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Wang J, Verkerk AO, Wilders R, Zhang Y, Zhang K, Prakosa A, Rivaud MR, Marsman EMJ, Boender AR, Klerk M, Fokkert L, de Jonge B, Neef K, Kirzner OF, Bezzina CR, Remme CA, Tan HL, Boukens BJ, Devalla HD, Trayanova NA, Christoffels VM, Barnett P, Boink GJJ. SCN10A-short gene therapy to restore conduction and protect against malignant cardiac arrhythmias. Eur Heart J 2025; 46:1747-1762. [PMID: 39973098 PMCID: PMC12055233 DOI: 10.1093/eurheartj/ehaf053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Revised: 05/27/2024] [Accepted: 01/23/2025] [Indexed: 02/21/2025] Open
Abstract
BACKGROUND AND AIMS Life-threatening arrhythmias are a well-established consequence of reduced cardiac sodium current (INa). Gene therapy approaches to increase INa have demonstrated potential benefits to prevent arrhythmias. However, the development of such therapies is hampered by the large size of sodium channels. In this study, SCN10A-short (S10s), a short transcript encoding the carboxy-terminal domain of the human neuronal sodium channel, was evaluated as a gene therapy target to increase INa and prevent arrhythmias. METHODS Adeno-associated viral vector overexpressing S10s was injected into wild type and Scn5a-haploinsufficient mice on which patch-clamp studies, optical mapping, electrocardiogram analyses, and ischaemia reperfusion were performed. In vitro and in silico studies were conducted to further explore the effect of S10s gene therapy in the context of human hearts. RESULTS Cardiac S10s overexpression increased cellular INa, maximal action potential upstroke velocity, and action potential amplitude in Scn5a-haploinsufficient cardiomyocytes. S10s gene therapy rescues conduction slowing in Scn5a-haploinsufficient mice and prevented ventricular tachycardia induced by ischaemia-reperfusion in wild type mice. S10s overexpression increased maximal action potential upstroke velocity in human inducible pluripotent stem cell-derived cardiomyocytes and prevented inducible arrhythmias in simulated human heart models. CONCLUSIONS S10s gene therapy may be effective to treat cardiac conduction abnormalities and associated arrhythmias.
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Affiliation(s)
- Jianan Wang
- Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, University of Amsterdam, Meibergdreef 15, Amsterdam 1105 AZ, The Netherlands
| | - Arie O Verkerk
- Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, University of Amsterdam, Meibergdreef 15, Amsterdam 1105 AZ, The Netherlands
- Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, University of Amsterdam, Meibergdreef 15, Amsterdam 1105 AZ, The Netherlands
| | - Ronald Wilders
- Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, University of Amsterdam, Meibergdreef 15, Amsterdam 1105 AZ, The Netherlands
| | - Yingnan Zhang
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21218, USA
| | - Kelly Zhang
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21218, USA
| | - Adityo Prakosa
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21218, USA
| | - Mathilde R Rivaud
- Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, University of Amsterdam, Meibergdreef 15, Amsterdam 1105 AZ, The Netherlands
| | - E Madelief J Marsman
- Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, University of Amsterdam, Meibergdreef 15, Amsterdam 1105 AZ, The Netherlands
| | - Arie R Boender
- Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, University of Amsterdam, Meibergdreef 15, Amsterdam 1105 AZ, The Netherlands
- PacingCure B.V., Roetersstraat 35, Amsterdam 1018 WB, The Netherlands
| | - Mischa Klerk
- Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, University of Amsterdam, Meibergdreef 15, Amsterdam 1105 AZ, The Netherlands
| | - Lianne Fokkert
- Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, University of Amsterdam, Meibergdreef 15, Amsterdam 1105 AZ, The Netherlands
| | - Berend de Jonge
- Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, University of Amsterdam, Meibergdreef 15, Amsterdam 1105 AZ, The Netherlands
| | - Klaus Neef
- PacingCure B.V., Roetersstraat 35, Amsterdam 1018 WB, The Netherlands
- Netherlands Heart Institute, Moreelsepark 1, Utrecht 3511 EP, The Netherlands
| | - Osne F Kirzner
- PacingCure B.V., Roetersstraat 35, Amsterdam 1018 WB, The Netherlands
- Department of Anaesthesiology, Amsterdam University Medical Centers, De Boelelaan 1117, Amsterdam 1081 HV, The Netherlands
| | - Connie R Bezzina
- Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, University of Amsterdam, Meibergdreef 15, Amsterdam 1105 AZ, The Netherlands
| | - Carol Ann Remme
- Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, University of Amsterdam, Meibergdreef 15, Amsterdam 1105 AZ, The Netherlands
| | - Hanno L Tan
- Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, University of Amsterdam, Meibergdreef 15, Amsterdam 1105 AZ, The Netherlands
- PacingCure B.V., Roetersstraat 35, Amsterdam 1018 WB, The Netherlands
- Netherlands Heart Institute, Moreelsepark 1, Utrecht 3511 EP, The Netherlands
| | - Bastiaan J Boukens
- Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, University of Amsterdam, Meibergdreef 15, Amsterdam 1105 AZ, The Netherlands
- Department of Physiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Universiteitssingel 50, Maastricht 6229 ER, The Netherlands
| | - Harsha D Devalla
- Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, University of Amsterdam, Meibergdreef 15, Amsterdam 1105 AZ, The Netherlands
| | - Natalia A Trayanova
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21218, USA
- Alliance for Cardiovascular Diagnostic and Treatment Innovation, Johns Hopkins University, Baltimore, MD 21218, USA
| | - Vincent M Christoffels
- Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, University of Amsterdam, Meibergdreef 15, Amsterdam 1105 AZ, The Netherlands
| | - Phil Barnett
- Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, University of Amsterdam, Meibergdreef 15, Amsterdam 1105 AZ, The Netherlands
| | - Gerard J J Boink
- Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, University of Amsterdam, Meibergdreef 15, Amsterdam 1105 AZ, The Netherlands
- PacingCure B.V., Roetersstraat 35, Amsterdam 1018 WB, The Netherlands
- Department of Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, University of Amsterdam, Meibergdreef 9, Amsterdam 1105 AZ, The Netherlands
