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1
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Prakash N, Cha Y, Koh WG, Park H, Bello AB, Lee SH. Derivation of Mesenchymal Stem Cells through Sequential Presentation of Growth Factors via Gelatin Microparticles in Pluripotent Stem Cell Spheroids. Biomater Res 2025; 29:0184. [PMID: 40303481 PMCID: PMC12038162 DOI: 10.34133/bmr.0184] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2024] [Revised: 03/10/2025] [Accepted: 03/15/2025] [Indexed: 05/02/2025] Open
Abstract
The use of mesenchymal stem cells (MSCs) in regenerative medicine has gained considerable attention in recent years with the development of clinically relevant MSCs from induced pluripotent stem cells (iPSCs) and embryonic stem cells. Through sequential presentations of appropriate growth factors (GFs), iPSCs can be differentiated into mesodermal cells and then into MSCs. Furthermore, the formation of 3-dimensional cell spheroids, known as embryoid bodies, can be used to mimic in vivo conditions. However, the compact nature of embryoid bodies restricts the efficient and uniform delivery of GFs, leading to the formation of necrotic zones and hindered differentiation. To address this, we developed 2 types of gelatin microparticles (GelMPs) with distinct degradation rates for sequential delivery of GFs to enhance differentiation while preventing necrotic zones. In 2-dimensional culture, bone morphogenetic protein-4 (BMP4) and fibroblast growth factor 2 (FGF2) were identified as key proteins inducing iPSC differentiation into mesodermal cells and MSCs. The sequential presentation of these GFs was optimized for a 3-dimensional culture system by engineering fast-degrading GelMPs conjugated with BMP4 and slow-degrading GelMPs conjugated with FGF2. Our approach facilitated efficient iPSC differentiation into induced mesenchymal stem cells (iMSCs), as demonstrated by enhanced expression of mesodermal markers during the early stages of differentiation and MSC-specific markers at later stages. The resulting iMSCs exhibited characteristic surface markers (e.g., CD73, CD90, CD105, and CD44) and trilineage differentiation capability and were genetically stable. Compared to adult-derived MSCs, iMSCs showed superior proliferative capacity and reduced senescence, making them advantageous for cell therapy and regenerative medicine. This innovative approach of generating iMSCs has vast potential for therapeutic applications.
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Affiliation(s)
- Nityanand Prakash
- Department of Biomedical Engineering,
Dongguk University, Seoul 04620, Republic of Korea
| | - Young Cha
- Molecular Neurobiology Laboratory, McLean Hospital and Department of Psychiatry,
Harvard Medical School, Belmont, MA 02478, USA
| | - Won-Gun Koh
- Department of Chemical and Biomolecular Engineering,
Yonsei University, Seoul 03722, Republic of Korea
| | - Hansoo Park
- School of Integrative Engineering,
Chung-Ang University, Seoul 06911, Republic of Korea
| | - Alvin Bacero Bello
- Department of Biomedical Engineering,
Dongguk University, Seoul 04620, Republic of Korea
| | - Soo-Hong Lee
- Department of Biomedical Engineering,
Dongguk University, Seoul 04620, Republic of Korea
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2
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Silva B, Bragança J. Induced pluripotent stem cell-derived mesenchymal stem cells for modeling and treating metabolic associated fatty liver disease and metabolic associated steatohepatitis: Challenges and opportunities. World J Stem Cells 2025; 17:99331. [DOI: 10.4252/wjsc.v17.i2.99331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Revised: 11/21/2024] [Accepted: 01/14/2025] [Indexed: 02/24/2025] Open
Abstract
The potential of induced pluripotent stem cells (iPSCs) for modeling and treating metabolic associated fatty liver disease (MAFLD) and metabolic associated steatohepatitis (MASH) is emerging. MAFLD is a growing global health concern, currently with limited treatment options. While primary mesenchymal stem cells hold promise, iPSCs offer a versatile alternative due to their ability to differentiate into various cell types, including iPSC-derived mesenchymal stem cells. However, challenges remain, including optimizing differentiation protocols, ensuring cell safety, and addressing potential tumorigenicity risks. In addition, iPSCs offer the possibility to generate complex cellular models, including three-dimensional organoid models, which are closer representations of the human disease than animal models. Those models would also be valuable for drug discovery and personalized medicine approaches. Overall, iPSCs and their derivatives offer new perspectives for advancing MAFLD/MASH research and developing novel therapeutic strategies. Further research is needed to overcome current limitations and translate this potential into effective clinical applications.
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Affiliation(s)
- Bárbara Silva
- Algarve Biomedical Center-Research Institute, University of Algarve, Faro 8005-139, Portugal
- Algarve Biomedical Center, University of Algarve, Faro 8005-139, Portugal
- Faculty of Medicine and Biomedical Sciences, University of Algarve, Faro 8005-139, Portugal
- PhD Program in Biomedical Sciences, Faculty of Medicine and Biomedical Sciences, University of Algarve, Faro 8005-139, Portugal
| | - José Bragança
- Algarve Biomedical Center, University of Algarve, Faro 8005-139, Portugal
- Faculty of Medicine and Biomedical Sciences, University of Algarve, Faro 8005-139, Portugal
- Faculty of Medicine and Biomedical Sciences, Algarve Biomedical Center-Research Institute, University of Algarve, Faro 8005-139, Portugal
- Champalimaud Research Program, Champalimaud Centre for the Unknown, Lisbon 1000-001, Portugal
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3
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Gallo MC, Elias A, Reynolds J, Ball JR, Lieberman JR. Regional Gene Therapy for Bone Tissue Engineering: A Current Concepts Review. Bioengineering (Basel) 2025; 12:120. [PMID: 40001640 PMCID: PMC11852166 DOI: 10.3390/bioengineering12020120] [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: 12/24/2024] [Revised: 01/20/2025] [Accepted: 01/24/2025] [Indexed: 02/27/2025] Open
Abstract
The management of segmental bone defects presents a complex reconstruction challenge for orthopedic surgeons. Current treatment options are limited by efficacy across the spectrum of injury, morbidity, and cost. Regional gene therapy is a promising tissue engineering strategy for bone repair, as it allows for local implantation of nucleic acids or genetically modified cells to direct specific protein expression. In cell-based gene therapy approaches, a variety of different cell types have been described including mesenchymal stem cells (MSCs) derived from multiple sources-bone marrow, adipose, skeletal muscle, and umbilical cord tissue, among others. MSCs, in particular, have been well studied, as they serve as a source of osteoprogenitor cells in addition to providing a vehicle for transgene delivery. Furthermore, MSCs possess immunomodulatory properties, which may support the development of an allogeneic "off-the-shelf" gene therapy product. Identifying an optimal cell type is paramount to the successful clinical translation of cell-based gene therapy approaches. Here, we review current strategies for the management of segmental bone loss in orthopedic surgery, including bone grafting, bone graft substitutes, and operative techniques. We also highlight regional gene therapy as a tissue engineering strategy for bone repair, with a focus on cell types and cell sources suitable for this application.
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Affiliation(s)
- Matthew C. Gallo
- Department of Orthopaedic Surgery, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA; (M.C.G.); (A.E.); (J.R.); (J.R.B.)
| | - Aura Elias
- Department of Orthopaedic Surgery, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA; (M.C.G.); (A.E.); (J.R.); (J.R.B.)
| | - Julius Reynolds
- Department of Orthopaedic Surgery, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA; (M.C.G.); (A.E.); (J.R.); (J.R.B.)
| | - Jacob R. Ball
- Department of Orthopaedic Surgery, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA; (M.C.G.); (A.E.); (J.R.); (J.R.B.)
| | - Jay R. Lieberman
- Department of Orthopaedic Surgery, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA; (M.C.G.); (A.E.); (J.R.); (J.R.B.)
- Alfred E. Mann Department of Biomedical Engineering, Viterbi School of Engineering, University of Southern California, Los Angeles, CA 90089, USA
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Lee S, Kim EW, Lee HR, Lim SU, Jung CK, Kang YJ, Jung GA, Oh IH. Establishment of iPSC-Derived MSCs Expressing hsa-miR-4662a-5p for Enhanced Immune Modulation in Graft-Versus-Host Disease (GVHD). Int J Mol Sci 2025; 26:847. [PMID: 39859561 PMCID: PMC11766046 DOI: 10.3390/ijms26020847] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2024] [Revised: 01/17/2025] [Accepted: 01/18/2025] [Indexed: 01/27/2025] Open
Abstract
The immune-modulatory effects of mesenchymal stromal cells (MSCs) are widely used to treat inflammatory disorders, with indoleamine 2,4-dioxygenase-1 (IDO-1) playing a pivotal role in suppressing stimulated T-cell proliferation. Taking that three-dimensional (3D) cultures enhance MSCs' anti-inflammatory properties compared with two-dimensional (2D) cultures, the differentially expressed miRNAs were examined. Thus, we identified hsa-miR-4662a-5p (miR-4662a) as a key inducer of IDO-1 via its suppression of bridging integrator-1 (BIN-1), a negative regulator of the IDO-1 gene. The IDO-1-inducing potential of miR-4662a was conserved across primary MSCs from various donors and sources but exhibited variability. Notably, iPSC-derived MSCs (iMSCs) demonstrated superior IDO-1 induction and immune-modulatory efficacy compared with their donor-matched primary MSCs. Accordingly, iMSCs expressing miR-4662a (4662a/iMSC) exhibited stronger suppressive effects on T-cell proliferation and more potent suppressive effects on graft-versus-host disease (GVHD), improving survival rates and reducing tissue damage in the liver and gut. Our results point to the therapeutic potential of standardized, off-the-shelf 4662a/iMSC as a robust immune-modulating cell therapy for GVHD.
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Affiliation(s)
- Susie Lee
- Catholic High-Performance Cell Therapy Center & Department of Medical Life Science, College of Medicine, The Catholic University of Korea, Seocho-gu, Seoul 06591, Republic of Korea
- Department of Medical Sciences, College of Medicine, The Catholic University of Korea, Seocho-gu, Seoul 06591, Republic of Korea
| | - Eung-Won Kim
- Catholic High-Performance Cell Therapy Center & Department of Medical Life Science, College of Medicine, The Catholic University of Korea, Seocho-gu, Seoul 06591, Republic of Korea
| | - Hae-Ri Lee
- Catholic High-Performance Cell Therapy Center & Department of Medical Life Science, College of Medicine, The Catholic University of Korea, Seocho-gu, Seoul 06591, Republic of Korea
- RegenInnopharm Inc., Seocho-gu, Seoul 06591, Republic of Korea
| | - Sun-Ung Lim
- Catholic High-Performance Cell Therapy Center & Department of Medical Life Science, College of Medicine, The Catholic University of Korea, Seocho-gu, Seoul 06591, Republic of Korea
- RegenInnopharm Inc., Seocho-gu, Seoul 06591, Republic of Korea
| | - Chan Kwon Jung
- Department of Pathology, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seocho-gu, Seoul 06591, Republic of Korea
| | - Young-Ju Kang
- Catholic High-Performance Cell Therapy Center & Department of Medical Life Science, College of Medicine, The Catholic University of Korea, Seocho-gu, Seoul 06591, Republic of Korea
- RegenInnopharm Inc., Seocho-gu, Seoul 06591, Republic of Korea
| | - Gyung-Ah Jung
- Catholic High-Performance Cell Therapy Center & Department of Medical Life Science, College of Medicine, The Catholic University of Korea, Seocho-gu, Seoul 06591, Republic of Korea
- Department of Medical Sciences, College of Medicine, The Catholic University of Korea, Seocho-gu, Seoul 06591, Republic of Korea
| | - Il-Hoan Oh
- Catholic High-Performance Cell Therapy Center & Department of Medical Life Science, College of Medicine, The Catholic University of Korea, Seocho-gu, Seoul 06591, Republic of Korea
- Department of Medical Sciences, College of Medicine, The Catholic University of Korea, Seocho-gu, Seoul 06591, Republic of Korea
- RegenInnopharm Inc., Seocho-gu, Seoul 06591, Republic of Korea
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Parmentier L, D'Haese S, Van der Meeren L, Szabó A, Skirtach AG, Dmitriev RI, Locs J, Van Vlierberghe S. Mimicking the Bone Extracellular Matrix through a Calcium Phosphate-Containing Thiol-Ene Cross-Linked Gelatin Composite. Biomacromolecules 2025; 26:332-340. [PMID: 39680045 DOI: 10.1021/acs.biomac.4c01182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2024]
Abstract
Hydroxyapatite (HAP) and amorphous calcium phosphate (ACP) nanoparticles were incorporated into a thiol-ene clickable gelatin network to elucidate to what extent osteogenic differentiation of human dental pulp- and adipose-derived stem cells (HDPSCs/HASCs) could be further boosted. ACP nanoparticles increased the specific surface area by 23% and reduced the density by 13% while maintaining a comparable particle size (ACP: 25 ± 3 nm; HAP: 27 ± 3 nm). Overall, the incorporation of ceramic nanoparticles did not significantly alter the mechanical properties of the ceramic-containing composites compared to the unsubstituted thiol-ene network. ACP nanoparticles at high concentrations promoted a 21-day osteogenic response in HASCs (72.09 ± 20.20 ng Ca2+/ng DNA) comparable to HDPSCs, with the latter showing high calcium production irrespective of the ceramic content (78.45 ± 10.87 ng Ca2+/ng DNA), suggesting that the provided cues must be optimized according to the investigated cell type toward a cell-interactive coating application stimulating osteogenesis.
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Affiliation(s)
- Laurens Parmentier
- Polymer Chemistry and Biomaterials (PBM) Group, Centre of Macromolecular Chemistry (CMaC), Department of Organic and Macromolecular Chemistry, Faculty of Sciences, Ghent University, Krijgslaan 281, Building S4, Ghent 9000, Belgium
| | - Sophie D'Haese
- Polymer Chemistry and Biomaterials (PBM) Group, Centre of Macromolecular Chemistry (CMaC), Department of Organic and Macromolecular Chemistry, Faculty of Sciences, Ghent University, Krijgslaan 281, Building S4, Ghent 9000, Belgium
| | - Louis Van der Meeren
- Nano-biotechnology Laboratory, Department of Biotechnology, Faculty of Bioscience Engineering, Ghent university, Proeftuinstraat 86, Ghent 9000, Belgium
| | - Anna Szabó
- Polymer Chemistry and Biomaterials (PBM) Group, Centre of Macromolecular Chemistry (CMaC), Department of Organic and Macromolecular Chemistry, Faculty of Sciences, Ghent University, Krijgslaan 281, Building S4, Ghent 9000, Belgium
| | - Andre G Skirtach
- Nano-biotechnology Laboratory, Department of Biotechnology, Faculty of Bioscience Engineering, Ghent university, Proeftuinstraat 86, Ghent 9000, Belgium
| | - Ruslan I Dmitriev
- Tissue Engineering and Biomaterials Group, Department of Human Structure and Repair, Faculty of Medical and Health Sciences, Ghent University, C. Heymanslaan 10, Ghent 9000, Belgium
| | - Janis Locs
- Institute of Biomaterials and Bioengineering, Faculty of Natural Sciences and Technology, Riga Technical University, Pulka 3, Riga LV-1007, Latvia
- Baltic Biomaterials Centre of Excellence, Headquarters at Riga Technical University, Riga LV-1658, Latvia
| | - Sandra Van Vlierberghe
- Polymer Chemistry and Biomaterials (PBM) Group, Centre of Macromolecular Chemistry (CMaC), Department of Organic and Macromolecular Chemistry, Faculty of Sciences, Ghent University, Krijgslaan 281, Building S4, Ghent 9000, Belgium
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6
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Paola S, Lara G, Michela M, Silvia DC, Serena M, Rosalba P, Maria NA, Eleonora C, Fiorella C, Giulia G, Giovanna T, Giuseppe N, Federica S. When do the pathological signs become evident? Study of human mesenchymal stem cells in MDPL syndrome. Aging (Albany NY) 2024; 16:13505-13525. [PMID: 39611849 PMCID: PMC11723661 DOI: 10.18632/aging.206159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Accepted: 11/11/2024] [Indexed: 11/30/2024]
Abstract
Aging syndromes are rare genetic disorders sharing the features of accelerated senescence. Among these, Mandibular hypoplasia, Deafness and Progeroid features with concomitant Lipodystrophy (MDPL; OMIM #615381) is a rare autosomal dominant disease due to a de novo in-frame deletion in POLD1 gene, encoding the catalytic subunit of DNA polymerase delta. Here, we investigated how MSCs may contribute to the phenotypes and progression of premature aging syndromes such as MDPL. In human induced pluripotent stem cells (hiPSCs)-derived MSCs of three MDPL patients we detected several hallmarks of senescence, including (i) abnormal nuclear morphology, (ii) micronuclei presence, (iii) slow cell proliferation and cell cycle progression, (iv) reduced telomere length, and (v) increased levels of mitochondrial reactive oxygen species (ROS). We newly demonstrated that the pathological hallmarks of senescence manifest at an early stage of human development and represent a warning sign for the progression of the disease. Dissecting the mechanisms underlying stem cell dysfunction during aging can thereby contribute to the development of timely pharmacological therapies for ameliorating the pathological phenotype.
