetal derived-MSC do not express OCT-4A (or by default OCT-4B). Reports suggesting OCT-4 expression in fetal-derived MSC warrant reassessment, paying attention to gene and protein isoforms, pseudogenes, and antibody choice as well as primer design. Critical examination of the OCT-4 literature leads us to suggest that OCT-4 expression in fetal MSC may be a case of "The Emperor's New Clothes" with early reports of (false) positive expression amplified in subsequent studies without critical attention to emerging refinements in knowledge and methodology.
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Affiliation(s)
- Jennifer M Ryan
- UQ Centre for Clinical Research, University of Queensland, Herston campus, Brisbane 4029, Australia.
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Al-Salam S, Hashmi S. Galectin-1 in early acute myocardial infarction. PLoS One 2014; 9:e86994. [PMID: 24498007 PMCID: PMC3909026 DOI: 10.1371/journal.pone.0086994] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2013] [Accepted: 12/17/2013] [Indexed: 02/02/2023] Open
Abstract
Myocardial infarction (MI) is the most serious manifestation of coronary artery disease and the cause of significant mortality and morbidity worldwide. Galectin-1(GAL-1), a divalent 14.5-kDa protein, is present both inside and outside cells, and has both intracellular and extracellular functions. Hypoxia inducible factor-1 alpha (HIF-1α) is a transcription factor mediating early and late responses to myocardial ischemia. Identification of the pattern of expression of GAL-1 and HIF-1α in the heart during the first 24 hours following acute MI will help in understanding early molecular changes in this event and may provide methods to overcome serious complications. Mouse model of MI was used and heart samples were processed for immunohistochemical and immunofluorescent labeling and Enzyme linked immunosorbent assay to identify GAL-1 and HIF 1α levels in the heart during the first 24 hours following MI. There was significant increase in left ventricular GAL-1 at 20 (p = 0.001) and 30 minutes (p = 0.004) following MI. There was also a significant increase in plasma GAL-1 at 4 hours (p = 0.012) and 24 hours (p = 0.001) following MI. A significant increase in left ventricular HIF-1 α was seen at 20 minutes (p = 0.047) following MI. In conclusion, we show for the first time that GAL-1 level in the left ventricle is increased in early ischemic period. We also report for the first time that HIF-1 α is significantly increased at 20 minutes following MI. In addition we report for the first time that mouse plasma GAL-1 level is significantly raised as early as 4 hours following MI.
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Affiliation(s)
- Suhail Al-Salam
- Department of Pathology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, Abu Dhabi, United Arab Emirates
- * E-mail:
| | - Satwat Hashmi
- Department of Pathology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, Abu Dhabi, United Arab Emirates
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Biphasic recruitment of microchimeric fetal mesenchymal cells in fibrosis following acute kidney injury. Kidney Int 2013; 85:600-10. [PMID: 24304884 DOI: 10.1038/ki.2013.459] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2013] [Revised: 09/03/2013] [Accepted: 09/05/2013] [Indexed: 12/19/2022]
Abstract
Fetal microchimeric cells (FMCs) enter the maternal circulation and persist in tissue for decades. They have capacity to home to injured maternal tissue and differentiate along that tissue's lineage. This raises the question of the origin(s) of cells transferred to the mother during pregnancy. FMCs with a mesenchymal phenotype have been documented in several studies, which makes mesenchymal stem cells an attractive explanation for their broad plasticity. Here we assessed the recruitment and mesenchymal lineage contribution of FMCs in response to acute kidney fibrosis induced by aristolochic acid injection. Serial in vivo bioluminescence imaging revealed a biphasic recruitment of active collagen-producing FMCs during the repair process of injured kidney in post-partum wild-type mothers that had delivered transgenic pups expressing luciferase under the collagen type I-promoter. The presence of FMCs long-term post injury (day 60) was associated with profibrotic molecules (TGF-β/CTGF), serum urea levels, and collagen deposition. Immunostaining confirmed FMCs at short term (day 15) using post-partum wild-type mothers that had delivered green fluorescent protein-positive pups and suggested a mainly hematopoietic phenotype. We conclude that there is biphasic recruitment to, and activity of, FMCs at the injury site. Moreover, we identified five types of FMC, implicating them all in the reparative process at different stages of induced renal interstitial fibrosis.