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Ding S. Therapeutic Reprogramming toward Regenerative Medicine. Chem Rev 2025; 125:1805-1822. [PMID: 39907153 DOI: 10.1021/acs.chemrev.4c00332] [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: 02/06/2025]
Abstract
Therapeutic reprogramming represents a transformative paradigm in regenerative medicine, developing new approaches in cell therapy, small molecule drugs, biologics, and gene therapy to address unmet medical challenges. This paradigm encompasses the precise modulation of cellular fate and function to either generate safe and functional cells ex vivo for cell-based therapies or to directly reprogram endogenous cells in vivo or in situ for tissue repair and regeneration. Building on the discovery of induced pluripotent stem cells (iPSCs), advancements in chemical modulation and CRISPR-based gene editing have propelled a new iterative medicine paradigm, focusing on developing scalable, standardized cell therapy products from universal starting materials and enabling iterative improvements for more effective therapeutic profiles. Beyond cell-based therapies, non-cell-based therapeutic strategies targeting endogenous cells may offer a less invasive, more convenient, accessible, and cost-effective alternative for treating a broad range of diseases, potentially rejuvenating tissues and extending healthspan.
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Affiliation(s)
- Sheng Ding
- New Cornerstone Science Laboratory, School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China
- Tsinghua-Peking Joint Center for Life Sciences, Tsinghua University, Beijing 100084, China
- Global Health Drug Discovery Institute, Beijing 100192, China
- CRE Life Institute, Beijing 100192, China
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3
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Garmany A, Terzic A. Artificial intelligence powers regenerative medicine into predictive realm. Regen Med 2024; 19:611-616. [PMID: 39660914 PMCID: PMC11703382 DOI: 10.1080/17460751.2024.2437281] [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: 09/25/2024] [Accepted: 11/29/2024] [Indexed: 12/12/2024] Open
Abstract
The expanding regenerative medicine toolkit is reaching a record number of lives. There is a pressing need to enhance the precision, efficiency, and effectiveness of regenerative approaches and achieve reliable outcomes. While regenerative medicine has relied on an empiric paradigm, availability of big data along with advances in informatics and artificial intelligence offer the opportunity to inform the next generation of regenerative sciences along the discovery, translation, and application pathway. Artificial intelligence can streamline discovery and development of optimized biotherapeutics by aiding in the interpretation of readouts associated with optimal repair outcomes. In advanced biomanufacturing, artificial intelligence holds potential in ensuring quality control and assuring scalability through automated monitoring of process-critical variables mandatory for product consistency. In practice application, artificial intelligence can guide clinical trial design, patient selection, delivery strategies, and outcome assessment. As artificial intelligence transforms the regenerative horizon, caution is necessary to reduce bias, ensure generalizability, and mitigate ethical concerns with the goal of equitable access for patients and populations.
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Affiliation(s)
- Armin Garmany
- Marriott Heart Disease Research Program, Department of Cardiovascular Medicine, Department of Molecular Pharmacology & Experimental Therapeutics, Department of Clinical Genomics, Mayo Clinic, Rochester, MN, USA
- Mayo Clinic Alix School of Medicine, Regenerative Sciences Track, Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, MN, USA
| | - Andre Terzic
- Marriott Heart Disease Research Program, Department of Cardiovascular Medicine, Department of Molecular Pharmacology & Experimental Therapeutics, Department of Clinical Genomics, Mayo Clinic, Rochester, MN, USA
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Zou XF, Zhang BZ, Qian WW, Cheng FM. Bone marrow mesenchymal stem cells in treatment of peripheral nerve injury. World J Stem Cells 2024; 16:799-810. [PMID: 39219723 PMCID: PMC11362854 DOI: 10.4252/wjsc.v16.i8.799] [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: 03/07/2024] [Revised: 05/20/2024] [Accepted: 08/05/2024] [Indexed: 08/26/2024] Open
Abstract
Peripheral nerve injury (PNI) is a common neurological disorder and complete functional recovery is difficult to achieve. In recent years, bone marrow mesenchymal stem cells (BMSCs) have emerged as ideal seed cells for PNI treatment due to their strong differentiation potential and autologous transplantation ability. This review aims to summarize the molecular mechanisms by which BMSCs mediate nerve repair in PNI. The key mechanisms discussed include the differentiation of BMSCs into multiple types of nerve cells to promote repair of nerve injury. BMSCs also create a microenvironment suitable for neuronal survival and regeneration through the secretion of neurotrophic factors, extracellular matrix molecules, and adhesion molecules. Additionally, BMSCs release pro-angiogenic factors to promote the formation of new blood vessels. They modulate cytokine expression and regulate macrophage polarization, leading to immunomodulation. Furthermore, BMSCs synthesize and release proteins related to myelin sheath formation and axonal regeneration, thereby promoting neuronal repair and regeneration. Moreover, this review explores methods of applying BMSCs in PNI treatment, including direct cell transplantation into the injured neural tissue, implantation of BMSCs into nerve conduits providing support, and the application of genetically modified BMSCs, among others. These findings confirm the potential of BMSCs in treating PNI. However, with the development of this field, it is crucial to address issues related to BMSC therapy, including establishing standards for extracting, identifying, and cultivating BMSCs, as well as selecting application methods for BMSCs in PNI such as direct transplantation, tissue engineering, and genetic engineering. Addressing these issues will help translate current preclinical research results into clinical practice, providing new and effective treatment strategies for patients with PNI.