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Affiliation(s)
- Spitalieri Paola
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
| | - Guerrieri Lara
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
| | - Murdocca Michela
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
| | - Di Cesare Silvia
- Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Maccaroni Serena
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
| | - Pecorari Rosalba
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, Rome, Italy
| | | | - Candi Eleonora
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, Rome, Italy
| | - Colasuonno Fiorella
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, Rome, Italy
- Department of Science – LIME, Roma Tre University, Rome, Italy
| | - Gori Giulia
- Meyer Children’s Hospital IRCCS, Florence, Italy
| | | | - Novelli Giuseppe
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
| | - Sangiuolo Federica
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
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7
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González-Cubero E, González-Fernández ML, Esteban-Blanco M, Pérez-Castrillo S, Pérez-Fernández E, Navasa N, Aransay AM, Anguita J, Villar-Suárez V. The Therapeutic Potential of Adipose-Derived Mesenchymal Stem Cell Secretome in Osteoarthritis: A Comprehensive Study. Int J Mol Sci 2024; 25:11287. [PMID: 39457070 PMCID: PMC11508730 DOI: 10.3390/ijms252011287] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Revised: 10/06/2024] [Accepted: 10/09/2024] [Indexed: 10/28/2024] Open
Abstract
Osteoarthritis (OA) is a degenerative joint disease characterized by cartilage degradation and inflammation. This study investigates the therapeutic potential of secretome derived from adipose tissue mesenchymal stem cells (ASCs) in mitigating inflammation and promoting cartilage repair in an in vitro model of OA. Our in vitro model comprised chondrocytes inflamed with TNF. To assess the therapeutic potential of secretome, inflamed chondrocytes were treated with it and concentrations of pro-inflammatory cytokines, metalloproteinases (MMPs) and extracellular matrix markers were measured. In addition, secretome-treated chondrocytes were subject to a microarray analysis to determine which genes were upregulated and which were downregulated. Treating TNF-inflamed chondrocytes with secretome in vitro inhibits the NF-κB pathway, thereby mediating anti-inflammatory and anti-catabolic effects. Additional protective effects of secretome on cartilage are revealed in the inhibition of hypertrophy markers such as RUNX2 and COL10A1, increased production of COL2A1 and ACAN and upregulation of SOX9. These findings suggest that ASC-derived secretome can effectively reduce inflammation, promote cartilage repair, and maintain chondrocyte phenotype. This study highlights the potential of ASC-derived secretome as a novel, non-cell-based therapeutic approach for OA, offering a promising alternative to current treatments by targeting inflammation and cartilage repair mechanisms.
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Affiliation(s)
- Elsa González-Cubero
- Department of Neurosurgery, Stanford School of Medicine, Stanford University, Palo Alto, CA 94304, USA;
- Department of Anatomy, Faculty of Veterinary Sciences, Campus de Vegazana, University of Léon-Universidad de León, 24071 León, Spain; (M.L.G.-F.); (M.E.-B.); (S.P.-C.); (E.P.-F.)
| | - Maria Luisa González-Fernández
- Department of Anatomy, Faculty of Veterinary Sciences, Campus de Vegazana, University of Léon-Universidad de León, 24071 León, Spain; (M.L.G.-F.); (M.E.-B.); (S.P.-C.); (E.P.-F.)
| | - Marta Esteban-Blanco
- Department of Anatomy, Faculty of Veterinary Sciences, Campus de Vegazana, University of Léon-Universidad de León, 24071 León, Spain; (M.L.G.-F.); (M.E.-B.); (S.P.-C.); (E.P.-F.)
| | - Saúl Pérez-Castrillo
- Department of Anatomy, Faculty of Veterinary Sciences, Campus de Vegazana, University of Léon-Universidad de León, 24071 León, Spain; (M.L.G.-F.); (M.E.-B.); (S.P.-C.); (E.P.-F.)
| | - Esther Pérez-Fernández
- Department of Anatomy, Faculty of Veterinary Sciences, Campus de Vegazana, University of Léon-Universidad de León, 24071 León, Spain; (M.L.G.-F.); (M.E.-B.); (S.P.-C.); (E.P.-F.)
| | - Nicolás Navasa
- Department of Molecular Biology, Faculty of Veterinary Sciences, Campus de Vegazana, University of Léon-Universidad de León, 24071 León, Spain;
- Center for Cooperative Research in Biosciences (CIC bioGUNE)-Basque Research and Technology Alliance (BRTA), Parque Tecnológico de Bizkaia, Building 801-A, 48160 Derio, Spain; (A.M.A.); (J.A.)
| | - Ana M. Aransay
- Center for Cooperative Research in Biosciences (CIC bioGUNE)-Basque Research and Technology Alliance (BRTA), Parque Tecnológico de Bizkaia, Building 801-A, 48160 Derio, Spain; (A.M.A.); (J.A.)
- CIBERehd, ISCIII, 28029 Madrid, Spain
| | - Juan Anguita
- Center for Cooperative Research in Biosciences (CIC bioGUNE)-Basque Research and Technology Alliance (BRTA), Parque Tecnológico de Bizkaia, Building 801-A, 48160 Derio, Spain; (A.M.A.); (J.A.)
- IKERBASQUE, Basque Foundation for Science, 48011 Bilbao, Spain
| | - Vega Villar-Suárez
- Department of Anatomy, Faculty of Veterinary Sciences, Campus de Vegazana, University of Léon-Universidad de León, 24071 León, Spain; (M.L.G.-F.); (M.E.-B.); (S.P.-C.); (E.P.-F.)
- Institute of Biomedicine (IBIOMED), Faculty of Veterinary Sciences, Campus de Vegazana, University of León-Universidad de León, 24071 León, Spain
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8
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Winston T, Song Y, Shi H, Yang J, Alsudais M, Kontaridis MI, Wu Y, Gaborski TR, Meng Q, Cooney RN, Ma Z. Lineage-Specific Mesenchymal Stromal Cells Derived from Human iPSCs Showed Distinct Patterns in Transcriptomic Profile and Extracellular Vesicle Production. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2308975. [PMID: 38757640 PMCID: PMC11267277 DOI: 10.1002/advs.202308975] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Revised: 04/16/2024] [Indexed: 05/18/2024]
Abstract
Over the past decades, mesenchymal stromal cells (MSCs) have been extensively investigated as a potential therapeutic cell source for the treatment of various disorders. Differentiation of MSCs from human induced pluripotent stem cells (iMSCs) has provided a scalable approach for the biomanufacturing of MSCs and related biological products. Although iMSCs shared typical MSC markers and functions as primary MSCs (pMSCs), there is a lack of lineage specificity in many iMSC differentiation protocols. Here, a stepwise hiPSC-to-iMSC differentiation method is employed via intermediate cell stages of neural crest and cytotrophoblast to generate lineage-specific MSCs with varying differentiation efficiencies and gene expression. Through a comprehensive comparison between early developmental cell types (hiPSCs, neural crest, and cytotrophoblast), two lineage-specific iMSCs, and six source-specific pMSCs, are able to not only distinguish the transcriptomic differences between MSCs and early developmental cells, but also determine the transcriptomic similarities of iMSC subtypes to postnatal or perinatal pMSCs. Additionally, it is demonstrated that different iMSC subtypes and priming conditions affected EV production, exosomal protein expression, and cytokine cargo.
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Affiliation(s)
- Tackla Winston
- Department of Biomedical & Chemical EngineeringSyracuse University329 Link HallSyracuseNY13244USA
- BioInspired Institute for Materials and Living SystemsSyracuse University318 Bowne HallSyracuseNY13244USA
| | - Yuanhui Song
- Department of Biomedical & Chemical EngineeringSyracuse University329 Link HallSyracuseNY13244USA
- BioInspired Institute for Materials and Living SystemsSyracuse University318 Bowne HallSyracuseNY13244USA
| | - Huaiyu Shi
- Department of Biomedical & Chemical EngineeringSyracuse University329 Link HallSyracuseNY13244USA
- BioInspired Institute for Materials and Living SystemsSyracuse University318 Bowne HallSyracuseNY13244USA
| | - Junhui Yang
- Department of Biomedical & Chemical EngineeringSyracuse University329 Link HallSyracuseNY13244USA
- BioInspired Institute for Materials and Living SystemsSyracuse University318 Bowne HallSyracuseNY13244USA
| | - Munther Alsudais
- Departments of Biomedical and Chemical EngineeringRochester Institute of TechnologyOne Lomb Memorial DriveRochesterNY14623USA
| | - Maria I. Kontaridis
- Department of Biomedical Research and Translational MedicineMasonic Medical Research Institute2150 Bleecker StreetUticaNY13501USA
- Department of Medicine, Division of Cardiology, Beth Israel Deaconess Medical CenterHarvard Medical School330 Brookline AveBostonMA02215USA
- Department of Biological Chemistry and Molecular PharmacologyHarvard Medical SchoolBuilding C, 240 Longwood AveBostonMA02115USA
| | - Yaoying Wu
- Department of Biomedical & Chemical EngineeringSyracuse University329 Link HallSyracuseNY13244USA
- BioInspired Institute for Materials and Living SystemsSyracuse University318 Bowne HallSyracuseNY13244USA
- Department of Microbiology & ImmunologySUNY Upstate Medical University766 Irving AvenueSyracuseNY13210USA
| | - Thomas R. Gaborski
- Departments of Biomedical and Chemical EngineeringRochester Institute of TechnologyOne Lomb Memorial DriveRochesterNY14623USA
| | - Qinghe Meng
- Department of SurgeryState University of New York Upstate Medical University750 East Adams StreetSyracuseNY13210USA
- Sepsis Interdisciplinary Research CenterState University of New York Upstate Medical University766 Irving AvenueSyracuseNY13210USA
| | - Robert N. Cooney
- Department of SurgeryState University of New York Upstate Medical University750 East Adams StreetSyracuseNY13210USA
- Sepsis Interdisciplinary Research CenterState University of New York Upstate Medical University766 Irving AvenueSyracuseNY13210USA
| | - Zhen Ma
- Department of Biomedical & Chemical EngineeringSyracuse University329 Link HallSyracuseNY13244USA
- BioInspired Institute for Materials and Living SystemsSyracuse University318 Bowne HallSyracuseNY13244USA
- Department of BiologySyracuse University107 College PlSyracuseNY13210USA
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9
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Vaheb S, Afshin S, Ghoshouni H, Ghaffary EM, Farzan M, Shaygannejad V, Thapa S, Zabeti A, Mirmosayyeb O. Neurological efficacy and safety of mesenchymal stem cells (MSCs) therapy in people with multiple sclerosis (pwMS): An updated systematic review and meta-analysis. Mult Scler Relat Disord 2024; 87:105681. [PMID: 38838423 DOI: 10.1016/j.msard.2024.105681] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2024] [Revised: 04/26/2024] [Accepted: 05/10/2024] [Indexed: 06/07/2024]
Abstract
BACKGROUND Current therapeutic strategies for multiple sclerosis (MS) aim to suppress the immune response and reduce relapse rates. As alternative treatments, mesenchymal stem cells (MSCs) are being explored. MSCs show promise in repairing nerve tissue and reducing autoimmune responses in people with MS (pwMS). OBJECTIVE This review delves into the literature on the efficacy and safety of MSC therapy for pwMS. METHODS A comprehensive search strategy was employed to identify relevant articles from five databases until January 2024. The inclusion criteria encompassed interventional studies. Efficacy and safety data concerning MSC therapy in relapsing-remitting MS (RRMS), secondary progressive MS (SPMS), and primary progressive MS (PPMS) groups were extracted and analyzed. RESULTS A comprehensive analysis encompassing 30 studies revealed that individuals who underwent intrathecal (IT) protocol-based transplantation of MSCs experienced a noteworthy improvement in their expanded disability status scale (EDSS) compared to the placebo group. Weighted mean difference (WMD) was -0.28; 95 % CI -0.53 to -0.03, I2 = 0 %, p-value = 0.028); however, the intravenous (IV) group did not show significant changes in EDSS scores. The annualized relapse rate (ARR) did not significantly decrease among pwMS (WMD = -0.34; 95 % CI -1.05 to 0.38, I2 = 98 %, p-value = 0.357). Favorable results were observed in magnetic resonance imaging (MRI), with only 19.11 % of pwMS showing contrast-enhanced lesions (CEL) in the short term and no long-term MRI activity. The most common complications in both short-term and long-term follow-ups were infection, back pain, and gastrointestinal symptoms. CONCLUSIONS The study highlights the safety potential of MSC therapy for pwMS. While MRI-based neural regeneration shows significant treatment potential, the effectiveness of MSC therapy remains uncertain due to study limitations and ineffective outcome measures. Further research is needed to establish efficacy and optimize evaluation methods for MSC therapy on pwMS.
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Affiliation(s)
- Saeed Vaheb
- Isfahan Neurosciences Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Sahra Afshin
- Department of Neurology, School of Medicine, Hormozgan University of Medical Sciences, Bandarabbas, Iran
| | - Hamed Ghoshouni
- Isfahan Neurosciences Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Elham Moases Ghaffary
- Isfahan Neurosciences Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mahour Farzan
- Students Research Committee, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Vahid Shaygannejad
- Isfahan Neurosciences Research Center, Isfahan University of Medical Sciences, Isfahan, Iran; Department of Neurology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Sangharsha Thapa
- Jacobs School of Biomedical Sciences, University of Buffalo, Department of Neurology, Buffalo, USA
| | - Aram Zabeti
- University of Cincinnati, Cincinnati, OH, USA
| | - Omid Mirmosayyeb
- Isfahan Neurosciences Research Center, Isfahan University of Medical Sciences, Isfahan, Iran; Department of Neurology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.
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Guo Q, Chen J, Bu Q, Zhang J, Ruan M, Chen X, Zhao M, Tu X, Zhao C. Establishing stable and highly osteogenic hiPSC-derived MSCs for 3D-printed bone graft through microenvironment modulation by CHIR99021-treated osteocytes. Mater Today Bio 2024; 26:101111. [PMID: 38933413 PMCID: PMC11201125 DOI: 10.1016/j.mtbio.2024.101111] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2024] [Revised: 05/17/2024] [Accepted: 05/31/2024] [Indexed: 06/28/2024] Open
Abstract
Human induced pluripotent stem cell (hiPSC)-derived mesenchymal stem cells (iMSCs) are ideal candidates for the production of standardised and scalable bioengineered bone grafts. However, stable induction and osteogenic differentiation of iMSCs pose challenges in the industry. We developed a precise differentiation method to produce homogeneous and fully differentiated iMSCs. In this study, we established a standardised system to prepare iMSCs with increased osteogenic potential and improved bioactivity by introducing a CHIR99021 (C91)-treated osteogenic microenvironment (COOME). COOME enhances the osteogenic differentiation and mineralisation of iMSCs via canonical Wnt signalling. Global transcriptome analysis and co-culturing experiments indicated that COOME increased the pro-angiogenesis/neurogenesis activity of iMSCs. The superior osteogenic differentiation and mineralisation abilities of COOME-treated iMSCs were also confirmed in a Bio3D module generated using a polycaprolactone (PCL) and cell-integrated 3D printing (PCI3D) system, which is the closest model to in vivo research. This COOME-treated iMSCs differentiation system offers a new perspective for generating highly osteogenic, bioactive, and anatomically matched grafts for clinical applications. Statement of significance Although human induced pluripotent stem cell-derived MSCs (iMSCs) are ideal seed cells for synthetic bone implants, the challenges of stable induction and osteogenic differentiation hinder their clinical application. This study established a standardised system for the scalable preparation of iMSCs with improved osteogenic potential by combining our precise iMSC differentiation method with the CHIR99021 (C91)-treated osteocyte osteogenic microenvironment (COOME) through the activation of canonical Wnt signalling. Moreover, COOME upregulated the pro-angiogenic and pro-neurogenic capacities of iMSCs, which are crucial for the integration of implanted bone grafts. The superior osteogenic ability of COOME-treated iMSCs was confirmed in Bio3D modules generated using PCL and cell-integrated 3D printing systems, highlighting their functional potential in vivo. This study contributes to tissue engineering by providing insights into the functional differentiation of iMSCs for bone regeneration.