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Stern-Straeter J, Bonaterra GA, Juritz S, Birk R, Goessler UR, Bieback K, Bugert P, Schultz J, Hörmann K, Kinscherf R, Faber A. Evaluation of the effects of different culture media on the myogenic differentiation potential of adipose tissue- or bone marrow-derived human mesenchymal stem cells. Int J Mol Med 2013; 33:160-70. [PMID: 24220225 DOI: 10.3892/ijmm.2013.1555] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2013] [Accepted: 10/25/2013] [Indexed: 11/06/2022] Open
Abstract
The creation of functional muscles/muscle tissue from human stem cells is a major goal of skeletal muscle tissue engineering. Mesenchymal stem cells (MSCs) from fat/adipose tissue (AT-MSCs), as well as bone marrow (BM-MSCs) have been shown to bear myogenic potential, which makes them candidate stem cells for skeletal muscle tissue engineering applications. The aim of this study was to analyse the myogenic differentiation potential of human AT-MSCs and BM-MSCs cultured in six different cell culture media containing different mixtures of growth factors. The following cell culture media were used in our experiments: mesenchymal stem cell growth medium (MSCGM)™ as growth medium, MSCGM + 5-azacytidine (5-Aza), skeletal muscle myoblast cell growth medium (SkGM)-2 BulletKit™, and 5, 30 and 50% conditioned cell culture media, i.e., supernatant of human satellite cell cultures after three days in cell culture mixed with MSCGM. Following the incubation of human AT-MSCs or BM-MSCs for 0, 4, 8, 11, 16 or 21 days with each of the cell culture media, cell proliferation was measured using the alamarBlue® assay. Myogenic differentiation was evaluated by quantitative gene expression analyses, using quantitative RT-PCR (qRT-PCR) and immunocytochemical staining (ICC), using well-defined skeletal markers, such as desmin (DES), myogenic factor 5 (MYF5), myosin, heavy chain 8, skeletal muscle, perinatal (MYH8), myosin, heavy chain 1, skeletal muscle, adult (MYH1) and skeletal muscle actin-α1 (ACTA1). The highest proliferation rates were observed in the AT-MSCs and BM-MSCs cultured with SkGM-2 BulletKit medium. The average proliferation rate was higher in the AT-MSCs than in the BM-MSCs, taking all six culture media into account. qRT-PCR revealed the expression levels of the myogenic markers, ACTA1, MYH1 and MYH8, in the AT-MSC cell cultures, but not in the BM-MSC cultures. The muscle-specific intermediate filament, DES, was only detected (by ICC) in the AT-MSCs, but not in the BM-MSCs. The strongest DES expression was observed using the 30% conditioned cell culture medium. The detection of myogenic markers using different cell culture media as stimuli was only achieved in the AT-MSCs, but not in the BM-MSCs. The strongest myogenic differentiation, in terms of the markers examined, was induced by the 30% conditioned cell culture medium.
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Affiliation(s)
- Jens Stern-Straeter
- Department of Otorhinolaryngology, Head and Neck Surgery, Medical Faculty Mannheim, University of Heidelberg, 68167 Mannheim, Germany
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Intrinsic ability of adult stem cell in skeletal muscle: an effective and replenishable resource to the establishment of pluripotent stem cells. Stem Cells Int 2013; 2013:420164. [PMID: 23818907 PMCID: PMC3684130 DOI: 10.1155/2013/420164] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2012] [Revised: 04/03/2013] [Accepted: 05/07/2013] [Indexed: 02/06/2023] Open
Abstract
Adult stem cells play an essential role in mammalian organ maintenance and repair throughout adulthood since they ensure that organs retain their ability to regenerate. The choice of cell fate by adult stem cells for cellular proliferation, self-renewal, and differentiation into multiple lineages is critically important for the homeostasis and biological function of individual organs. Responses of stem cells to stress, injury, or environmental change are precisely regulated by intercellular and intracellular signaling networks, and these molecular events cooperatively define the ability of stem cell throughout life. Skeletal muscle tissue represents an abundant, accessible, and replenishable source of adult stem cells. Skeletal muscle contains myogenic satellite cells and muscle-derived stem cells that retain multipotent differentiation abilities. These stem cell populations have the capacity for long-term proliferation and high self-renewal. The molecular mechanisms associated with deficits in skeletal muscle and stem cell function have been extensively studied. Muscle-derived stem cells are an obvious, readily available cell resource that offers promise for cell-based therapy and various applications in the field of tissue engineering. This review describes the strategies commonly used to identify and functionally characterize adult stem cells, focusing especially on satellite cells, and discusses their potential applications.
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