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Affiliation(s)
- Xiong-Fei Zou
- Department of Orthopedic Surgery, Peking Union Medical College Hospital, Beijing 100730, China
| | - Bao-Zhong Zhang
- Department of Orthopedic Surgery, Peking Union Medical College Hospital, Beijing 100730, China.
| | - Wen-Wei Qian
- Department of Orthopedic Surgery, Peking Union Medical College Hospital, Beijing 100730, China
| | - Florence Mei Cheng
- College of Nursing, The Ohio State University, Ohio, OH 43210, United States
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5
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Swain HN, Boyce PD, Bromet BA, Barozinksy K, Hance L, Shields D, Olbricht GR, Semon JA. Mesenchymal stem cells in autoimmune disease: A systematic review and meta-analysis of pre-clinical studies. Biochimie 2024; 223:54-73. [PMID: 38657832 DOI: 10.1016/j.biochi.2024.04.009] [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: 01/30/2024] [Revised: 04/08/2024] [Accepted: 04/20/2024] [Indexed: 04/26/2024]
Abstract
Mesenchymal Stem Cells (MSCs) are of interest in the clinic because of their immunomodulation capabilities, capacity to act upstream of inflammation, and ability to sense metabolic environments. In standard physiologic conditions, they play a role in maintaining the homeostasis of tissues and organs; however, there is evidence that they can contribute to some autoimmune diseases. Gaining a deeper understanding of the factors that transition MSCs from their physiological function to a pathological role in their native environment, and elucidating mechanisms that reduce their therapeutic relevance in regenerative medicine, is essential. We conducted a Systematic Review and Meta-Analysis of human MSCs in preclinical studies of autoimmune disease, evaluating 60 studies that included 845 patient samples and 571 control samples. MSCs from any tissue source were included, and the study was limited to four autoimmune diseases: multiple sclerosis, rheumatoid arthritis, systemic sclerosis, and lupus. We developed a novel Risk of Bias tool to determine study quality for in vitro studies. Using the International Society for Cell & Gene Therapy's criteria to define an MSC, most studies reported no difference in morphology, adhesion, cell surface markers, or differentiation into bone, fat, or cartilage when comparing control and autoimmune MSCs. However, there were reported differences in proliferation. Additionally, 308 biomolecules were differentially expressed, and the abilities to migrate, invade, and form capillaries were decreased. The findings from this study could help to explain the pathogenic mechanisms of autoimmune disease and potentially lead to improved MSC-based therapeutic applications.
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Affiliation(s)
- Hailey N Swain
- Department of Biological Sciences, Missouri University of Science and Technology, USA
| | - Parker D Boyce
- Department of Biological Sciences, Missouri University of Science and Technology, USA
| | - Bradley A Bromet
- Department of Biological Sciences, Missouri University of Science and Technology, USA
| | - Kaiden Barozinksy
- Department of Biological Sciences, Missouri University of Science and Technology, USA
| | - Lacy Hance
- Department of Biological Sciences, Missouri University of Science and Technology, USA
| | - Dakota Shields
- Department of Mathematics and Statistics, Missouri University of Science and Technology, USA
| | - Gayla R Olbricht
- Department of Mathematics and Statistics, Missouri University of Science and Technology, USA
| | - Julie A Semon
- Department of Biological Sciences, Missouri University of Science and Technology, USA.
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Drozdova M, Makhonina A, Gladkikh D, Artyukhov A, Bryukhanov L, Mezhuev Y, Lozinsky V, Markvicheva E. Hydroxyapatite-loaded macroporous calcium alginate hydrogels: Preparation, characterization, and in vitro evaluation. Biopolymers 2024; 115:e23583. [PMID: 38661371 DOI: 10.1002/bip.23583] [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: 11/21/2023] [Revised: 04/02/2024] [Accepted: 04/12/2024] [Indexed: 04/26/2024]
Abstract
Hydrogels from natural polysaccharides are of great interest for tissue engineering. This study aims (1) to prepare hydroxyapatite-loaded macroporous calcium alginate hydrogels by novel one-step technique using internal gelation in water-frozen solutions; (2) to evaluate their physicochemical properties; (3) to estimate their ability to support cell growth and proliferation in vitro. The structure of the hydrogel samples in a swollen state was studied by confocal laser scanning microscopy and was shown to represent a system of interconnected macropores with sizes of tens micron. The swelling behavior of the hydrogels, their mechanical properties (Young's moduli) in function of a hydroxyapatite content (5-30 mass%) were studied. All hydrogel samples loaded with hydroxyapatite were found to support growth and proliferation of mouse fibroblasts (L929) at long-term cultivation for 7 days. The obtained macroporous composite Ca-Alg-HA hydrogels could be promising for tissue engineering.