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Affiliation(s)
- Qiuling Guo
- Laboratory of Skeletal Development and Regeneration, Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016, China
| | - Jingjing Chen
- Laboratory of Skeletal Development and Regeneration, Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016, China
| | - Qiqi Bu
- Laboratory of Skeletal Development and Regeneration, Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016, China
| | - Jinling Zhang
- Laboratory of Skeletal Development and Regeneration, Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016, China
| | - Minjie Ruan
- Laboratory of Skeletal Development and Regeneration, Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016, China
| | - Xiaoyu Chen
- Center for Medical Epigenetics, School of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, China
| | - Mingming Zhao
- Center for Medical Epigenetics, School of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, China
| | - Xiaolin Tu
- Laboratory of Skeletal Development and Regeneration, Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016, China
| | - Chengzhu Zhao
- Laboratory of Skeletal Development and Regeneration, Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016, China
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11
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Habiba UE, Khan N, Greene DL, Shamim S, Umer A. The therapeutic effect of mesenchymal stem cells in diabetic kidney disease. J Mol Med (Berl) 2024; 102:537-570. [DOI: https:/doi.org/10.1007/s00109-024-02432-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 02/02/2024] [Accepted: 02/12/2024] [Indexed: 03/07/2024]
Abstract
Abstract
Diabetes mellitus (DM) often causes chronic kidney damage despite best medical practices. Diabetic kidney disease (DKD) arises from a complex interaction of factors within the kidney and the whole body. Targeting specific disease-causing agents using drugs has not been effective in treating DKD. However, stem cell therapies offer a promising alternative by addressing multiple disease pathways and promoting kidney regeneration. Mesenchymal stem cells (MSCs) offer great promise due to their superior accessibility ratio from adult tissues and remarkable modes of action, such as the production of paracrine anti-inflammatory and cytoprotective substances. This review critically evaluates the development of MSC treatment for DKD as it moves closer to clinical application. Results from animal models suggest that systemic MSC infusion may positively impact DKD progression. However, few registered and completed clinical trials exist, and whether the treatments are effective in humans is still being determined. Significant knowledge gaps and research opportunities exist, including establishing the ideal source, dose, and timing of MSC delivery, better understanding of in vivo mechanisms, and developing quantitative indicators to obtain a more significant therapeutic response. This paper reviews recent literature on using MSCs in preclinical and clinical trials in DKD. Potent biomarkers related to DKD are also highlighted, which may help better understand MSCs’ action in this disease progression.
Key messages
Mesenchymal stem cells have anti-inflammatory and paracrine effects in diabetic kidney disease.
Mesenchymal stem cells alleviate in animal models having diabetic kidney disease.
Mesenchymal stem cells possess promise for the treatment of diabetic kidney disease.
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12
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Habiba UE, Khan N, Greene DL, Shamim S, Umer A. The therapeutic effect of mesenchymal stem cells in diabetic kidney disease. J Mol Med (Berl) 2024; 102:537-570. [PMID: 38418620 PMCID: PMC10963471 DOI: 10.1007/s00109-024-02432-w] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 02/02/2024] [Accepted: 02/12/2024] [Indexed: 03/02/2024]
Abstract
Diabetes mellitus (DM) often causes chronic kidney damage despite best medical practices. Diabetic kidney disease (DKD) arises from a complex interaction of factors within the kidney and the whole body. Targeting specific disease-causing agents using drugs has not been effective in treating DKD. However, stem cell therapies offer a promising alternative by addressing multiple disease pathways and promoting kidney regeneration. Mesenchymal stem cells (MSCs) offer great promise due to their superior accessibility ratio from adult tissues and remarkable modes of action, such as the production of paracrine anti-inflammatory and cytoprotective substances. This review critically evaluates the development of MSC treatment for DKD as it moves closer to clinical application. Results from animal models suggest that systemic MSC infusion may positively impact DKD progression. However, few registered and completed clinical trials exist, and whether the treatments are effective in humans is still being determined. Significant knowledge gaps and research opportunities exist, including establishing the ideal source, dose, and timing of MSC delivery, better understanding of in vivo mechanisms, and developing quantitative indicators to obtain a more significant therapeutic response. This paper reviews recent literature on using MSCs in preclinical and clinical trials in DKD. Potent biomarkers related to DKD are also highlighted, which may help better understand MSCs' action in this disease progression. KEY MESSAGES: Mesenchymal stem cells have anti-inflammatory and paracrine effects in diabetic kidney disease. Mesenchymal stem cells alleviate in animal models having diabetic kidney disease. Mesenchymal stem cells possess promise for the treatment of diabetic kidney disease.
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Affiliation(s)
- Umm E Habiba
- Pak-American Hospital Pvt. Ltd, Jahangir Multiplex, Peshawar Road, Sector H-13, Islamabad, 44000, Pakistan.
- R3 Medical Research LLC, 10045 East Dynamite Boulevard Suite 260, Scottsdale, AZ, 85262, USA.
| | - Nasar Khan
- Pak-American Hospital Pvt. Ltd, Jahangir Multiplex, Peshawar Road, Sector H-13, Islamabad, 44000, Pakistan.
- R3 Medical Research LLC, 10045 East Dynamite Boulevard Suite 260, Scottsdale, AZ, 85262, USA.
- Bello Bio Labs and Therapeutics (SMC) Pvt. Ltd., Jahangir Multiplex, Peshawar Road, Sector H-13, Islamabad, 44000, Pakistan.
| | - David Lawrence Greene
- Pak-American Hospital Pvt. Ltd, Jahangir Multiplex, Peshawar Road, Sector H-13, Islamabad, 44000, Pakistan
- R3 Medical Research LLC, 10045 East Dynamite Boulevard Suite 260, Scottsdale, AZ, 85262, USA
- Bello Bio Labs and Therapeutics (SMC) Pvt. Ltd., Jahangir Multiplex, Peshawar Road, Sector H-13, Islamabad, 44000, Pakistan
| | - Sabiha Shamim
- Pak-American Hospital Pvt. Ltd, Jahangir Multiplex, Peshawar Road, Sector H-13, Islamabad, 44000, Pakistan
- R3 Medical Research LLC, 10045 East Dynamite Boulevard Suite 260, Scottsdale, AZ, 85262, USA
| | - Amna Umer
- Pak-American Hospital Pvt. Ltd, Jahangir Multiplex, Peshawar Road, Sector H-13, Islamabad, 44000, Pakistan
- R3 Medical Research LLC, 10045 East Dynamite Boulevard Suite 260, Scottsdale, AZ, 85262, USA
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13
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Kuang PP, Liu XQ, Li CG, He BX, Xie YC, Wu ZC, Li CL, Deng XH, Fu QL. Mesenchymal stem cells overexpressing interleukin-10 prevent allergic airway inflammation. Stem Cell Res Ther 2023; 14:369. [PMID: 38093354 PMCID: PMC10720159 DOI: 10.1186/s13287-023-03602-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2023] [Accepted: 12/05/2023] [Indexed: 12/17/2023] Open
Abstract
BACKGROUNDS Allergic airway inflammation is prevalent worldwide and imposes a considerable burden on both society and affected individuals. This study aimed to investigate the therapeutic advantages of mesenchymal stem cells (MSCs) overexpressed interleukin-10 (IL-10) for the treatment of allergic airway inflammation, as both IL-10 and MSCs possess immunosuppressive properties. METHODS Induced pluripotent stem cell (iPSC)-derived MSCs were engineered to overexpress IL-10 via lentiviral transfection (designated as IL-10-MSCs). MSCs and IL-10-MSCs were administered intravenously to mice with allergic inflammation induced by ovalbumin (OVA), and the features of allergic inflammation including inflammatory cell infiltration, Th cells in the lungs, and T helper 2 cell (Th2) cytokine levels in bronchoalveolar lavage fluid (BALF) were examined. MSCs and IL-10-MSCs were co-cultured with CD4+ T cells from patients with allergic rhinitis (AR), and the levels of Th2 cells and corresponding type 2 cytokines were studied. RNA-sequence was performed to further investigate the potential effects of MSCs and IL-10-MSCs on CD4+ T cells. RESULTS Stable IL-10-MSCs were established and characterised by high IL-10 expression. IL-10-MSCs significantly reduced inflammatory cell infiltration and epithelial goblet cell numbers in the lung tissues of mice with allergic airway inflammation. Inflammatory cell and cytokine levels in BALF also decreased after the administration of IL-10-MSCs. Moreover, IL-10-MSCs showed a stronger capacity to inhibit the levels of Th2 after co-cultured with CD4+ T cells from patients with AR. Furthermore, we elucidated lower levels of IL-5 and IL-13 in IL-10-MSCs treated CD4+ T cells, and blockade of IL-10 significantly reversed the inhibitory effects of IL-10-MSCs. We also reported the mRNA profiles of CD4+ T cells treated with IL-10-MSCs and MSCs, in which IL-10 played an important role. CONCLUSION IL-10-MSCs showed positive effects in the treatment of allergic airway inflammation, providing solid support for the use of genetically engineered MSCs as a potential novel therapy for allergic airway inflammation.
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Affiliation(s)
- Peng-Peng Kuang
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road II, Guangzhou, 510080, Guangdong, People's Republic of China
- Division of Allergy, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Xiao-Qing Liu
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road II, Guangzhou, 510080, Guangdong, People's Republic of China
- Division of Allergy, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Chan-Gu Li
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road II, Guangzhou, 510080, Guangdong, People's Republic of China
- Division of Allergy, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Bi-Xin He
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road II, Guangzhou, 510080, Guangdong, People's Republic of China
- Division of Allergy, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Ying-Chun Xie
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road II, Guangzhou, 510080, Guangdong, People's Republic of China
- Division of Allergy, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Zi-Cong Wu
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road II, Guangzhou, 510080, Guangdong, People's Republic of China
- Extracellular Vesicle Research and Clinical Translational Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, People's Republic of China
| | - Cheng-Lin Li
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road II, Guangzhou, 510080, Guangdong, People's Republic of China
| | - Xiao-Hui Deng
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road II, Guangzhou, 510080, Guangdong, People's Republic of China
- Extracellular Vesicle Research and Clinical Translational Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, People's Republic of China
| | - Qing-Ling Fu
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road II, Guangzhou, 510080, Guangdong, People's Republic of China.
- Division of Allergy, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China.
- Extracellular Vesicle Research and Clinical Translational Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, People's Republic of China.
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14
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Zhou AK, Jou E, Lu V, Zhang J, Chabra S, Abishek J, Wong E, Zeng X, Guo B. Using Pre-Clinical Studies to Explore the Potential Clinical Uses of Exosomes Secreted from Induced Pluripotent Stem Cell-Derived Mesenchymal Stem cells. Tissue Eng Regen Med 2023; 20:793-809. [PMID: 37651091 PMCID: PMC10519927 DOI: 10.1007/s13770-023-00557-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2023] [Revised: 05/09/2023] [Accepted: 05/16/2023] [Indexed: 09/01/2023] Open
Abstract
Recent studies of exosomes derived from mesenchymal stem cells (MSCs) have indicated high potential clinical applications in many diseases. However, the limited source of MSCs impedes their clinical research and application. Most recently, induced pluripotent stem cells (iPSCs) have become a promising source of MSCs. Exosome therapy based on iPSC-derived MSCs (iMSCs) is a novel technique with much of its therapeutic potential untapped. Compared to MSCs, iMSCs have proved superior in cell proliferation, immunomodulation, generation of exosomes capable of controlling the microenvironment, and bioactive paracrine factor secretion, while also theoretically eliminating the dependence on immunosuppression drugs. The therapeutic effects of iMSC-derived exosomes are explored in many diseases and are best studied in wound healing, cardiovascular disease, and musculoskeletal pathology. It is pertinent clinicians have a strong understanding of stem cell therapy and the latest advances that will eventually translate into clinical practice. In this review, we discuss the various applications of exosomes derived from iMSCs in clinical medicine.
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Affiliation(s)
- Andrew Kailin Zhou
- Addenbrookes Major Trauma Unit, Department of Trauma And Orthopaedics, Cambridge University Hospitals, Cambridge, UK
- Watford General Hospital, London, UK
| | - Eric Jou
- Addenbrookes Major Trauma Unit, Department of Trauma And Orthopaedics, Cambridge University Hospitals, Cambridge, UK
- School Of Clinical Medicine, University Of Cambridge, Cambridge, UK
| | - Victor Lu
- Addenbrookes Major Trauma Unit, Department of Trauma And Orthopaedics, Cambridge University Hospitals, Cambridge, UK
- School Of Clinical Medicine, University Of Cambridge, Cambridge, UK
| | - James Zhang
- Addenbrookes Major Trauma Unit, Department of Trauma And Orthopaedics, Cambridge University Hospitals, Cambridge, UK
- School Of Clinical Medicine, University Of Cambridge, Cambridge, UK
| | - Shirom Chabra
- School Of Clinical Medicine, University Of Cambridge, Cambridge, UK
| | | | | | - Xianwei Zeng
- Beijing Rehabilitation Hospital Affiliated to National Research Centre for Rehabilitation Technical Aids, Ministry of Civil Affairs of China, Beijing, China.
- Weifang People's Hospital, Weifang City, Shandong Province, China.
| | - Baoqiang Guo
- Department of Life Science, Faculty of Science and Engineering, Manchester Metropolitan University, Manchester, UK.
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15
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Valsecchi C, Croce S, Lenta E, Acquafredda G, Comoli P, Avanzini MA. TITLE: New therapeutic approaches in pediatric diseases: Mesenchymal stromal cell and mesenchymal stromal cell-derived extracellular vesicles as new drugs. Pharmacol Res 2023; 192:106796. [PMID: 37207738 DOI: 10.1016/j.phrs.2023.106796] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Revised: 05/12/2023] [Accepted: 05/16/2023] [Indexed: 05/21/2023]
Abstract
Mesenchymal Stromal Cell (MSC) clinical applications have been widely reported and their therapeutic potential has been documented in several diseases. MSCs can be isolated from several human tissues and easily expanded in vitro, they are able to differentiate in a variety of cell lineages, and they are known to interact with most immunological cells, showing immunosuppressive and tissue repair properties. Their therapeutic efficacy is closely associated with the release of bioactive molecules, namely Extracellular Vesicles (EVs), effective as their parental cells. EVs isolated from MSCs act by fusing with target cell membrane and releasing their content, showing a great potential for the treatment of injured tissues and organs, and for the modulation of the host immune system. EV-based therapies provide, as major advantages, the possibility to cross the epithelium and blood barrier and their activity is not influenced by the surrounding environment. In the present review, we deal with pre-clinical reports and clinical trials to provide data in support of MSC and EV clinical efficacy with particular focus on neonatal and pediatric diseases. Considering pre-clinical and clinical data so far available, it is likely that cell-based and cell-free therapies could become an important therapeutic approach for the treatment of several pediatric diseases.
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Affiliation(s)
- Chiara Valsecchi
- Pediatric Hematology Oncology Unit and Cell Factory, Fondazione IRCCS Policlinico S. Matteo, 27100 Pavia, Italy.
| | - Stefania Croce
- Cell Factory, Fondazione IRCCS Policlinico S. Matteo, 27100 Pavia, Italy.
| | - Elisa Lenta
- Cell Factory, Fondazione IRCCS Policlinico S. Matteo, 27100 Pavia, Italy.
| | - Gloria Acquafredda
- Pediatric Hematology Oncology Unit and Cell Factory, Fondazione IRCCS Policlinico S. Matteo, 27100 Pavia, Italy.
| | - Patrizia Comoli
- Pediatric Hematology Oncology Unit and Cell Factory, Fondazione IRCCS Policlinico S. Matteo, 27100 Pavia, Italy.
| | - Maria Antonietta Avanzini
- Pediatric Hematology Oncology Unit and Cell Factory, Fondazione IRCCS Policlinico S. Matteo, 27100 Pavia, Italy.
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16
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Yang C, Du XY, Luo W. Clinical application prospects and transformation value of dental follicle stem cells in oral and neurological diseases. World J Stem Cells 2023; 15:136-149. [PMID: 37181000 PMCID: PMC10173814 DOI: 10.4252/wjsc.v15.i4.136] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Revised: 01/18/2023] [Accepted: 03/21/2023] [Indexed: 04/26/2023] Open
Abstract
Since dental pulp stem cells (DPSCs) were first reported, six types of dental SCs (DSCs) have been isolated and identified. DSCs originating from the craniofacial neural crest exhibit dental-like tissue differentiation potential and neuro-ectodermal features. As a member of DSCs, dental follicle SCs (DFSCs) are the only cell type obtained at the early developing stage of the tooth prior to eruption. Dental follicle tissue has the distinct advantage of large tissue volume compared with other dental tissues, which is a prerequisite for obtaining a sufficient number of cells to meet the needs of clinical applications. Furthermore, DFSCs exhibit a significantly higher cell proliferation rate, higher colony-formation capacity, and more primitive and better anti-inflammatory effects than other DSCs. In this respect, DFSCs have the potential to be of great clinical significance and translational value in oral and neurological diseases, with natural advantages based on their origin. Lastly, cryopreservation preserves the biological properties of DFSCs and enables them to be used as off-shelf products for clinical applications. This review summarizes and comments on the properties, application potential, and clinical transformation value of DFSCs, thereby inspiring novel perspectives in the future treatment of oral and neurological diseases.