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Affiliation(s)
- Maria Drozdova
- Shemyakin & Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia
| | - Alika Makhonina
- Shemyakin & Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia
- Department of Biomaterials, Mendeleev University of Chemical Technology of Russia, Moscow, Russia
| | - Daria Gladkikh
- Shemyakin & Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia
- Department of Biomaterials, Mendeleev University of Chemical Technology of Russia, Moscow, Russia
| | - Alexander Artyukhov
- Department of Biomaterials, Mendeleev University of Chemical Technology of Russia, Moscow, Russia
- Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, Moscow, Russia
| | - Leonid Bryukhanov
- Department of Biomaterials, Mendeleev University of Chemical Technology of Russia, Moscow, Russia
| | - Yaroslav Mezhuev
- Department of Biomaterials, Mendeleev University of Chemical Technology of Russia, Moscow, Russia
- Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, Moscow, Russia
| | - Vladimir Lozinsky
- Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, Moscow, Russia
| | - Elena Markvicheva
- Shemyakin & Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia
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Liu X, Astudillo Potes MD, Dashtdar B, Schreiber AC, Tilton M, Li L, Elder BD, Lu L. 3D Stem Cell Spheroids with 2D Hetero-Nanostructures for In Vivo Osteogenic and Immunologic Modulated Bone Repair. Adv Healthc Mater 2024; 13:e2303772. [PMID: 38271276 PMCID: PMC11404522 DOI: 10.1002/adhm.202303772] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Indexed: 01/27/2024]
Abstract
3D stem cell spheroids have immense potential for various tissue engineering applications. However, current spheroid fabrication techniques encounter cell viability issues due to limited oxygen access for cells trapped within the core, as well as nonspecific differentiation issues due to the complicated environment following transplantation. In this study, functional 3D spheroids are developed using mesenchymal stem cells with 2D hetero-nanostructures (HNSs) composed of single-stranded DNA (ssDNA) binding carbon nanotubes (sdCNTs) and gelatin-bind black phosphorus nanosheets (gBPNSs). An osteogenic molecule, dexamethasone (DEX), is further loaded to fabricate an sdCNTgBP-DEX HNS. This approach aims to establish a multifunctional cell-inductive 3D spheroid with improved oxygen transportation through hollow nanotubes, stimulated stem cell growth by phosphate ions supplied from BP oxidation, in situ immunoregulation, and osteogenesis induction by DEX molecules after implantation. Initial transplantation of the 3D spheroids in rat calvarial bone defect shows in vivo macrophage shifts to an M2 phenotype, leading to a pro-healing microenvironment for regeneration. Prolonged implantation demonstrates outstanding in vivo neovascularization, osteointegration, and new bone regeneration. Therefore, these engineered 3D spheroids hold great promise for bone repair as they allow for stem cell delivery and provide immunoregulative and osteogenic signals within an all-in-one construct.
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Affiliation(s)
- Xifeng Liu
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN 55905, USA
| | - Maria D. Astudillo Potes
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN 55905, USA
| | - Babak Dashtdar
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN 55905, USA
| | - Areonna C. Schreiber
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN 55905, USA
| | - Maryam Tilton
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN 55905, USA
| | - Linli Li
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN 55905, USA
| | - Benjamin D. Elder
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN 55905, USA
- Department of Neurologic Surgery, Mayo Clinic, Rochester, MN 55905, USA
| | - Lichun Lu
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN 55905, USA
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Hu X, Wu H, Yong X, Wang Y, Yang S, Fan D, Xiao Y, Che L, Shi K, Li K, Xiong C, Zhu H, Qian Z. Cyclical endometrial repair and regeneration: Molecular mechanisms, diseases, and therapeutic interventions. MedComm (Beijing) 2023; 4:e425. [PMID: 38045828 PMCID: PMC10691302 DOI: 10.1002/mco2.425] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 10/21/2023] [Accepted: 10/27/2023] [Indexed: 12/05/2023] Open
Abstract
The endometrium is a unique human tissue with an extraordinary ability to undergo a hormone-regulated cycle encompassing shedding, bleeding, scarless repair, and regeneration throughout the female reproductive cycle. The cyclical repair and regeneration of the endometrium manifest as changes in endometrial epithelialization, glandular regeneration, and vascularization. The mechanisms encompass inflammation, coagulation, and fibrinolytic system balance. However, specific conditions such as endometriosis or TCRA treatment can disrupt the process of cyclical endometrial repair and regeneration. There is uncertainty about traditional clinical treatments' efficacy and side effects, and finding new therapeutic interventions is essential. Researchers have made substantial progress in the perspective of regenerative medicine toward maintaining cyclical endometrial repair and regeneration in recent years. Such progress encompasses the integration of biomaterials, tissue-engineered scaffolds, stem cell therapies, and 3D printing. This review analyzes the mechanisms, diseases, and interventions associated with cyclical endometrial repair and regeneration. The review discusses the advantages and disadvantages of the regenerative interventions currently employed in clinical practice. Additionally, it highlights the significant advantages of regenerative medicine in this domain. Finally, we review stem cells and biologics among the available interventions in regenerative medicine, providing insights into future therapeutic strategies.