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Affiliation(s)
- Chao Yang
- Research and Development Department, Shenzhen Uni-medica Technology Co., Ltd, Shenzhen 518051, Guangdong Province, China
- Department of Stomatology, The People’s Hospital of Longhua, Shenzhen 518109, Guangdong Province, China
| | - Xin-Ya Du
- Department of Stomatology, The People’s Hospital of Longhua, Shenzhen 518109, Guangdong Province, China
| | - Wen Luo
- Department of Stomatology, The First Affiliated Hospital of Hainan Medical University, Haikou 570102, Hainan Province, China
- School of Stomatology, Hainan Medical University, Haikou 571199, Hainan Province, China
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Ning C, Li P, Gao C, Fu L, Liao Z, Tian G, Yin H, Li M, Sui X, Yuan Z, Liu S, Guo Q. Recent advances in tendon tissue engineering strategy. Front Bioeng Biotechnol 2023; 11:1115312. [PMID: 36890920 PMCID: PMC9986339 DOI: 10.3389/fbioe.2023.1115312] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2022] [Accepted: 02/06/2023] [Indexed: 02/22/2023] Open
Abstract
Tendon injuries often result in significant pain and disability and impose severe clinical and financial burdens on our society. Despite considerable achievements in the field of regenerative medicine in the past several decades, effective treatments remain a challenge due to the limited natural healing capacity of tendons caused by poor cell density and vascularization. The development of tissue engineering has provided more promising results in regenerating tendon-like tissues with compositional, structural and functional characteristics comparable to those of native tendon tissues. Tissue engineering is the discipline of regenerative medicine that aims to restore the physiological functions of tissues by using a combination of cells and materials, as well as suitable biochemical and physicochemical factors. In this review, following a discussion of tendon structure, injury and healing, we aim to elucidate the current strategies (biomaterials, scaffold fabrication techniques, cells, biological adjuncts, mechanical loading and bioreactors, and the role of macrophage polarization in tendon regeneration), challenges and future directions in the field of tendon tissue engineering.
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Affiliation(s)
- Chao Ning
- Chinese PLA Medical School, Beijing, China
- Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma and War Injuries PLA, Institute of Orthopedics, Chinese PLA General Hospital, Beijing, China
| | - Pinxue Li
- Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma and War Injuries PLA, Institute of Orthopedics, Chinese PLA General Hospital, Beijing, China
| | - Cangjian Gao
- Chinese PLA Medical School, Beijing, China
- Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma and War Injuries PLA, Institute of Orthopedics, Chinese PLA General Hospital, Beijing, China
| | - Liwei Fu
- Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma and War Injuries PLA, Institute of Orthopedics, Chinese PLA General Hospital, Beijing, China
| | - Zhiyao Liao
- Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma and War Injuries PLA, Institute of Orthopedics, Chinese PLA General Hospital, Beijing, China
| | - Guangzhao Tian
- Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma and War Injuries PLA, Institute of Orthopedics, Chinese PLA General Hospital, Beijing, China
| | - Han Yin
- Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma and War Injuries PLA, Institute of Orthopedics, Chinese PLA General Hospital, Beijing, China
| | - Muzhe Li
- Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma and War Injuries PLA, Institute of Orthopedics, Chinese PLA General Hospital, Beijing, China
| | - Xiang Sui
- Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma and War Injuries PLA, Institute of Orthopedics, Chinese PLA General Hospital, Beijing, China
| | - Zhiguo Yuan
- Department of Bone and Joint Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Shuyun Liu
- Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma and War Injuries PLA, Institute of Orthopedics, Chinese PLA General Hospital, Beijing, China
| | - Quanyi Guo
- Chinese PLA Medical School, Beijing, China
- Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma and War Injuries PLA, Institute of Orthopedics, Chinese PLA General Hospital, Beijing, China
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18
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iPSC-Derived MSCs Are a Distinct Entity of MSCs with Higher Therapeutic Potential than Their Donor-Matched Parental MSCs. Int J Mol Sci 2023; 24:ijms24010881. [PMID: 36614321 PMCID: PMC9821152 DOI: 10.3390/ijms24010881] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Revised: 12/23/2022] [Accepted: 12/28/2022] [Indexed: 01/05/2023] Open
Abstract
Mesenchymal stromal cells derived from induced pluripotent stem cells (iMSCs) have been proposed as alternative sources of primary MSCs with various advantages for cell therapeutic trials. However, precise evaluation of the differences between iMSCs and primary MSCs is lacking due to individual variations in the donor cells, which obscure direct comparisons between the two. In this study, we generated donor-matched iMSCs from individual bone marrow-derived MSCs and directly compared their cell-autonomous and paracrine therapeutic effects. We found that the transition from primary MSCs to iMSCs is accompanied by a functional shift towards higher proliferative activity, with variations in differentiation potential in a donor cell-dependent manner. The transition from MSCs to iMSCs was associated with common changes in transcriptomic and proteomic profiles beyond the variations of their individual donors, revealing expression patterns unique for the iMSCs. These iMSC-specific patterns were characterized by a shift in cell fate towards a pericyte-like state and enhanced secretion of paracrine cytokine/growth factors. Accordingly, iMSCs exhibited higher support for the self-renewing expansion of primitive hematopoietic progenitors and more potent immune suppression of allogenic immune responses than MSCs. Our study suggests that iMSCs represent a separate entity of MSCs with unique therapeutic potential distinct from their parental MSCs, but points to the need for iMSC characterization in the individual basis.
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19
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Liang XS, Sun ZW, Thomas AM, Li S. Mesenchymal Stem Cell Therapy for Huntington Disease: A Meta-Analysis. Stem Cells Int 2023; 2023:1109967. [PMID: 37168444 PMCID: PMC10164866 DOI: 10.1155/2023/1109967] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 12/06/2022] [Accepted: 04/11/2023] [Indexed: 05/13/2023] Open
Abstract
Objective Mesenchymal stem cell (MSC) therapy has been explored in Huntington disease (HD) as a potential therapeutic approach; however, a complete synthesis of these results is lacking. We conducted a meta-analysis to evaluate the effects of MSCs on HD. Method Eligible studies published before November 2022 were screened from Embase, PubMed, Web of Science, Medline, and Cochrane in accordance with PRISMA guidelines. ClinicalTrial.gov and the World Health Organization International Clinical Trials Registry Platform were also searched for registered clinical trials. The outcomes in rodent studies evaluated included morphological changes (striatal volume and ventricular volume), motor function (rotarod test, wire hang test, grip strength test, limb-clasping test, apomorphine-induced rotation test, and neuromuscular electromyography activity), cognition (Morris water maze test), and body weight. Result The initial search returned 362 records, of which 15 studies incorporating 346 HD rodents were eligible for meta-analysis. Larger striatal and smaller ventricular volumes were observed in MSC-treated animals compared to controls. MSCs transplanted before the occurrence of motor dysfunction rescued the motor incoordination of HD. Among different MSC sources, bone marrow mesenchymal stem cells were the most investigated cells and were effective in improving motor coordination. MSC therapy improved muscle strength, neuromuscular electromyography activity, cortex-related motor function, and striatum-related motor function, while cognition was not changed. The body weight of male HD rodents increased after MSC transplantation, while that of females was not affected. Conclusion Meta-analysis showed a positive effect of MSCs on HD rodents overall, as reflected in morphological changes, motor coordination, muscle strength, neuromuscular electromyography activity, cortex-related motor function, and striatum-related motor function, while cognition was not changed by MSC therapy.
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Affiliation(s)
- Xue-Song Liang
- Department of Neurology and Psychiatry, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
- Beijing Institute of Brain Disorders, Capital Medical University, Beijing, China
| | - Zheng-Wu Sun
- Department of Clinical Pharmacy, Dalian Municipal Central Hospital, Dalian, China
| | - Aline M. Thomas
- The Russell H. Morgan Department of Radiology and Radiological Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Shen Li
- Department of Neurology and Psychiatry, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
- Beijing Institute of Brain Disorders, Capital Medical University, Beijing, China
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20
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Huang S, Li Y, Zeng J, Chang N, Cheng Y, Zhen X, Zhong D, Chen R, Ma G, Wang Y. Mesenchymal Stem/Stromal Cells in Asthma Therapy: Mechanisms and Strategies for Enhancement. Cell Transplant 2023; 32:9636897231180128. [PMID: 37318186 DOI: 10.1177/09636897231180128] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/16/2023] Open
Abstract
Asthma is a complex and heterogeneous disease characterized by chronic airway inflammation, airway hyperresponsiveness, and airway remodeling. Most asthmatic patients are well-established using standard treatment strategies and advanced biologicals. However, a small group of patients who do not respond to biological treatments or are not effectively controlled by available treatment strategies remain a clinical challenge. Therefore, new therapies are urgently needed for poorly controlled asthma. Mesenchymal stem/stromal cells (MSCs) have shown therapeutic potential in relieving airway inflammation and repairing impaired immune balance in preclinical trials owing to their immunomodulatory abilities. Noteworthy, MSCs exerted a therapeutic effect on steroid-resistant asthma with rare side effects in asthmatic models. Nevertheless, adverse factors such as limited obtained number, nutrient and oxygen deprivation in vitro, and cell senescence or apoptosis affected the survival rate and homing efficiency of MSCs, thus limiting the efficacy of MSCs in asthma. In this review, we elaborate on the roles and underlying mechanisms of MSCs in the treatment of asthma from the perspective of their source, immunogenicity, homing, differentiation, and immunomodulatory capacity and summarize strategies to improve their therapeutic effect.
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Affiliation(s)
- Si Huang
- Department of Pediatrics, Shunde Women and Children's Hospital of Guangdong Medical University, Foshan, China
- Institute of Respiratory Diseases, Shunde Women and Children's Hospital, Guangdong Medical University, Foshan, China
| | - Yiyang Li
- Department of Pediatrics, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Jieqing Zeng
- Department of Pediatrics, Shunde Women and Children's Hospital of Guangdong Medical University, Foshan, China
- Institute of Respiratory Diseases, Shunde Women and Children's Hospital, Guangdong Medical University, Foshan, China
| | - Ning Chang
- Department of Pediatrics, Shunde Women and Children's Hospital of Guangdong Medical University, Foshan, China
- Institute of Respiratory Diseases, Shunde Women and Children's Hospital, Guangdong Medical University, Foshan, China
| | - Yisen Cheng
- Department of Pediatrics, Shunde Women and Children's Hospital of Guangdong Medical University, Foshan, China
- Institute of Respiratory Diseases, Shunde Women and Children's Hospital, Guangdong Medical University, Foshan, China
| | - Xiangfan Zhen
- Department of Pediatrics, Shunde Women and Children's Hospital of Guangdong Medical University, Foshan, China
- Institute of Respiratory Diseases, Shunde Women and Children's Hospital, Guangdong Medical University, Foshan, China
| | - Dan Zhong
- Department of Pediatrics, Shunde Women and Children's Hospital of Guangdong Medical University, Foshan, China
- Institute of Respiratory Diseases, Shunde Women and Children's Hospital, Guangdong Medical University, Foshan, China
| | - Riling Chen
- Department of Pediatrics, Shunde Women and Children's Hospital of Guangdong Medical University, Foshan, China
- Institute of Respiratory Diseases, Shunde Women and Children's Hospital, Guangdong Medical University, Foshan, China
| | - Guoda Ma
- Department of Pediatrics, Shunde Women and Children's Hospital of Guangdong Medical University, Foshan, China
- Institute of Respiratory Diseases, Shunde Women and Children's Hospital, Guangdong Medical University, Foshan, China
| | - Yajun Wang
- Department of Pediatrics, Shunde Women and Children's Hospital of Guangdong Medical University, Foshan, China
- Institute of Respiratory Diseases, Shunde Women and Children's Hospital, Guangdong Medical University, Foshan, China
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21
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Thanaskody K, Jusop AS, Tye GJ, Wan Kamarul Zaman WS, Dass SA, Nordin F. MSCs vs. iPSCs: Potential in therapeutic applications. Front Cell Dev Biol 2022; 10:1005926. [PMID: 36407112 PMCID: PMC9666898 DOI: 10.3389/fcell.2022.1005926] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Accepted: 10/21/2022] [Indexed: 01/24/2023] Open
Abstract
Over the past 2 decades, mesenchymal stem cells (MSCs) have attracted a lot of interest as a unique therapeutic approach for a variety of diseases. MSCs are capable of self-renewal and multilineage differentiation capacity, immunomodulatory, and anti-inflammatory properties allowing it to play a role in regenerative medicine. Furthermore, MSCs are low in tumorigenicity and immune privileged, which permits the use of allogeneic MSCs for therapies that eliminate the need to collect MSCs directly from patients. Induced pluripotent stem cells (iPSCs) can be generated from adult cells through gene reprogramming with ectopic expression of specific pluripotency factors. Advancement in iPS technology avoids the destruction of embryos to make pluripotent cells, making it free of ethical concerns. iPSCs can self-renew and develop into a plethora of specialized cells making it a useful resource for regenerative medicine as they may be created from any human source. MSCs have also been used to treat individuals infected with the SARS-CoV-2 virus. MSCs have undergone more clinical trials than iPSCs due to high tumorigenicity, which can trigger oncogenic transformation. In this review, we discussed the overview of mesenchymal stem cells and induced pluripotent stem cells. We briefly present therapeutic approaches and COVID-19-related diseases using MSCs and iPSCs.
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Affiliation(s)
- Kalaiselvaan Thanaskody
- Centre for Tissue Engineering and Regenerative Medicine (CTERM), Faculty of Medicine, University Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Amirah Syamimi Jusop
- Centre for Tissue Engineering and Regenerative Medicine (CTERM), Faculty of Medicine, University Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Gee Jun Tye
- Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia, Gelugor, Malaysia
| | - Wan Safwani Wan Kamarul Zaman
- Department of Biomedical Engineering, Faculty of Engineering, Universiti Malaya, Kuala Lumpur, Malaysia,Centre for Innovation in Medical Engineering (CIME), Department of Biomedical Engineering, Faculty of Engineering, Universiti Malaya, Kuala Lumpur, Malaysia
| | - Sylvia Annabel Dass
- Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia, Gelugor, Malaysia
| | - Fazlina Nordin
- Centre for Tissue Engineering and Regenerative Medicine (CTERM), Faculty of Medicine, University Kebangsaan Malaysia, Kuala Lumpur, Malaysia,*Correspondence: Fazlina Nordin,
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22
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Cheng J, Feng Y, Feng X, Wu D, Lu X, Rao Z, Li C, Lin N, Jia C, Zhang Q. Improving the immunomodulatory function of mesenchymal stem cells by defined chemical approach. Front Immunol 2022; 13:1005426. [PMID: 36203584 PMCID: PMC9530344 DOI: 10.3389/fimmu.2022.1005426] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Accepted: 08/31/2022] [Indexed: 11/30/2022] Open
Abstract
Mesenchymal stem cell (MSC) is a potential therapeutic material that has self-renewal, multilineage differentiation, and immunomodulation properties. However, the biological function of MSCs may decline due to the influence of donor differences and the in vitro expansion environment, which hinders the advancement of MSC-based clinical therapy. Here, we investigated a method for improving the immunomodulatory function of MSCs with the help of small-molecule compounds, A-83-01, CHIR99021, and Y27632 (ACY). The results showed that small-molecule induced MSCs (SM-MSCs) could enhance their immunosuppressive effects on T cells and macrophages. In vivo studies showed that, in contrast to control MSCs (Ctrl-MSCs), SM-MSCs could inhibit the inflammatory response in mouse models of delayed hypersensitivity and acute peritonitis more effectively. In addition, SM-MSCs showed the stronger ability to inhibit the infiltration of pro-inflammatory T cells and macrophages. Thus, small-molecule compounds ACY could better promote the immunomodulatory effect of MSCs, indicating it could be a potential improving method in MSC culture.
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Affiliation(s)
- Jintao Cheng
- Cell-Gene Therapy Translational Medicine Research Center, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yuan Feng
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xiao Feng
- Department of Hepatic Surgery, Liver Transplantation Center, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Donghao Wu
- Department of Medical Oncology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xu Lu
- Department of Hepatic Surgery, Liver Transplantation Center, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Zhihua Rao
- Tangxia Laboratory, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Cuiping Li
- Cell-Gene Therapy Translational Medicine Research Center, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Nan Lin
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- *Correspondence: Nan Lin, ; Changchang Jia, ; Qi Zhang,
| | - Changchang Jia
- Cell-Gene Therapy Translational Medicine Research Center, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- *Correspondence: Nan Lin, ; Changchang Jia, ; Qi Zhang,
| | - Qi Zhang
- Cell-Gene Therapy Translational Medicine Research Center, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- *Correspondence: Nan Lin, ; Changchang Jia, ; Qi Zhang,
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23
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Gao S, Zhang Y, Liang K, Bi R, Du Y. Mesenchymal Stem Cells (MSCs): A Novel Therapy for Type 2 Diabetes. Stem Cells Int 2022; 2022:8637493. [PMID: 36045953 PMCID: PMC9424025 DOI: 10.1155/2022/8637493] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Revised: 02/15/2022] [Accepted: 07/05/2022] [Indexed: 11/25/2022] Open
Abstract
Although plenty of drugs are currently available for type 2 diabetes mellitus (T2DM), a subset of patients still failed to restore normoglycemia. Recent studies proved that symptoms of T2DM patients who are unresponsive to conventional medications could be relieved with mesenchymal stem/stromal cell (MSC) therapy. However, the lack of systematic summary and analysis for animal and clinical studies of T2DM has limited the establishment of standard guidelines in anti-T2DM MSC therapy. Besides, the therapeutic mechanisms of MSCs to combat T2DM have not been thoroughly understood. In this review, we present an overview of the current status of MSC therapy in treating T2DM for both animal studies and clinical studies. Potential mechanisms of MSC-based intervention on multiple pathological processes of T2DM, such as β-cell exhaustion, hepatic dysfunction, insulin resistance, and systemic inflammation, are also delineated. Moreover, we highlight the importance of understanding the pharmacokinetics (PK) of transplanted cells and discuss the hurdles in MSC-based T2DM therapy toward future clinical applications.
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Affiliation(s)
- Shuang Gao
- Department of Biomedical Engineering, School of Medicine, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China
| | - Yuanyuan Zhang
- Department of Biomedical Engineering, School of Medicine, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China
| | - Kaini Liang
- Department of Biomedical Engineering, School of Medicine, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China
| | - Ran Bi
- Department of Biomedical Engineering, School of Medicine, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China
| | - Yanan Du
- Department of Biomedical Engineering, School of Medicine, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China
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24
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Hua Z, Li S, Liu Q, Yu M, Liao M, Zhang H, Xiang X, Wu Q. Low-Intensity Pulsed Ultrasound Promotes Osteogenic Potential of iPSC-Derived MSCs but Fails to Simplify the iPSC-EB-MSC Differentiation Process. Front Bioeng Biotechnol 2022; 10:841778. [PMID: 35656194 PMCID: PMC9152674 DOI: 10.3389/fbioe.2022.841778] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 04/07/2022] [Indexed: 11/29/2022] Open
Abstract
Induced pluripotent stem cell (iPSC)-derived mesenchymal stem cells (iMSCs) are a promising cell source for bone tissue engineering. However, iMSCs have less osteogenic potential than BMSCs, and the classical iPSC-EB-iMSC process to derive iMSCs from iPSCs is too laborious as it involves multiple in vitro steps. Low-intensity pulsed ultrasound (LIPUS) is a safe therapeutic modality used to promote osteogenic differentiation of stem cells. Whether LIPUS can facilitate osteogenic differentiation of iMSCs and simplify the iPSC-EB-iMSC process is unknown. We stimulated iMSCs with LIPUS at different output intensities (20, 40, and 60 mW/cm2) and duty cycles (20, 50, and 80%). Results of ALP activity assay, osteogenic gene expression, and mineralization quantification demonstrated that LIPUS was able to promote osteogenic differentiation of iMSCs, and it worked best at the intensity of 40 mW/cm2 and the duty cycle of 50% (LIPUS40/50). The Wnt/β-catenin signaling pathway was involved in LIPUS40/50-mediated osteogenesis. When cranial bone defects were implanted with iMSCs, LIPUS40/50 stimulation resulted in a significant higher new bone filling rate (72.63 ± 17.04)% than the non-stimulated ones (34.85 ± 4.53)%. Daily exposure to LIPUS40/50 may accelerate embryoid body (EB)-MSC transition, but it failed to drive iPSCs or EB cells to an osteogenic lineage directly. This study is the first to demonstrate the pro-osteogenic effect of LIPUS on iMSCs. Although LIPUS40/50 failed to simplify the classical iPSC-EB-MSC differentiation process, our preliminary results suggest that LIPUS with a more suitable parameter set may achieve the goal. LIPUS is a promising method to establish an efficient model for iPSC application.
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Affiliation(s)
| | | | | | | | | | | | | | - Qingqing Wu
- *Correspondence: Qingqing Wu, ; Xuerong Xiang,
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25
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Zhang L, Ma XJN, Fei YY, Han HT, Xu J, Cheng L, Li X. Stem cell therapy in liver regeneration: Focus on mesenchymal stem cells and induced pluripotent stem cells. Pharmacol Ther 2022; 232:108004. [PMID: 34597754 DOI: 10.1016/j.pharmthera.2021.108004] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 08/11/2021] [Accepted: 09/23/2021] [Indexed: 02/07/2023]
Abstract
The liver has the ability to repair itself after injury; however, a variety of pathological changes in the liver can affect its ability to regenerate, and this could lead to liver failure. Mesenchymal stem cells (MSCs) are considered a good source of cells for regenerative medicine, as they regulate liver regeneration through different mechanisms, and their efficacy has been demonstrated by many animal experiments and clinical studies. Induced pluripotent stem cells, another good source of MSCs, have also made great progress in the establishment of organoids, such as liver disease models, and in drug screening. Owing to the recent developments in MSCs and induced pluripotent stem cells, combined with emerging technologies including graphene, nano-biomaterials, and gene editing, precision medicine and individualized clinical treatment may be realized in the near future.
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Affiliation(s)
- Lu Zhang
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou 730000, PR China; Key Laboratory Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou 730000, PR China; The First School of Clinical Medicine, Lanzhou University, Lanzhou 730000, PR China
| | - Xiao-Jing-Nan Ma
- The First School of Clinical Medicine, Lanzhou University, Lanzhou 730000, PR China
| | - Yuan-Yuan Fei
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou 730000, PR China; Key Laboratory Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou 730000, PR China
| | - Heng-Tong Han
- The First School of Clinical Medicine, Lanzhou University, Lanzhou 730000, PR China
| | - Jun Xu
- The First School of Clinical Medicine, Lanzhou University, Lanzhou 730000, PR China
| | - Lu Cheng
- Key Laboratory Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou 730000, PR China
| | - Xun Li
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou 730000, PR China; Key Laboratory Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou 730000, PR China; Medical Frontier Innovation Research Center, The First Hospital of Lanzhou University, Lanzhou 730000, PR China; Hepatopancreatobiliary Surgery Institute of Gansu Province, Lanzhou 730000, PR China; The First School of Clinical Medicine, Lanzhou University, Lanzhou 730000, PR China.
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26
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Wang S, Umrath F, Cen W, Salgado AJ, Reinert S, Alexander D. Pre-Conditioning with IFN-γ and Hypoxia Enhances the Angiogenic Potential of iPSC-Derived MSC Secretome. Cells 2022; 11:cells11060988. [PMID: 35326438 PMCID: PMC8946902 DOI: 10.3390/cells11060988] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 03/03/2022] [Accepted: 03/10/2022] [Indexed: 12/23/2022] Open
Abstract
Induced pluripotent stem cell (iPSC) derived mesenchymal stem cells (iMSCs) represent a promising source of progenitor cells for approaches in the field of bone regeneration. Bone formation is a multi-step process in which osteogenesis and angiogenesis are both involved. Many reports show that the secretome of mesenchymal stromal stem cells (MSCs) influences the microenvironment upon injury, promoting cytoprotection, angiogenesis, and tissue repair of the damaged area. However, the effects of iPSC-derived MSCs secretome on angiogenesis have seldom been investigated. In the present study, the angiogenic properties of IFN-γ pre-conditioned iMSC secretomes were analyzed. We detected a higher expression of the pro-angiogenic genes and proteins of iMSCs and their secretome under IFN-γ and hypoxic stimulation (IFN-H). Tube formation and wound healing assays revealed a higher angiogenic potential of HUVECs in the presence of IFN-γ conditioned iMSC secretome. Sprouting assays demonstrated that within Coll/HA scaffolds, HUVECs spheroids formed significantly more and longer sprouts in the presence of IFN-γ conditioned iMSC secretome. Through gene expression analyses, pro-angiogenic genes (FLT-1, KDR, MET, TIMP-1, HIF-1α, IL-8, and VCAM-1) in HUVECs showed a significant up-regulation and down-regulation of two anti-angiogenic genes (TIMP-4 and IGFBP-1) compared to the data obtained in the other groups. Our results demonstrate that the iMSC secretome, pre-conditioned under inflammatory and hypoxic conditions, induced the highest angiogenic properties of HUVECs. We conclude that pre-activated iMSCs enhance their efficacy and represent a suitable cell source for collagen/hydroxyapatite with angiogenic properties.
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Affiliation(s)
- Suya Wang
- Department of Oral and Maxillofacial Surgery, University Hospital Tübingen, 72076 Tübingen, Germany; (S.W.); (F.U.); (W.C.); (S.R.)
| | - Felix Umrath
- Department of Oral and Maxillofacial Surgery, University Hospital Tübingen, 72076 Tübingen, Germany; (S.W.); (F.U.); (W.C.); (S.R.)
| | - Wanjing Cen
- Department of Oral and Maxillofacial Surgery, University Hospital Tübingen, 72076 Tübingen, Germany; (S.W.); (F.U.); (W.C.); (S.R.)
| | - António José Salgado
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal;
- ICVS/3B’s–PT Government Associate Laboratory, University of Minho, 4710-057 Braga, Portugal
| | - Siegmar Reinert
- Department of Oral and Maxillofacial Surgery, University Hospital Tübingen, 72076 Tübingen, Germany; (S.W.); (F.U.); (W.C.); (S.R.)
| | - Dorothea Alexander
- Department of Oral and Maxillofacial Surgery, University Hospital Tübingen, 72076 Tübingen, Germany; (S.W.); (F.U.); (W.C.); (S.R.)
- Correspondence:
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27
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Verma N, Fazioli A, Matijasich P. Natural recovery and regeneration of the central nervous system. Regen Med 2022; 17:233-244. [DOI: 10.2217/rme-2021-0084] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The diagnosis and management of CNS injuries comprises a large portion of psychiatric practice. Many clinical and preclinical studies have demonstrated the benefit of treating CNS injuries using various regenerative techniques and materials such as stem cells, biomaterials and genetic modification. Therefore it is the goal of this review article to briefly summarize the pathogenesis of CNS injuries, including traumatic brain injuries, spinal cord injuries and cerebrovascular accidents. Next, we discuss the role of natural recovery and regeneration of the CNS, explore the relevance in clinical practice and discuss emerging and cutting-edge treatments and current barriers in the field of regenerative medicine.
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Affiliation(s)
- Nikhil Verma
- Essential Sports & Spine Solutions, 6100 East Main Street 107, Columbus, OH 43213, USA
| | - Alex Fazioli
- Lake Erie College of Osteopathic Medicine, Erie, PA 16509, USA
| | - Paige Matijasich
- University of Toledo College of Medicine & Life Sciences, Toledo, OH 43614, USA
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28
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Ding L, Zhou B, Hou Y, Xu L. Stem cells in tendon regeneration and factors governing tenogenesis. Curr Stem Cell Res Ther 2022; 17:503-512. [PMID: 35086458 DOI: 10.2174/1574888x17666220127111135] [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: 08/23/2021] [Revised: 11/16/2021] [Accepted: 12/08/2021] [Indexed: 11/22/2022]
Abstract
Tendons are connective tissue structures of paramount importance to the human ability of locomotion. Tendinopathy and tendon rupture can be resistant to treatment and often recurs, thus resulting in a significant health problem with a relevant social impact worldwide. Unfortunately, existing treatment approaches are suboptimal. A better understanding of the basic biology of tendons may provide a better way to solve these problems and promote tendon regeneration. Stem cells, either obtained from tendons or non-tendon sources, such as bone marrow (BMSCs), adipose tissue (AMSCs), as well as embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), have received increasing attention toward enhancing tendon healing. There are many studies showing that stem cells can contribute to improving tendon healing. Hence, in this review, the current knowledge of BMSCs, AMSCs, TSPCs, ESCs and iPSCs for tendon regeneration, as well as the advantages and limitations among them, has been highlighted. Moreover, the transcriptional and bioactive factors governing tendon healing processes have been discussed.
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Affiliation(s)
- Lingli Ding
- Lingnan Medical Research Center, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - BingYu Zhou
- Lingnan Medical Research Center, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yonghui Hou
- Key Laboratory of Orthopaedics & Traumatology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, PR China
| | - Liangliang Xu
- Lingnan Medical Research Center, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
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Shah P, Shende P. Biotherapy using sperm cell-oriented transportation of therapeutics in female reproductive tract cancer. Curr Pharm Biotechnol 2022; 23:1359-1366. [PMID: 35049429 DOI: 10.2174/1389201023666220113111441] [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: 08/23/2021] [Revised: 11/08/2021] [Accepted: 12/28/2021] [Indexed: 12/24/2022]
Abstract
Female reproductive tract cancers like ovarian, cervical, vaginal, etc. have led to a serious concern for reproductive health as well as an increase in physical and psychological stresses amongst women. Various conventional techniques like surgery, radiation and chemotherapy are employed but possess limitations such as organ toxicity, infection, nausea, vomiting, etc. Also, several nanotechnology-based synthetic vehicle delivery systems like liposomes, nanoparticles, etc. are used but they lack targeting efficiency that results in poor propulsion and control. Therefore, there is a need for naturally-driven drug carriers to overcome such limitations. Sperm-based drug delivery is the new area for targeted delivery that offers self-propulsion to tumor sites, higher biocompatibility, longer lifespan and increased tissue penetration with enhanced localization. Drug-loaded sperm cells are harnessed with micro/nanomotor that will guide them to the intended target site. The critical analysis of the sperm-based drug delivery system was executed and summarized along with the current challenges. This article deals with the art of delivering the anticancer drug to female reproductive cancer sites with proof-of-concept-based research data and critical discussion on challenges in formulating the sperm-based delivery with a future perspective.
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Affiliation(s)
- Priyank Shah
- Shobhaben Pratapbhai Patel School of Pharmacy and Technology Management, SVKM' S NMIMS, V. L. Mehta Road, Vile Parle (W), Mumbai, India
| | - Pravin Shende
- Shobhaben Pratapbhai Patel School of Pharmacy and Technology Management, SVKM' S NMIMS, V. L. Mehta Road, Vile Parle (W), Mumbai, India
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30
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Wang Z, Chen H, Wang P, Zhou M, Li G, Hu Z, Hu Q, Zhao J, Liu X, Wu L, Liang D. OUP accepted manuscript. Stem Cells Transl Med 2022; 11:297-309. [PMID: 35267023 PMCID: PMC8968737 DOI: 10.1093/stcltm/szab031] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Accepted: 11/22/2021] [Indexed: 11/27/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are a promising cellular vehicle for transferring anti-cancer factors to malignant tumors. Currently, a variety of anti-cancer agents, including the tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), have been loaded into MSCs derived from a range of sources through different engineering methods. These engineered MSCs exhibit enormous therapeutic potential for various cancers. To avoid the intrinsic defects of MSCs derived from tissues and the potential risk of viral vectors, TRAIL was site-specifically integrated into the ribosomal DNA (rDNA) locus of human-induced pluripotent stem cells (iPSCs) using a non-viral rDNA-targeting vector and transcription activator-like effector nickases (TALENickases). These genetically modified human iPSCs were differentiated into an unlimited number of homogeneous induced MSCs (TRAIL-iMSCs) that overexpressed TRAIL in both culture supernatants and cell lysates while maintaining MSC-like characteristics over continuous passages. We found that TRAIL-iMSCs significantly induced apoptosis in A375, A549, HepG2, and MCF-7 cells in vitro. After intravenous infusion, TRAIL-iMSCs had a prominent tissue tropism for A549 or MCF-7 xenografts and significantly inhibited tumor growth through the activation of apoptotic signaling pathways without obvious side effects in tumor-bearing mice models. Altogether, our results showed that TRAIL-iMSCs have strong anti-tumor effects in vitro and in vivo on a range of cancers. This study allows for the development of an unlimited number of therapeutic gene-targeted MSCs with stable quality and high homogeneity for cancer therapy, thus highlighting a universal and safe strategy for stem cell-based gene therapy with high potential for clinical applications.
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Affiliation(s)
- Zujia Wang
- Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, People’s Republic of China
| | - Hongting Chen
- Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, People’s Republic of China
| | - Peiyun Wang
- Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, People’s Republic of China
| | - Miaojin Zhou
- Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, People’s Republic of China
| | - Guangxu Li
- Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, People’s Republic of China
| | - Zhiqing Hu
- Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, People’s Republic of China
| | - Qian Hu
- Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, People’s Republic of China
| | - Junya Zhao
- Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, People’s Republic of China
| | - Xionghao Liu
- Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, People’s Republic of China
| | - Lingqian Wu
- Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, People’s Republic of China
- Corresponding authors: Lingqian Wu, MD, PhD, Professor, Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, 110 Xiangya Road, Changsha, Hunan 410078, People’s Republic of China. Tel: +86-731-84805252; Fax: +86-731-84478152;
| | - Desheng Liang
- Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, People’s Republic of China
- Desheng Liang, MD, PhD, Professor, Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, 110 Xiangya Road, Changsha, Hunan 410078, People’s Republic of China. Tel: +86-731-84805252; Fax: +86-731-84478152;
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Weng Z, Wang Y, Ouchi T, Liu H, Qiao X, Wu C, Zhao Z, Li L, Li B. OUP accepted manuscript. Stem Cells Transl Med 2022; 11:356-371. [PMID: 35485439 PMCID: PMC9052415 DOI: 10.1093/stcltm/szac004] [Citation(s) in RCA: 128] [Impact Index Per Article: 42.7] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Accepted: 12/19/2021] [Indexed: 11/14/2022] Open
Affiliation(s)
| | | | - Takehito Ouchi
- Department of Physiology, Tokyo Dental College, Tokyo, Japan
| | - Hanghang Liu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Oral Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, People’s Republic of China
| | - Xianghe Qiao
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, People’s Republic of China
| | - Chenzhou Wu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, People’s Republic of China
| | - Zhihe Zhao
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, People’s Republic of China
| | - Longjiang Li
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, People’s Republic of China
| | - Bo Li
- Corresponding author: Bo Li, DDS, PhD, State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, No.14, 3rd Section of Ren Min Nan Rd. Chengdu, Sichuan 610041, People’s Republic of China.