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Affiliation(s)
- Xulin Hu
- Clinical Medical College and Affiliated Hospital of Chengdu UniversityChengdu UniversityChengduSichuanChina
- Department of BiotherapyCancer Center and State Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengduSichuanChina
| | - Haoming Wu
- Clinical Medical College and Affiliated Hospital of Chengdu UniversityChengdu UniversityChengduSichuanChina
| | - Xin Yong
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Department of Paediatrics, West China Second University Hospital, State Key Laboratory of Biotherapy and Collaborative Innovation Center of BiotherapySichuan UniversityChengduSichuanChina
| | - Yao Wang
- Clinical Medical College and Affiliated Hospital of Chengdu UniversityChengdu UniversityChengduSichuanChina
| | - Shuhao Yang
- Department of OrthopedicsThe First Affiliated Hospital of Chongqing Medical UniversityChongqingChina
| | - Diyi Fan
- Clinical Medical College and Affiliated Hospital of Chengdu UniversityChengdu UniversityChengduSichuanChina
| | - Yibo Xiao
- Clinical Medical College and Affiliated Hospital of Chengdu UniversityChengdu UniversityChengduSichuanChina
| | - Lanyu Che
- Clinical Medical College and Affiliated Hospital of Chengdu UniversityChengdu UniversityChengduSichuanChina
| | - Kun Shi
- Department of BiotherapyCancer Center and State Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengduSichuanChina
| | - Kainan Li
- Clinical Medical College and Affiliated Hospital of Chengdu UniversityChengdu UniversityChengduSichuanChina
| | | | - Huili Zhu
- Department of Reproductive Medicine, Key Laboratory of Birth Defects and Related Diseases of Women and Children of Ministry of EducationWest China Second University Hospital of Sichuan UniversityChengduSichuanChina
| | - Zhiyong Qian
- Department of BiotherapyCancer Center and State Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengduSichuanChina
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9
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Hong J, Ahn H, Moon SY, Kang HJ, Yi KW. Effect of collagen endometrial patch loaded with adipose-derived mesenchymal stem cells on endometrial regeneration in rats with a thin endometrium. Front Endocrinol (Lausanne) 2023; 14:1287789. [PMID: 38089603 PMCID: PMC10714005 DOI: 10.3389/fendo.2023.1287789] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2023] [Accepted: 10/31/2023] [Indexed: 12/18/2023] Open
Abstract
Background This study aimed to investigate the effects of a collagen endometrial patch (EM patch) loaded with adipose-derived mesenchymal stem cells (ADSCs) on endometrial regeneration in a rat model with thin endometrium. Materials and methods Thin endometrium was induced in female rats and divided into treatment groups as outlined: control, group 1(G1), local injection of ADSCs into the uterus, group 2 (G2), an EM patch without ADSCs, group 3 (G3), and an EM patch loaded with ADSCs, group 4 (G4). The rats were euthanized at either two weeks or four weeks after modeling and treatment followed by histological and biochemical analyses to examine the regenerative effects on the injured endometrium. Results Transplantation of the ADSC-loaded EM patch significantly promoted endometrial proliferation and increased the luminal epithelial area. Two weeks after treatment, the mean number of von Villebrand factor (vWF)+ or cluster of differentiation (CD) 31+-stained blood vessels was significantly higher in G4 than in G1 and G2. The mRNA and protein expression levels of TGF-β and FGF2 were significantly upregulated in G4 compared to those in the control. G4 exhibited significantly increased LIF mRNA levels and immunoreactivity compared with the other groups at both two weeks and four weeks after treatment. Cell tracking after ADSCs treatment revealed the presence of a substantial number of ADSCs grafted in the uterine tissues of G4, whereas a low number of ADSCs that were focally clustered were present in G2. Conclusion Transplantation of EM patches loaded with ADSCs resulted in the histological and biochemical restoration of an injured endometrium. The strategic integration of EM patches and ADSCs holds significant promise as an innovative therapeutic approach for effectively treating impaired endometrial conditions.