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32
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Tieu A, Hu K, Gnyra C, Montroy J, Fergusson DA, Allan DS, Stewart DJ, Thébaud B, Lalu MM. Mesenchymal stromal cell extracellular vesicles as therapy for acute and chronic respiratory diseases: A meta-analysis. J Extracell Vesicles 2021; 10:e12141. [PMID: 34596349 PMCID: PMC8485337 DOI: 10.1002/jev2.12141] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Revised: 07/30/2021] [Accepted: 08/23/2021] [Indexed: 12/15/2022] Open
Abstract
Preclinical studies suggest mesenchymal stromal cell extracellular vesicles (MSC-EVs) reduce inflammation and improve organ function in lung diseases; however, an objective analysis of all available data is needed prior to translation. Using rigorous meta-research methods, we determined the effectiveness of MSC-EVs for preclinical respiratory diseases and identified experimental conditions that may further refine this therapy. A systematic search of MEDLINE/Embase identified 1167 records. After screening, 52 articles were included for data extraction and evaluated for risk of bias and quality of reporting in study design. A random effects meta-analysis was conducted for acute lung injury (ALI; N = 23), bronchopulmonary dysplasia (BPD; N = 8) and pulmonary arterial hypertension (PAH; N = 7). Subgroup analyses identified EV methods/characteristics that may be associated with improved efficacy. Data is presented as standardized mean differences (SMD) or risk ratios (RR) with 95% confidence intervals (CI). For ALI, MSC-EVs markedly reduced lung injury (SMD -4.33, CI -5.73 to -2.92), vascular permeability (SMD -2.43, CI -3.05 to -1.82), and mortality (RR 0.39, CI 0.22 to 0.68). Small EVs were more consistently effective than large EVs whereas no differences were observed between tissue sources, immunocompatibility or isolation techniques. For BPD, alveolarization was improved by MSC-EVs (SMD -1.45, CI -2.08 to -0.82) with small EVs more consistently beneficial then small/large EVs. In PAH, right ventricular systolic pressure (SMD -4.16, CI -5.68 to -2.64) and hypertrophy (SMD -2.80, CI -3.68 to -1.91) were significantly attenuated by EVs. In BPD and PAH, EVs isolated by ultracentrifugation demonstrated therapeutic benefit whereas tangential flow filtration (N = 2) displayed minimal efficacy. Lastly, risk of bias and quality of reporting for experimental design were consistently unclear across all studies. Our findings demonstrate clear potential of MSC-EVs to be developed as therapy for acute and chronic lung diseases. However, greater transparency in research design and direct comparisons of isolation technique and EV subtypes are needed to generate robust evidence to guide clinical translation. Protocol Registration: PROSPERO CRD42020145334.
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Affiliation(s)
- Alvin Tieu
- Department of Cellular and Molecular MedicineUniversity of OttawaOttawaOntarioCanada
- Clinical Epidemiology ProgramBLUEPRINT Translational Research Group, Ottawa Hospital Research InstituteOttawaOntarioCanada
- Regenerative Medicine ProgramOttawa Hospital Research InstituteOttawaOntarioCanada
| | - Kevin Hu
- Clinical Epidemiology ProgramBLUEPRINT Translational Research Group, Ottawa Hospital Research InstituteOttawaOntarioCanada
| | - Catherine Gnyra
- Clinical Epidemiology ProgramBLUEPRINT Translational Research Group, Ottawa Hospital Research InstituteOttawaOntarioCanada
| | - Joshua Montroy
- Clinical Epidemiology ProgramBLUEPRINT Translational Research Group, Ottawa Hospital Research InstituteOttawaOntarioCanada
| | - Dean A. Fergusson
- Clinical Epidemiology ProgramBLUEPRINT Translational Research Group, Ottawa Hospital Research InstituteOttawaOntarioCanada
- Department of MedicineThe Ottawa HospitalOttawaOntarioCanada
| | - David S. Allan
- Clinical Epidemiology ProgramBLUEPRINT Translational Research Group, Ottawa Hospital Research InstituteOttawaOntarioCanada
- Regenerative Medicine ProgramOttawa Hospital Research InstituteOttawaOntarioCanada
- Department of MedicineThe Ottawa HospitalOttawaOntarioCanada
| | - Duncan J. Stewart
- Department of Cellular and Molecular MedicineUniversity of OttawaOttawaOntarioCanada
- Regenerative Medicine ProgramOttawa Hospital Research InstituteOttawaOntarioCanada
- Department of MedicineThe Ottawa HospitalOttawaOntarioCanada
| | - Bernard Thébaud
- Department of Cellular and Molecular MedicineUniversity of OttawaOttawaOntarioCanada
- Regenerative Medicine ProgramOttawa Hospital Research InstituteOttawaOntarioCanada
- Division of NeonatologyDepartment of PediatricsChildren's Hospital of Eastern OntarioOttawaOntarioCanada
| | - Manoj M. Lalu
- Department of Cellular and Molecular MedicineUniversity of OttawaOttawaOntarioCanada
- Clinical Epidemiology ProgramBLUEPRINT Translational Research Group, Ottawa Hospital Research InstituteOttawaOntarioCanada
- Regenerative Medicine ProgramOttawa Hospital Research InstituteOttawaOntarioCanada
- Departments of Anesthesiology and Pain Medicine, The Ottawa HospitalOttawaOntarioCanada
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Gonçalves AM, Moreira A, Weber A, Williams GR, Costa PF. Osteochondral Tissue Engineering: The Potential of Electrospinning and Additive Manufacturing. Pharmaceutics 2021; 13:983. [PMID: 34209671 PMCID: PMC8309012 DOI: 10.3390/pharmaceutics13070983] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Revised: 06/22/2021] [Accepted: 06/25/2021] [Indexed: 12/14/2022] Open
Abstract
The socioeconomic impact of osteochondral (OC) damage has been increasing steadily over time in the global population, and the promise of tissue engineering in generating biomimetic tissues replicating the physiological OC environment and architecture has been falling short of its projected potential. The most recent advances in OC tissue engineering are summarised in this work, with a focus on electrospun and 3D printed biomaterials combined with stem cells and biochemical stimuli, to identify what is causing this pitfall between the bench and the patients' bedside. Even though significant progress has been achieved in electrospinning, 3D-(bio)printing, and induced pluripotent stem cell (iPSC) technologies, it is still challenging to artificially emulate the OC interface and achieve complete regeneration of bone and cartilage tissues. Their intricate architecture and the need for tight spatiotemporal control of cellular and biochemical cues hinder the attainment of long-term functional integration of tissue-engineered constructs. Moreover, this complexity and the high variability in experimental conditions used in different studies undermine the scalability and reproducibility of prospective regenerative medicine solutions. It is clear that further development of standardised, integrative, and economically viable methods regarding scaffold production, cell selection, and additional biochemical and biomechanical stimulation is likely to be the key to accelerate the clinical translation and fill the gap in OC treatment.
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Affiliation(s)
| | - Anabela Moreira
- BIOFABICS, Rua Alfredo Allen 455, 4200-135 Porto, Portugal; (A.M.G.); (A.M.)
| | - Achim Weber
- Fraunhofer Institute for Interfacial Engineering and Biotechnology IGB, Nobelstrasse 12, 70569 Stuttgart, Germany;
| | - Gareth R. Williams
- UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London WC1N 1AX, UK;
| | - Pedro F. Costa
- BIOFABICS, Rua Alfredo Allen 455, 4200-135 Porto, Portugal; (A.M.G.); (A.M.)
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34
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Lee MS, Yip HK, Yang CC, Chiang JY, Huang TH, Li YC, Chen KH, Sung PH. Overexpression of miR-19a and miR-20a in iPS-MSCs preserves renal function of chronic kidney disease with acute ischaemia-reperfusion injury in rat. J Cell Mol Med 2021; 25:7675-7689. [PMID: 34161651 PMCID: PMC8358869 DOI: 10.1111/jcmm.16613] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 04/19/2021] [Accepted: 04/23/2021] [Indexed: 12/29/2022] Open
Abstract
This study tested the hypothesis that therapy with double overexpression of miR‐19a‐3p and miR‐20a‐5p (miRDOE) to human inducible pluripotent stem cell–derived mesenchymal stem cells (iPS‐MSCs) was superior to iPS‐MSCs alone for preserving renal function in rat with pre‐existing chronic kidney disease (CKD), followed by ischaemia‐reperfusion (IR) injury. In vitro study demonstrated that the protein expressions of oxidative stress (NOX‐1/NOX‐2/NOX4/oxidized protein/p22phox), inflammatory downstream signalling (TLR2&4/MyD88/TRAF6/IKK‐ß/p‐NFκB/IL‐1ß/IL‐6/MMP‐9) and cell apoptosis/death signalling (cleaved caspase‐3/mitochondrial Bax/p‐ERKs/p‐JNK/p‐p38) at time‐points of 24‐hour/48‐hour cell cultures were significantly increased in p‐Cresol‐treated NRK‐52E cells than in the control that was significantly reversed by miR‐19a‐3p‐transfected iPS‐MSC (all P < .001). Animals were categorized into group 1 (sham‐operated control), group 2 (CKD‐IR), group 3 (CKD‐IR + oligo‐miRDOE of iPS‐MSCs/6.0 ×105/intra‐renal artery transfusion/3 hours after IR procedure), group 4 (CKD‐IR + iPS‐MSCs) and group 5 (CKD‐IR + miRDOE of iPS‐MSCs/6.0 ×105/intra‐renal artery transfusion/3 hour after IR procedure). By day 35, the creatinine/BUN levels were lowest in group 1, highest in group 2 and significantly lower in group 5 than in groups 3 and 4 (all P < .0001) but they showed no difference between the latter two groups. The protein expressions of oxidative stress, inflammatory downstream signalling and cell apoptosis/death signalling exhibited an identical pattern of creatinine level among the five groups (all P < .00001). Also, the microscopic findings demonstrated that the kidney injury score/fibrotic area/number of inflammatory cells (CD14+/CD68+) exhibited an identical pattern of creatine level (all P < .0001). The miRDOE of iPS‐MSCs was superior to iPS‐MSCs for preserving the residual kidney function and architecture in CKD‐IR rat.
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Affiliation(s)
- Mel S Lee
- Department of Orthopedics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Hon-Kan Yip
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.,Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.,Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.,Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan.,Department of Nursing, Asia University, Taichung, Taiwan.,Division of Cardiology, Department of Internal Medicine, Xiamen Chang Gung Hospital, Xiamen, China
| | - Chih-Chao Yang
- Division of Nephrology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - John Y Chiang
- Department of Computer Science and Engineering, National Sun Yat-Sen University, Kaohsiung, Taiwan
| | - Tien-Hung Huang
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.,Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.,Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Yi-Chen Li
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Kuan-Hung Chen
- Department of Anesthesiology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Pei-Hsun Sung
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.,Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.,Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
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Chung MJ, Son JY, Park S, Park SS, Hur K, Lee SH, Lee EJ, Park JK, Hong IH, Kim TH, Jeong KS. Mesenchymal Stem Cell and MicroRNA Therapy of Musculoskeletal Diseases. Int J Stem Cells 2021; 14:150-167. [PMID: 33377459 PMCID: PMC8138662 DOI: 10.15283/ijsc20167] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 11/24/2020] [Accepted: 11/30/2020] [Indexed: 02/06/2023] Open
Abstract
The therapeutic effects of mesenchymal stem cells (MSCs) in musculoskeletal diseases (MSDs) have been verified in many human and animal studies. Although some tissues contain MSCs, the number of cells harvested from those tissues and rate of proliferation in vitro are not enough for continuous transplantation. In order to produce and maintain stable MSCs, many attempts are made to induce differentiation from pluripotent stem cells (iPSCs) into MSCs. In particular, it is also known that the paracrine action of stem cell-secreted factors could promote the regeneration and differentiation of target cells in damaged tissue. MicroRNAs (miRNAs), one of the secreted factors, are small non-coding RNAs that regulate the translation of a gene. It is known that miRNAs help communication between stem cells and their surrounding niches through exosomes to regulate the proliferation and differentiation of stem cells. While studies have so far been underway targeting therapeutic miRNAs of MSDs, studies on specific miRNAs secreted from MSCs are still minimal. Hence, our ultimate goal is to obtain sufficient amounts of exosomes from iPSC-MSCs and develop them into therapeutic agents, furthermore to select specific miRNAs and provide safe cell-free clinical setting as a cell-free status with purpose of delivering them to target cells. This review article focuses on stem cell therapy on MSDs, specific microRNAs regulating MSDs and updates on novel approaches.
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Affiliation(s)
- Myung-Jin Chung
- Department of Pathology, College of Veterinary Medicine, Kyungpook National University, Daegu, Korea
| | - Ji-Yoon Son
- Department of Pathology, College of Veterinary Medicine, Kyungpook National University, Daegu, Korea
| | - SunYoung Park
- Department of Pathology, College of Veterinary Medicine, Kyungpook National University, Daegu, Korea.,Stem Cell Therapeutic Research Institute, Kyungpook National University, Daegu, Korea
| | - Soon-Seok Park
- Department of Pathology, College of Veterinary Medicine, Kyungpook National University, Daegu, Korea
| | - Keun Hur
- School of Medicine, Kyungpook National University, Daegu, Korea
| | - Sang-Han Lee
- Department of Food Science & Biotechnology, Kyungpook National University, Daegu, Korea
| | - Eun-Joo Lee
- Department of Pathology, College of Veterinary Medicine, Kyungpook National University, Daegu, Korea
| | - Jin-Kyu Park
- Department of Pathology, College of Veterinary Medicine, Kyungpook National University, Daegu, Korea.,Stem Cell Therapeutic Research Institute, Kyungpook National University, Daegu, Korea
| | - Il-Hwa Hong
- Department of Veterinary Pathology, College of Veterinary Medicine, Gyeongsang National University, Jinju, Korea
| | - Tae-Hwan Kim
- Department of Pathology, College of Veterinary Medicine, Kyungpook National University, Daegu, Korea
| | - Kyu-Shik Jeong
- Department of Pathology, College of Veterinary Medicine, Kyungpook National University, Daegu, Korea.,Stem Cell Therapeutic Research Institute, Kyungpook National University, Daegu, Korea
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Kamaraj A, Kyriacou H, Seah KTM, Khan WS. Use of human induced pluripotent stem cells for cartilage regeneration in vitro and within chondral defect models of knee joint cartilage in vivo: a Preferred Reporting Items for Systematic Reviews and Meta-Analyses systematic literature review. Cytotherapy 2021; 23:647-661. [PMID: 34059422 DOI: 10.1016/j.jcyt.2021.03.008] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 03/16/2021] [Accepted: 03/27/2021] [Indexed: 12/16/2022]
Abstract
BACKGROUND AIMS Articular cartilage has limited regenerative ability when damaged through trauma or disease. Failure to treat focal chondral lesions results in changes that inevitably progress to osteoarthritis. Osteoarthritis is a major contributor to disability globally, which results in significant medical costs and lost wages every year. Human induced pluripotent stem cells (hiPSCs) have long been considered a potential autologous therapeutic option for the treatment of focal chondral lesions. Although there are significant advantages to hiPSCs over other stem cell options, such as mesenchymal and embryonic stem cells, there are concerns regarding their ability to form bona fide cartilage and their tumorgenicity in vivo. METHODS The authors carried out a systematic literature review on the use of hiPSCs to produce differentiated progeny capable of producing high-quality cartilage in vitro and regenerate cartilage in osteochondral defects in vivo in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Eight studies were included in the review that used hiPSCs or their derived progeny in xenogeneic transplants in animal models to regenerate cartilage in osteochondral defects of the knee joint. The in vitro-differentiated, hiPSC-derived and in vivo defect repair ability of the hiPSC-derived progeny transplants were assessed. RESULTS Most studies reported the generation of high-quality cartilage-producing progeny that were able to successfully repair cartilage defects in vivo. No tumorigenicity was observed. CONCLUSIONS The authors conclude that hiPSCs offer a valuable source of cartilage-producing progeny that show promise as an effective cell-based therapy in treating focal chondral lesions.