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Affiliation(s)
- Juyeon Hong
- Department of Obstetrics and Gynecology, Korea University College of Medicine, Seoul, Republic of Korea
| | - Hyojin Ahn
- Department of Obstetrics and Gynecology, Korea University College of Medicine, Seoul, Republic of Korea
| | - Soo Young Moon
- Department of Biomedical Laboratory Science, Honam University, Gwangju, Republic of Korea
| | - Hyo Jin Kang
- Department of Biomedical Laboratory Science, Honam University, Gwangju, Republic of Korea
| | - Kyong Wook Yi
- Department of Obstetrics and Gynecology, Korea University College of Medicine, Seoul, Republic of Korea
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10
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Abdellateif MS, Zekri ARN. Stem cell therapy for hepatocellular carcinoma and end-stage liver disease. J Egypt Natl Canc Inst 2023; 35:35. [PMID: 37926787 DOI: 10.1186/s43046-023-00194-z] [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: 12/19/2022] [Accepted: 10/20/2023] [Indexed: 11/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a major health problem worldwide, especially for patients who are suffering from end-stage liver disease (ESLD). The ESLD is considered a great challenge for clinicians due to the limited chance for liver transplantation, which is the only curative treatment for those patients. Stem cell-based therapy as a part of regenerative medicine represents a promising application for ESLD patients. Many clinical trials were performed to assess the utility of bone marrow-derived stem cells as a potential therapy for patients with liver diseases. The aim of the present study is to present and review the various types of stem cell-based therapy, including the mesenchymal stem cells (MSCs), BM-derived mononuclear cells (BM-MNCs), CD34 + hematopoietic stem cells (HSCs), induced pluripotent stem cells (iPSCs), and cancer stem cells.Though this type of therapy achieved promising results for the treatment of ESLD, however still there is a confounding data regarding its clinical application. A large body of evidence is highly required to evaluate the stem cell-based therapy after long-term follow-up, with respect to the incidence of toxicity, immunogenicity, and tumorigenesis that developed in many patients.
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Affiliation(s)
- Mona S Abdellateif
- Medical Biochemistry and Molecular Biology, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, 11976, Egypt.
| | - Abdel-Rahman N Zekri
- Molecular Virology and Immunology Unit, Cancer Biology Department, NCI, Cairo University, Cairo, 11976, Egypt
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11
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Hasani-Sadrabadi MM, Yuan W, Sevari S, Yu B, Ansari S, Moshaverinia A. An engineered biomaterial to harness the differentiation potential of endogenous human gingival mesenchymal stem cells (hGMSCs). FRONTIERS IN DENTAL MEDICINE 2023; 4:1235096. [PMID: 39916923 PMCID: PMC11797836 DOI: 10.3389/fdmed.2023.1235096] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Accepted: 07/14/2023] [Indexed: 02/09/2025] Open
Abstract
Here, we developed a stromal cell-derived factor-1a (SDF-1α) delivery biomaterial as an artificial polymeric-based niche with the ability to recruit local endogenous human gingival mesenchymal stem cells (hGMSCs) for craniofacial bone regeneration applications. Polydopamine-coated poly(ε-caprolactone) (PCL)-gelatin electrospun membranes were loaded with stromal cell-derived factor-1α (SDF-1α) via physical adsorption. Subsequently, the release profile of SDF-1α and the chemotactic capacity on human bone marrow mesenchymal stem cells (hBMMSCs) and hGMSCs were evaluated. The osteogenic differentiation capacity of the recruited MSCs was also assessed in vitro. Our results confirmed the sustainable release of SDF-1α from the developed biomaterial promoting the migration and homing of human bone marrow mesenchymal stem cells (hBMMSCs) and hGMSCs. Moreover, the results of the osteogenic differentiation assay showed that SDF-1α delivery significantly enhanced osteogenic differentiation of hBMMSCs and hGMSCs and up-regulated the gene expression of osteogenic markers compared to the control group. In conclusion, the current study successfully developed a novel and effective treatment modality for craniofacial bone regeneration by recruiting the autogenous progenitor cells including hGMSCs. The developed niches can potentially lead to the development of a novel platform for targeted manipulation of in vivo microenvironment to achieve efficient and safe craniofacial cell reprogramming, which also will pave the road to determine the capacity of local hGMSCs' contribution to in situ bone regeneration.
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Affiliation(s)
| | - Weihao Yuan
- Weintraub Center for Reconstructive Biotechnology, Section of Prosthodontics, School of Dentistry, University of California, Los Angeles, Los Angeles, CA, United States
| | - Sevda Sevari
- Weintraub Center for Reconstructive Biotechnology, Section of Prosthodontics, School of Dentistry, University of California, Los Angeles, Los Angeles, CA, United States
| | - Bo Yu
- Section of Restorative Dentistry, School of Dentistry, University of California, Los Angeles, Los Angeles, CA, United States
| | - Sahar Ansari
- Weintraub Center for Reconstructive Biotechnology, Section of Prosthodontics, School of Dentistry, University of California, Los Angeles, Los Angeles, CA, United States
| | - Alireza Moshaverinia
- Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA, United States
- Weintraub Center for Reconstructive Biotechnology, Section of Prosthodontics, School of Dentistry, University of California, Los Angeles, Los Angeles, CA, United States
- California NanoSystems Institute (CNSI), University of California, Los Angeles, Los Angeles, CA, United States
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12
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Angiolillo S, Micheli S, Laterza C, Gagliano O. NGN2-based neuronal programming of hiPSCs in an automated microfluidic platform. Biochem Biophys Res Commun 2023; 666:52-60. [PMID: 37178505 DOI: 10.1016/j.bbrc.2023.04.104] [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: 03/29/2023] [Accepted: 04/27/2023] [Indexed: 05/15/2023]
Abstract
The generation of induced pluripotent stem cells (iPSCs) via somatic cell reprogramming allowed to have an unlimited in vitro source of patient-specific cells. This achievement has introduced a new revolutionary way to create human in vitro models and to study human diseases starting from patient's own cells, especially important for inaccessible tissues like the brain. Recently, lab-on-a-chip technology has opened new reliable alternatives to conventional in vitro models able to replicate key aspects of human physiology, thanks to the intrinsic high surface-area-to-volume ratio, which allows fine control of the cellular microenvironment. The development of automated microfluidic platforms allowed the implementation of this technology to perform high-throughput, standardized and parallelized assays, suitable for drug screenings and developing new therapeutic approaches in a cost-effective way. However, the major challenges in the broad application of automated lab-on-a-chip in biological research are the lack of production robustness and ease of use of the devices. Here, we present an automated microfluidic platform able to host the rapid conversion of human iPSCs (hiPSCs) into neurons via viral-mediated overexpression of Neurogenin 2 (NGN2) in a user-friendly manner. The design of the platform, built with multilayer soft-lithography techniques, shows easiness in the fabrication and assembly thanks to the simple geometry and experimental reproducibility at the same time. All operations are managed automatically, from the cell seeding, medium change, doxycycline-mediated neuronal induction, selection of the genetically engineered cells, and analysis of the output of differentiation, including immunofluorescence assay. Our results show a high-throughput, efficient and homogenous conversion of hiPSCs into neurons in 10 days, characterized by the expression of the mature neuronal marker MAP2 and calcium signaling. The neurons-on-chip model here described represents a fully automated loop system able to address the challenges in the field of neurological diseases modelling in vitro and improve current preclinical models.
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Affiliation(s)
- S Angiolillo
- Department of Industrial Engineering (DII), University of Padova, Padova, Italy; Venetian Institute of Molecular Medicine (VIMM), Padova, Italy
| | - S Micheli
- Venetian Institute of Molecular Medicine (VIMM), Padova, Italy
| | - C Laterza
- Department of Industrial Engineering (DII), University of Padova, Padova, Italy; Venetian Institute of Molecular Medicine (VIMM), Padova, Italy
| | - O Gagliano
- Department of Industrial Engineering (DII), University of Padova, Padova, Italy; Venetian Institute of Molecular Medicine (VIMM), Padova, Italy; Stem Cell and Regenerative Medicine Section, GOS Institute of Child Health, University College London, London, UK.
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Kawabata S, Akeda K, Yamada J, Takegami N, Fujiwara T, Fujita N, Sudo A. Advances in Platelet-Rich Plasma Treatment for Spinal Diseases: A Systematic Review. Int J Mol Sci 2023; 24:ijms24087677. [PMID: 37108837 PMCID: PMC10145581 DOI: 10.3390/ijms24087677] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 04/18/2023] [Accepted: 04/19/2023] [Indexed: 04/29/2023] Open
Abstract
Spinal diseases are commonly associated with pain and neurological symptoms, which negatively impact patients' quality of life. Platelet-rich plasma (PRP) is an autologous source of multiple growth factors and cytokines, with the potential to promote tissue regeneration. Recently, PRP has been widely used for the treatment of musculoskeletal diseases, including spinal diseases, in clinics. Given the increasing popularity of PRP therapy, this article examines the current literature for basic research and emerging clinical applications of this therapy for treating spinal diseases. First, we review in vitro and in vivo studies, evaluating the potential of PRP in repairing intervertebral disc degeneration, promoting bone union in spinal fusion surgeries, and aiding in neurological recovery from spinal cord injury. Second, we address the clinical applications of PRP in treating degenerative spinal disease, including its analgesic effect on low back pain and radicular pain, as well as accelerating bone union during spinal fusion surgery. Basic research demonstrates the promising regenerative potential of PRP, and clinical studies have reported on the safety and efficacy of PRP therapy for treating several spinal diseases. Nevertheless, further high-quality randomized controlled trials would be required to establish clinical evidence of PRP therapy.
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Affiliation(s)
- Soya Kawabata
- Department of Orthopaedic Surgery, School of Medicine, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake 470-1192, Japan
| | - Koji Akeda
- Department of Orthopaedic Surgery, Mie University Graduate School of Medicine, Tsu 514-8507, Japan
| | - Junichi Yamada
- Department of Orthopaedic Surgery, Mie University Graduate School of Medicine, Tsu 514-8507, Japan
| | - Norihiko Takegami
- Department of Orthopaedic Surgery, Mie University Graduate School of Medicine, Tsu 514-8507, Japan
| | - Tatsuhiko Fujiwara
- Department of Orthopaedic Surgery, Mie University Graduate School of Medicine, Tsu 514-8507, Japan
| | - Nobuyuki Fujita
- Department of Orthopaedic Surgery, School of Medicine, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake 470-1192, Japan
| | - Akihiro Sudo
- Department of Orthopaedic Surgery, Mie University Graduate School of Medicine, Tsu 514-8507, Japan
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Allogeneic transplantation of epidermal cell sheets followed by endoscopic submucosal dissection to prevent severe esophageal stricture in a porcine model. Regen Ther 2022; 21:157-165. [PMID: 35891710 PMCID: PMC9284451 DOI: 10.1016/j.reth.2022.06.008] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2022] [Revised: 06/12/2022] [Accepted: 06/23/2022] [Indexed: 12/03/2022] Open
Abstract
Introduction Endoscopic submucosal dissection (ESD) is a minimally invasive treatment for early esophageal cancer. However, large mucosal defects after esophageal ESD result in refractory strictures. In the present study, we histologically evaluated the endoscopic transplantation of allogeneic epidermal cell sheets (ECSs) as a feasible therapy for preventing esophageal stricture after circumferential ESD in a porcine model. Methods Epidermal cells were isolated from the skin tissue of allogeneic pigs and cultured on temperature-responsive cell culture inserts for 2 weeks. Transplantable ECSs were harvested by reducing the temperature and endoscopically transplanting the sheets to ulcer sites immediately after esophageal ESD. The engraftment of transplanted ECSs was then evaluated in two pigs at 7 days after transplantation. Next, ten pigs were divided into two groups to evaluate the endoscopic transplantation of allogeneic ECSs for the prevention of esophageal strictures after ESD. Allogeneic ECSs were transplanted immediately after esophageal ESD in the transplantation group (n = 5), whereas the control group (n = 5) did not undergo transplantation. Results Most of the transplanted allogeneic ECSs were successfully engrafted at the ulcer sites in the early phase. Fluorescence in situ hybridization analysis revealed that several allogeneic cells were present in the transplanted area at 7 days after ESD. At 14 days after ESD, significant differences in body weight loss, dysphagia scores, and mucosal strictures were observed between the control and transplantation groups. Transplanting allogeneic ECSs after esophageal ESD promotes mucosal healing and angiogenesis and prevents excessive inflammation and granulation tissue formation. Conclusions Endoscopic and histological analyses revealed that allogeneic ECSs promoted artificial ulcer healing after ESD, preventing esophageal strictures after ESD.