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Affiliation(s)
- Achi Kamaraj
- Division of Trauma and Orthopedic Surgery, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK
| | - Harry Kyriacou
- Division of Trauma and Orthopedic Surgery, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK
| | - K T Matthew Seah
- Division of Trauma and Orthopedic Surgery, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK.
| | - Wasim S Khan
- Division of Trauma and Orthopedic Surgery, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK
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Induced pluripotent stem cell-derived mesenchymal stem cells deliver exogenous miR-105-5p via small extracellular vesicles to rejuvenate senescent nucleus pulposus cells and attenuate intervertebral disc degeneration. Stem Cell Res Ther 2021; 12:286. [PMID: 33985571 PMCID: PMC8117270 DOI: 10.1186/s13287-021-02362-1] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Accepted: 04/28/2021] [Indexed: 12/24/2022] Open
Abstract
Background Mesenchymal stem cell-derived small extracellular vesicles (MSC-sEVs) have emerged as a promising new therapeutic strategy for intervertebral disc degeneration (IVDD). However, the drawbacks of MSCs, including their invasive access, the donor age, and their limited proliferative capacity, hinder the quantity and quality of MSC-sEVs. Induced pluripotent stem cell-derived MSCs (iMSCs) provide an indefinite source of MSCs with well-defined phenotype and function. This study aimed to investigate the therapeutic effect of sEVs derived from iMSC (iMSC-sEVs) on IVDD and explore the underlying molecular mechanisms. Methods IVDD models were established by puncturing discs from the tails of rats. Then, iMSC-sEVs were injected into the punctured discs. The degeneration of punctured discs was assessed using MRI and HE and immunofluorescence staining. The age-related phenotypes were used to determine the effects of iMSC-sEVs on senescent nucleus pulposus cells (NPCs) in vitro. Western blotting was used to detect the expression of Sirt6. miRNA sequencing analysis was used to find miRNAs that potentially mediate the activation of Sirt6. Results After intradiscally injecting iMSC-sEVs, NPC senescence and IVDD were significantly improved. iMSC-sEVs could rejuvenate senescent NPCs and restore the age-related function by activating the Sirt6 pathway in vitro. Further, microRNA sequence analysis showed that iMSC-sEVs were highly enriched in miR-105-5p, which played a pivotal role in the iMSC-sEV-mediated therapeutic effect by downregulating the level of the cAMP-specific hydrolase PDE4D and could lead to Sirt6 activation. Conclusion iMSC-sEVs could rejuvenate the senescence of NPCs and attenuate the development of IVDD. iMSC-sEVs exerted their anti-ageing effects by delivering miR-105-5p to senescent NPCs and activating the Sirt6 pathway. Our findings indicate that iMSCs are a promising MSC candidate for obtaining sEVs on a large scale, while avoiding several defects related to the present applications of MSCs, and that iMSC-sEVs could be a novel cell-free therapeutic tool for the treatment of IVDD.
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Vadalà G, Ambrosio L, Russo F, Papalia R, Denaro V. Stem Cells and Intervertebral Disc Regeneration Overview-What They Can and Can't Do. Int J Spine Surg 2021; 15:40-53. [PMID: 34376495 DOI: 10.14444/8054] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Low back pain (LPB) is the main cause of disability worldwide with enormous socioeconomic burdens. A major cause of LBP is intervertebral disc degeneration (IDD): a chronic, progressive process associated with exhaustion of the resident cell population, tissue inflammation, degradation of the extracellular matrix and dehydration of the nucleus pulposus. Eventually, IDD may lead to serious sequelae including chronic LBP, disc herniation, segmental instability, and spinal stenosis, which may require invasive surgical interventions. However, no treatment is actually able to directly tackle IDD and hamper the degenerative process. In the last decade, the intradiscal injection of stem cells is raising as a promising approach to regenerate the intervertebral disc. This review aims to describe the rationale behind a regenerative stem cell therapy for IDD as well as the effect of stem cells following their implantation in the disc environment according to preclinical studies. Furthermore, actual clinical evidence and ongoing trials will be discussed, taking into account the future perspective and current limitations of this cutting-edge therapy. METHODS A literature analysis was performed for this narrative review. A database search of PubMed, Scopus and ClinicalTrials.gov was conducted using "stem cells" combined with "intervertebral disc", "degeneration" and "regeneration" without exclusion based on publication date. Articles were firstly screened on a title-abstract basis and, subsequently, full-text were reviewed. Both preclinical and clinical studies have been included. RESULTS The database search yielded recent publications from which the narrative review was completed. CONCLUSIONS Based on available evidence, intradiscal stem cell therapy has provided encouraging results in terms of regenerative effects and reduction of LBP. However, multicenter, prospective randomized trials are needed in order confirm the safety, efficacy and applicability of such a promising treatment.
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Affiliation(s)
- Gianluca Vadalà
- Department of Orthopaedic and Trauma Surgery, Campus Bio-Medico University of Rome, Rome, Italy
| | - Luca Ambrosio
- Department of Orthopaedic and Trauma Surgery, Campus Bio-Medico University of Rome, Rome, Italy
| | - Fabrizio Russo
- Department of Orthopaedic and Trauma Surgery, Campus Bio-Medico University of Rome, Rome, Italy
| | - Rocco Papalia
- Department of Orthopaedic and Trauma Surgery, Campus Bio-Medico University of Rome, Rome, Italy
| | - Vincenzo Denaro
- Department of Orthopaedic and Trauma Surgery, Campus Bio-Medico University of Rome, Rome, Italy
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In Vitro Generation of Vascular Wall-Typical Mesenchymal Stem Cells (VW-MSC) from Murine Induced Pluripotent Stem Cells Through VW-MSC-Specific Gene Transfer. Methods Mol Biol 2021. [PMID: 32474869 DOI: 10.1007/978-1-0716-0655-1_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] [Indexed: 10/13/2023]
Abstract
Among the adult stem cells, multipotent mesenchymal stem cells (MSCs) turned out to be a promising option for cell-based therapies for the treatment of various diseases including autoimmune and cardiovascular disorders. MSCs bear a high proliferation and differentiation capability and exert immunomodulatory functions while being still clinically safe. As tissue-resident stem cells, MSCs can be isolated from various tissue including peripheral or umbilical cord blood, placenta, blood, fetal liver, lung, adipose tissue, and blood vessels, although the most commonly used source for MSCs is the bone marrow. However, the proportion of MSCs in primary isolates from adult tissue biopsies is rather low, and therefore MSCs must be intensively expanded in vitro before the MSCs find particular use in therapies that may require extensive and repetitive cell replacement. Therefore, more easily accessible sources of MSCs are needed. Here, we present a detailed protocol to generate tissue-typical MSCs by direct linage conversion using transcription factors defining target MSC identity from murine induced pluripotent stem cells (iPSCs).
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Spellicy SE, Hess DC. The Immunomodulatory Capacity of Induced Pluripotent Stem Cells in the Post-stroke Environment. Front Cell Dev Biol 2021; 9:647415. [PMID: 33796535 PMCID: PMC8007866 DOI: 10.3389/fcell.2021.647415] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Accepted: 02/25/2021] [Indexed: 11/13/2022] Open
Abstract
Inflammation has proven to be a key contributing factor to the pathogenesis of ischemic and hemorrhagic stroke. This sequential and progressive response, marked by proliferation of resident immune cells and recruitment of peripheral immune populations, results in increased oxidative stress, and neuronal cell death. Therapeutics aimed at quelling various stages of this post-stroke inflammatory response have shown promise recently, one of which being differentiated induced pluripotent stem cells (iPSCs). While direct repopulation of damaged tissues and enhanced neurogenesis are hypothesized to encompass some of the therapeutic potential of iPSCs, recent evidence has demonstrated a substantial paracrine effect on neuroinflammation. Specifically, investigation of iPSCs, iPSC-neural progenitor cells (iPSC-NPCs), and iPSC-neuroepithelial like stem cells (iPSC-lt-NESC) has demonstrated significant immunomodulation of proinflammatory signaling and endogenous inflammatory cell populations, such as microglia. This review aims to examine the mechanisms by which iPSCs mediate neuroinflammation in the post-stroke environment, as well as delineate avenues for further investigation.
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Affiliation(s)
- Samantha E Spellicy
- MD-Ph.D. Program, Medical College of Georgia at Augusta University, Augusta, GA, United States
| | - David C Hess
- Dean's Office, Medical College of Georgia at Augusta University, Augusta, GA, United States
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Soudi A, Yazdanian M, Ranjbar R, Tebyanian H, Yazdanian A, Tahmasebi E, Keshvad A, Seifalian A. Role and application of stem cells in dental regeneration: A comprehensive overview. EXCLI JOURNAL 2021; 20:454-489. [PMID: 33746673 PMCID: PMC7975587 DOI: 10.17179/excli2021-3335] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/27/2020] [Accepted: 02/09/2021] [Indexed: 12/18/2022]
Abstract
Recently, a growing attention has been observed toward potential advantages of stem cell (SC)-based therapies in regenerative treatments. Mesenchymal stem/stromal cells (MSCs) are now considered excellent candidates for tissue replacement therapies and tissue engineering. Autologous MSCs importantly contribute to the state-of-the-art clinical strategies for SC-based alveolar bone regeneration. The donor cells and immune cells play a prominent role in determining the clinical success of MSCs therapy. In line with the promising future that stem cell therapy has shown for tissue engineering applications, dental stem cells have also attracted the attention of the relevant researchers in recent years. The current literature review aims to survey the variety and extension of SC-application in tissue-regenerative dentistry. In this regard, the relevant English written literature was searched using keywords: "tissue engineering", "stem cells", "dental stem cells", and "dentistry strategies". According to the available database, SCs application has become increasingly widespread because of its accessibility, plasticity, and high proliferative ability. Among the growing recognized niches and tissues containing higher SCs, dental tissues are evidenced to be rich sources of MSCs. According to the literature, dental SCs are mostly present in the dental pulp, periodontal ligament, and dental follicle tissues. In this regard, the present review has described the recent findings on the potential of dental stem cells to be used in tissue regeneration.
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Affiliation(s)
- Armin Soudi
- Research Center for Prevention of Oral and Dental Diseases, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Mohsen Yazdanian
- Research Center for Prevention of Oral and Dental Diseases, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Reza Ranjbar
- Research Center for Prevention of Oral and Dental Diseases, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Hamid Tebyanian
- Research Center for Prevention of Oral and Dental Diseases, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Alireza Yazdanian
- Department of Veterinary, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Elahe Tahmasebi
- Research Center for Prevention of Oral and Dental Diseases, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Ali Keshvad
- Research Center for Prevention of Oral and Dental Diseases, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Alexander Seifalian
- Nanotechnology and Regenerative Medicine Commercialization Centre (Ltd), The London Bioscience Innovation Centre, London, UK
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Gan QF, Foo CN, Leong PP, Cheong SK. Incorporating regenerative medicine into rehabilitation programmes: a potential treatment for ankle sprain. INTERNATIONAL JOURNAL OF THERAPY AND REHABILITATION 2021. [DOI: 10.12968/ijtr.2019.0119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Ankle sprain has a great effect on morbidity and complications of chronic diseases. Experts have come to a consensus where ankle sprain can be managed by rest, ice, compression and elevation, non-steroidal anti-inflammatory drugs, immobilisation, functional support such as the use of an ankle brace, exercise, surgery and other therapies that include physiotherapy modalities and acupuncture. However, the time required for healing is still relatively long in addition to post-operative complications. Because of the challenges and setbacks faced by interventions to manage ankle sprains and in view of the recent trend and development in the field of regenerative medicine, this article discusses future treatments focusing on a personalised and holistic approach for ankle sprain management. This narrative review provides a novel idea for incorporating regenerative medicine into conventional therapy as an intervention for ankle sprain based on theoretical concepts and available evidence on regenerative medicine involving ligament injuries.
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Affiliation(s)
- Quan Fu Gan
- Pre-clinical Department, Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Selangor, Malaysia
| | - Chai Nien Foo
- Population Medicine Department, Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Selangor, Malaysia
| | - Pooi Pooi Leong
- Pre-clinical Department, Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Selangor, Malaysia
| | - Soon Keng Cheong
- Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Selangor, Malaysia
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Gasson SB, Dobson LK, Chow L, Dow S, Gregory CA, Saunders WB. Optimizing In Vitro Osteogenesis in Canine Autologous and Induced Pluripotent Stem Cell-Derived Mesenchymal Stromal Cells with Dexamethasone and BMP-2. Stem Cells Dev 2021; 30:214-226. [PMID: 33356875 PMCID: PMC7891305 DOI: 10.1089/scd.2020.0144] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Accepted: 12/23/2020] [Indexed: 12/11/2022] Open
Abstract
A growing body of work suggests that canine mesenchymal stromal cells (cMSCs) require additional agonists such as bone morphogenic protein-2 (BMP-2) for consistent in vitro osteogenic differentiation. BMP-2 is costly and may challenge the translational relevance of the canine model. Dexamethasone enhances osteogenic differentiation of human MSCs (hMSCs) and is widely utilized in osteogenic protocols. The aim of this study was to determine the effect of BMP-2 and dexamethasone on early- and late-stage osteogenesis of autologous and induced pluripotent stem cell (iPS)-derived cMSCs. Two preparations of marrow-derived cMSCs were selected to represent exceptionally or marginally osteogenic autologous cMSCs. iPS-derived cMSCs were generated from canine fibroblasts. All preparations were evaluated using alkaline phosphatase (ALP) activity, Alizarin Red staining of osteogenic monolayers, and quantitative polymerase chain reaction. Data were reported as mean ± standard deviation and compared using one- or two-way analysis of variance and Tukey or Sidak post hoc tests. Significance was established at P < 0.05. In early-stage assays, dexamethasone decreased ALP activity for all cMSCs in the presence of BMP-2. In late-stage assays, inclusion of dexamethasone and BMP-2 at Day 1 of culture produced robust monolayer mineralization for autologous cMSCs. Delivering 100 nM dexamethasone at Day 1 improved mineralization and reduced the BMP-2 concentrations required to achieve mineralization of the marginal cMSCs. For iPS-cMSCs, dexamethasone was inhibitory to both ALP activity and monolayer mineralization. There was increased expression of osteocalcin and osterix with BMP-2 in autologous cMSCs but a more modest expression occurred in iPS cMSCs. While autologous and iPS-derived cMSCs respond similarly in early-stage osteogenic assays, they exhibit unique responses to dexamethasone and BMP-2 in late-stage mineralization assays. This study demonstrates that dexamethasone and BMP-2 can be titrated in a time- and concentration-dependent manner to enhance osteogenesis of autologous cMSC preparations. These results will prove useful for investigators performing translational studies with cMSCs while providing insight into iPS-derived cMSC osteogenesis.
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Affiliation(s)
- Shelby B. Gasson
- Department of Small Animal Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas, USA
| | - Lauren K. Dobson
- Department of Small Animal Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas, USA
| | - Lyndah Chow
- Department of Clinical Sciences, Center for Immune and Regenerative Medicine, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, Colorado, USA
| | - Steven Dow
- Department of Clinical Sciences, Center for Immune and Regenerative Medicine, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, Colorado, USA
| | - Carl A. Gregory
- Department of Molecular and Cellular Medicine, Institute for Regenerative Medicine, Texas A&M Health Science Center, College Station, Texas, USA
| | - William Brian Saunders
- Department of Small Animal Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas, USA
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Li S, Akrap N, Cerboni S, Porritt MJ, Wimberger S, Lundin A, Möller C, Firth M, Gordon E, Lazovic B, Sieńska A, Pane LS, Coelho MA, Ciotta G, Pellegrini G, Sini M, Xu X, Mitra S, Bohlooly-Y M, Taylor BJM, Sienski G, Maresca M. Universal toxin-based selection for precise genome engineering in human cells. Nat Commun 2021; 12:497. [PMID: 33479216 PMCID: PMC7820243 DOI: 10.1038/s41467-020-20810-z] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Accepted: 12/21/2020] [Indexed: 01/29/2023] Open
Abstract
Prokaryotic restriction enzymes, recombinases and Cas proteins are powerful DNA engineering and genome editing tools. However, in many primary cell types, the efficiency of genome editing remains low, impeding the development of gene- and cell-based therapeutic applications. A safe strategy for robust and efficient enrichment of precisely genetically engineered cells is urgently required. Here, we screen for mutations in the receptor for Diphtheria Toxin (DT) which protect human cells from DT. Selection for cells with an edited DT receptor variant enriches for simultaneously introduced, precisely targeted gene modifications at a second independent locus, such as nucleotide substitutions and DNA insertions. Our method enables the rapid generation of a homogenous cell population with bi-allelic integration of a DNA cassette at the selection locus, without clonal isolation. Toxin-based selection works in both cancer-transformed and non-transformed cells, including human induced pluripotent stem cells and human primary T-lymphocytes, as well as it is applicable also in vivo, in mice with humanized liver. This work represents a flexible, precise, and efficient selection strategy to engineer cells using CRISPR-Cas and base editing systems.
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Affiliation(s)
- Songyuan Li
- Translational Genomics, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
| | - Nina Akrap
- Translational Genomics, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Silvia Cerboni
- Translational Science and Experimental Medicine, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Michelle J Porritt
- Translational Genomics, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Sandra Wimberger
- Translational Genomics, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
- Department of Chemistry & Molecular Biology, University of Gothenburg, Gothenburg, Sweden
| | - Anders Lundin
- Translational Genomics, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Carl Möller
- Translational Genomics, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Mike Firth
- R&D Data Infrastructure & Tools, AstraZeneca, Cambridge, UK
| | - Euan Gordon
- Discovery Biology SWE, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Bojana Lazovic
- Translational Genomics, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
- Oulu Center for Cell-Matrix Research, Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland
| | - Aleksandra Sieńska
- Translational Genomics, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Luna Simona Pane
- Translational Genomics, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | | | - Giovanni Ciotta
- Discovery Biology UK, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
| | - Giovanni Pellegrini
- CVRM pathology, Clinical Pharmacology & Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Marcella Sini
- CVRM pathology, Clinical Pharmacology & Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Xiufeng Xu
- Department of Biosciences and Nutrition, Karolinska Institute, Stockholm, Sweden
| | - Suman Mitra
- Inserm UMR1277 CNRS UMR9020 - CANTHER, Institut pour la Recherche sur le Cancer de Lille, Lille, France
| | - Mohammad Bohlooly-Y
- Translational Genomics, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Benjamin J M Taylor
- Discovery Biology UK, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
| | - Grzegorz Sienski
- Translational Genomics, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
| | - Marcello Maresca
- Translational Genomics, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
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Tang H, Yi B, Wang X, Shen Y, Zhang Y. Understanding the cellular responses based on low-density electrospun fiber networks. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2020; 119:111470. [PMID: 33321594 DOI: 10.1016/j.msec.2020.111470] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 08/14/2020] [Accepted: 08/25/2020] [Indexed: 01/12/2023]
Abstract
Fibers produced from electrospinning are well-known to be extremely fine with diameters ranging from tens of nanometers to a few microns. Such ultrafine fibers not only allow for engineering scaffolds resembling the ultrastructure of the native extracellular matrix, but also offer possibility to explore the remodeling behavior of cells in vitro, due to their mechanically 'adequate' softness endowed by their ultrafine fineness. However, the remodeling effect of cells on the biomimicking fibrous substrates remains to be understood, because the crisscrossing and entangling among nanofibers in those tightly packed fibrous mats ultimately lead to merely a topological phenomenon, similar to that of the nanofiber-like topography embossed on the surface of a solid matter. In this study, the effect of nanofiber density on cellular response behavior was investigated by reducing the density of electrospun fiber networks. Using polycaprolactone (PCL) as a model polymer, randomly oriented fiber networks with various densities, namely, 37.7 ± 16.3 μg/cm2 (D1), 103.8 ± 16.3 μg/cm2 (D2), 198.2 ± 40.0 μg/cm2 (D3), and 471.8 ± 32.7 μg/cm2 (D4), were prepared by electrospinning for varied collection durations (10 s, 50 s, 100 s, and 10 min, respectively). By examining the responsive behavior of the human induced pluripotent stem cell-derived mesenchymal stem cells (hiPS-MSCs) cultured on these nanofibrous networks, we showed that the fiber network with a moderate density (D2) is beneficial to the cell attachment, spreading, actin polymerization, contractility and migration. There also showed an increased tendency in nuclear localization of the Yes-associated protein (YAP) and subsequent activation of YAP responsive gene transcription, and cell proliferation and collagen synthesis were also enhanced on the D2. However, further increasing the fiber density (D3, D4) gave rise to weakened induction effect of fibers on the cellular responses. These results enrich our understanding on the effect of fiber density on cell behavior, and disclose the dependence of cellular responses on fiber density. This study paves the way to precisely design biomimetic fibrous scaffolds for achieving enhanced cell-scaffold interactions and tissue regeneration.
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Affiliation(s)
- Han Tang
- College of Chemistry, Chemical Engineering & Biotechnology, Donghua University, Shanghai 201620, China
| | - Bingcheng Yi
- College of Chemistry, Chemical Engineering & Biotechnology, Donghua University, Shanghai 201620, China
| | - Xianliu Wang
- College of Chemistry, Chemical Engineering & Biotechnology, Donghua University, Shanghai 201620, China
| | - Yanbing Shen
- College of Chemistry, Chemical Engineering & Biotechnology, Donghua University, Shanghai 201620, China
| | - Yanzhong Zhang
- College of Chemistry, Chemical Engineering & Biotechnology, Donghua University, Shanghai 201620, China; Key Lab of Science & Technology of Eco-Textile, Ministry of Education, Donghua University, Shanghai 201620, China; Shanghai Key Laboratory of Tissue Engineering, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China; China Orthopaedic Regenerative Medicine Group (CORMed), Hangzhou 310058, China.
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Babaki D, Amoako K, Bahrami AR, Yaghoubi S, Mirahmadi M, Matin MM. MTA Enhances the Potential of Adipose-Derived Mesenchymal Stem Cells for Dentin-Pulp Complex Regeneration. MATERIALS (BASEL, SWITZERLAND) 2020; 13:E5712. [PMID: 33333801 PMCID: PMC7765251 DOI: 10.3390/ma13245712] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 12/02/2020] [Accepted: 12/07/2020] [Indexed: 11/16/2022]
Abstract
The aim of the current study was to investigate the effects of mineral trioxide aggregate (MTA) on the proliferation and differentiation of human adipose-derived mesenchymal stem cells (Ad-MSCs) as a surrogate cell source in futuristic stem-cell-based endodontic therapies. Human Ad-MSCs and mesenchymal stem cells derived from bone marrow (BM-MSCs) were isolated from liposuction waste adipose tissue and femur, respectively, and the effects of MTA-conditioned media on their viability, mineralization potential, and osteo/odontogenic differentiation capacity were subsequently evaluated. Alkaline phosphatase (ALP) activity, quantitative alizarin red S staining, and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analyses were performed to investigate and compare the osteo/odontogenic induction potential of MTA on the Ad/BM-MSCs. The results of cytotoxicity assay revealed that at different concentrations, MTA-conditioned medium was not only biocompatible toward both cell types, but also capable of promoting cell proliferation. ALP activity assay showed that 0.2 mg/mL was the optimal concentration of MTA-conditioned medium for osteo/odontogenic induction in Ad/BM-MSCs. The expression of osteo/odontogenic gene markers was increased in Ad/BM-MSCs treated with 0.2 mg/mL MTA-conditioned media. Our results indicated that MTA can efficiently enhance the osteo/odontogenic potential of Ad-MSCs, and thus they can be considered as a better cell source for dentin-pulp complex regeneration. However, further investigations are required to test these potentials in animal models.
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Affiliation(s)
- Danial Babaki
- Department of Biomedical Engineering, Tagliatela College of Engineering, University of New Haven, West Haven, CT 06516, USA; (D.B.); (K.A.)
| | - Kagya Amoako
- Department of Biomedical Engineering, Tagliatela College of Engineering, University of New Haven, West Haven, CT 06516, USA; (D.B.); (K.A.)
| | - Ahmad Reza Bahrami
- Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad 9177948974, Iran;
- Industrial Biotechnology Research Group, Institute of Biotechnology, Ferdowsi University of Mashhad, Mashhad 9177948974, Iran
| | - Sanam Yaghoubi
- Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA;
| | - Mahdi Mirahmadi
- Stem Cells and Regenerative Medicine Research Department, Iranian Academic Center for Education, Culture and Research (ACECR), Mashhad Branch, Mashhad 9177948974, Iran;
| | - Maryam M. Matin
- Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad 9177948974, Iran;
- Novel Diagnostics and Therapeutics Research Group, Institute of Biotechnology, Ferdowsi University of Mashhad, Mashhad 9177948974, Iran
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Induced Pluripotent Stem Cell-Differentiated Chondrocytes Repair Cartilage Defect in a Rabbit Osteoarthritis Model. Stem Cells Int 2020; 2020:8867349. [PMID: 33224204 PMCID: PMC7671807 DOI: 10.1155/2020/8867349] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 10/08/2020] [Accepted: 10/19/2020] [Indexed: 12/14/2022] Open
Abstract
The aim of this study was to explore the therapeutic effect of iPSC-mesenchymal stem cell (MSC)-derived chondrocytes in a rabbit osteoarthritis (OA) model. The iPSCs were characterized by gene expressions, immunostaining of pluripotent markers, and in vivo teratoma formation. iPSC-differentiated MSCs were characterized by flow cytometry and trilineage differentiation. A rabbit OA model was established by the transection of the anterior cruciate ligament. The therapeutic effect of transplanted iPSC-MSC-chondrocytes on the OA was evaluated by the histology, immunostaining, and qPCR of defective cartilage. The results showed iPSC could express pluripotency markers such as OCT4, SOX2, and NANOG and form an embryoid body and a teratoma. After differentiation of iPSCs for 30 days, MSCs were established. The iPSC-MSC could express typical MSC markers such as CD29, CD44, CD90, CD105, and HLA-ABC. They could differentiate into adipocytes, osteocytes, and chondrocytes. In this model, iPSC-MSC-chondrocytes significantly improved the histology and ICRS (International Cartilage Repair Society) scores. The transplanted cartilage expressed less IL-1β, TNF-α, and MMP13 than control cartilage. In conclusion, the iPSCs we derived might represent an emerging source for differentiated MSC-chondrocyte and might rescue cartilage defects through its anti-inflammatory and anti-catabolic effects.
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Fričová D, Korchak JA, Zubair AC. Challenges and translational considerations of mesenchymal stem/stromal cell therapy for Parkinson's disease. NPJ Regen Med 2020; 5:20. [PMID: 33298940 PMCID: PMC7641157 DOI: 10.1038/s41536-020-00106-y] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Accepted: 08/31/2020] [Indexed: 12/12/2022] Open
Abstract
Parkinson's disease (PD) is the second most common neurodegenerative disease characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta and the presence of Lewy bodies, which gives rise to motor and non-motor symptoms. Unfortunately, current therapeutic strategies for PD merely treat the symptoms of the disease, only temporarily improve the patients' quality of life, and are not sufficient for completely alleviating the symptoms. Therefore, cell-based therapies have emerged as a novel promising therapeutic approach in PD treatment. Mesenchymal stem/stromal cells (MSCs) have arisen as a leading contender for cell sources due to their regenerative and immunomodulatory capabilities, limited ethical concerns, and low risk of tumor formation. Although several studies have shown that MSCs have the potential to mitigate the neurodegenerative pathology of PD, variabilities in preclinical and clinical trials have resulted in inconsistent therapeutic outcomes. In this review, we strive to highlight the sources of variability in studies using MSCs in PD therapy, including MSC sources, the use of autologous or allogenic MSCs, dose, delivery methods, patient factors, and measures of clinical outcome. Available evidence indicates that while the use of MSCs in PD has largely been promising, conditions need to be standardized so that studies can be effectively compared with one another and experimental designs can be improved upon, such that this body of science can continue to move forward.
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Affiliation(s)
- Dominika Fričová
- Department of Laboratory Medicine and Pathology and Center for Regenerative Medicine, Mayo Clinic, Jacksonville, FL, USA
- Institute of Neuroimmunology, Slovak Academy of Sciences, Bratislava, Slovak Republic
| | - Jennifer A Korchak
- Department of Laboratory Medicine and Pathology and Center for Regenerative Medicine, Mayo Clinic, Jacksonville, FL, USA
| | - Abba C Zubair
- Department of Laboratory Medicine and Pathology and Center for Regenerative Medicine, Mayo Clinic, Jacksonville, FL, USA.
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Steens J, Unger K, Klar L, Neureiter A, Wieber K, Hess J, Jakob HG, Klump H, Klein D. Direct conversion of human fibroblasts into therapeutically active vascular wall-typical mesenchymal stem cells. Cell Mol Life Sci 2020; 77:3401-3422. [PMID: 31712992 PMCID: PMC7426315 DOI: 10.1007/s00018-019-03358-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Revised: 09/27/2019] [Accepted: 10/28/2019] [Indexed: 12/11/2022]
Abstract
Cell-based therapies using adult stem cells are promising options for the treatment of a number of diseases including autoimmune and cardiovascular disorders. Among these, vascular wall-derived mesenchymal stem cells (VW-MSCs) might be particularly well suited for the protection and curative treatment of vascular damage because of their tissue-specific action. Here we report a novel method for the direct conversion of human skin fibroblasts towards MSCs using a VW-MSC-specific gene code (HOXB7, HOXC6 and HOXC8) that directs cell fate conversion bypassing pluripotency. This direct programming approach using either a self-inactivating (SIN) lentiviral vector expressing the VW-MSC-specific HOX-code or a tetracycline-controlled Tet-On system for doxycycline-inducible gene expressions of HOXB7, HOXC6 and HOXC8 successfully mediated the generation of VW-typical MSCs with classical MSC characteristics in vitro and in vivo. The induced VW-MSCs (iVW-MSCs) fulfilled all criteria of MSCs as defined by the International Society for Cellular Therapy (ISCT). In terms of multipotency and clonogenicity, which are important specific properties to discriminate MSCs from fibroblasts, iVW-MSCs behaved like primary ex vivo isolated VW-MSCs and shared similar molecular and DNA methylation signatures. With respect to their therapeutic potential, these cells suppressed lymphocyte proliferation in vitro, and protected mice against vascular damage in a mouse model of radiation-induced pneumopathy in vivo, as well as ex vivo cultured human lung tissue. The feasibility to obtain patient-specific VW-MSCs from fibroblasts in large amounts by a direct conversion into induced VW-MSCs could potentially open avenues towards novel, MSC-based therapies.
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Affiliation(s)
- Jennifer Steens
- Institute for Cell Biology (Cancer Research), University Hospital Essen, Medical Faculty, University of Duisburg-Essen, Virchowstr. 173, Ger-45122, Essen, Germany
| | - Kristian Unger
- Research Unit Radiation Cytogenetics and Clinical Cooperation Group "Personalized Radiotherapy in Head and Neck Cancer, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, Neuherberg, Germany
- Department of Radiation Oncology, University Hospital, LMU Munich, Munich, Germany
| | - Lea Klar
- Institute for Cell Biology (Cancer Research), University Hospital Essen, Medical Faculty, University of Duisburg-Essen, Virchowstr. 173, Ger-45122, Essen, Germany
| | - Anika Neureiter
- Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Karolin Wieber
- Institute for Cell Biology (Cancer Research), University Hospital Essen, Medical Faculty, University of Duisburg-Essen, Virchowstr. 173, Ger-45122, Essen, Germany
| | - Julia Hess
- Research Unit Radiation Cytogenetics and Clinical Cooperation Group "Personalized Radiotherapy in Head and Neck Cancer, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, Neuherberg, Germany
- Department of Radiation Oncology, University Hospital, LMU Munich, Munich, Germany
| | - Heinz G Jakob
- Department of Thoracic and Cardiovascular Surgery, West-German Heart and Vascular Center Essen, University Duisburg-Essen, Essen, Germany
| | - Hannes Klump
- Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Diana Klein
- Institute for Cell Biology (Cancer Research), University Hospital Essen, Medical Faculty, University of Duisburg-Essen, Virchowstr. 173, Ger-45122, Essen, Germany.
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Tieu A, Lalu MM, Slobodian M, Gnyra C, Fergusson DA, Montroy J, Burger D, Stewart DJ, Allan DS. An Analysis of Mesenchymal Stem Cell-Derived Extracellular Vesicles for Preclinical Use. ACS NANO 2020; 14:9728-9743. [PMID: 32697573 DOI: 10.1021/acsnano.0c01363] [Citation(s) in RCA: 82] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) can reduce inflammation, promote healing, and improve organ function, thereby providing a potential "cell-free" therapy. Prior to clinical translation, it is critical to synthesize existing evidence on preclinical methods and efficacy. To address these issues, we used gold standard systematic review methodology to consolidate information from all published animal studies investigating MSC-EVs as an intervention. A systematic search of MEDLINE and Embase identified 206 studies. Data were extracted in duplicate for methodology, experimental design, interventional traits, modifications, and outcomes. MSC-EVs were used to treat a variety of diseases and demonstrated benefits in 97% of studies. Adverse effects were reported in only three studies, two demonstrating tumor growth. A quarter of articles modified EVs to enhance efficacy, with 72% leading to markedly improved outcomes as compared to unmodified EVs. However, several key methodological concerns were evident. Only 60% of studies used nomenclature consistent with the size definitions of EVs. Ultracentrifugation (70%) and isolation kits (23%) were the most common isolation techniques with noted differences in yield and purity. EVs were inconsistently dosed by protein (68%) or particle concentration (16%). Two-thirds of studies administered xenogeneic EVs, suggesting immunocompatibility. Less than 25% of studies assessed EV biodistribution. Approaches for determining size, protein markers, and morphology were highly heterogeneous, with only 12 and 4 studies meeting the MISEV 2014 and 2018 recommendations, respectively. Knowledge gaps identified from this systematic review highlight important opportunities to improve preclinical design and methodology in the rapidly growing field of EV therapeutics.
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Affiliation(s)
- Alvin Tieu
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Canada, K1H 8L1
| | - Manoj M Lalu
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Canada, K1H 8L1
- Departments of Anesthesiology and Pain Medicine, University of Ottawa, The Ottawa Hospital, Ottawa, Canada, K1H 8L6
| | | | | | | | | | - Dylan Burger
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Canada, K1H 8L1
| | - Duncan J Stewart
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Canada, K1H 8L1
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