Large mucosal defects of the esophagus cause severe strictures. Allogeneic epidermal cell sheets promote esophageal mucosal healing. Allogeneic epidermal cell sheets induce angiogenesis in esophageal ulcers. Allogeneic epidermal cell sheets prevent excessive inflammation in esophageal ulcers.
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Yan J, Zhang L, Li L, He W, Liu W. Developmentally engineered bio-assemblies releasing neurotrophic exosomes guide in situ neuroplasticity following spinal cord injury. Mater Today Bio 2022; 16:100406. [PMID: 36065352 PMCID: PMC9440432 DOI: 10.1016/j.mtbio.2022.100406] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 08/12/2022] [Accepted: 08/18/2022] [Indexed: 11/17/2022]
Abstract
The emerging tissue-engineered bio-assemblies are revolutionizing the regenerative medicine, and provide a potential program to guarantee predictive performance of stem-cell-derived treatments in vivo and hence support their clinical translation. Mesenchymal stem cell (MSC) showed the attractive potential for the therapy of nervous system injuries, especially spinal cord injury (SCI), and yet failed to make an impact on clinical outcomes. Herein, under the guidance of the embryonic development theory that appropriate cellular coarctations or clustering are pivotal initiators for the formation of geometric and functional tissue structures, a developmentally engineered strategy was established to assemble DPMSCs into a bio-assembly termed Spinor through a three-level sequential induction programme including reductant, energy and mechanical force stimulation. Spinor exhibited similar geometric construction with spinal cord tissue and attain autonomy to released exosome with the optimized quantity and quality for suppressing cicatrization and inflammation and promoting axonal regeneration. As a spinal cord fascia and exosome mothership, Spinor guided the in-situ neuroplasticity of spinal cord in vivo, and caused the significant motor improvement, sensory recovery, and faster urinary reflex restoration in rats following SCI, while maintaining a highly favorable biosafety profile. Collectively, Spinor not only is a potentially clinical therapeutic paradigm as a living “exosome mothership” for revisiting Prometheus' Myth in SCI, but can be viewed allowing developmentally engineered manufacturing of biomimetic bio-assemblies with complex topology features and inbuilt biofunction attributes towards the regeneration of complex tissues including nervous system.
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Affiliation(s)
- Jin Yan
- National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
| | - Liqiang Zhang
- Institute for Stem Cell & Regenerative Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
| | - Liya Li
- Institute for Stem Cell & Regenerative Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
| | - Wangxiao He
- Institute for Stem Cell & Regenerative Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
- Department of Medical Oncology and Department of Talent Highland, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
- Corresponding author. Institute for Stem Cell & Regenerative Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China.
| | - Wenjia Liu
- National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
- Institute for Stem Cell & Regenerative Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
- Corresponding author. National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China.
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Wang Z, Tian X, Wang C, Qi X, Gracia‐Sancho J, Dong L. Transforming one organ into another to overcome challenges in tissue engineering. PORTAL HYPERTENSION & CIRRHOSIS 2022; 1:116-124. [DOI: 10.1002/poh2.26] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Accepted: 07/11/2022] [Indexed: 01/03/2025]
Abstract
AbstractTissue engineering (TE) is promising for the regeneration of failed organs. However, immune rejection, shortage of seed cells, and unintegrated blood vessels restrict the development and clinical application of TE. The last factor is the most challenging and intractable. Harnessing the mature blood vessel network in existing dispensable organs could be a powerful approach to effectively overcome the obstacles. After being remodeled to harbor an immunosuppressive and proregenerative niche, these potential target organs can be transformed into other organs with specific physiological functions, compensating the latter's failed native functions. Organ transformation, such as a hepatized spleen, represents an effective and encouraging TE strategy. In this review, we discuss the current development and obstacles of TE and its feasibility and superiority in organ transformation.
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Affiliation(s)
- Zhenzhen Wang
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences Nanjing University Nanjing Jiangsu China
| | - Xuejiao Tian
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences Nanjing University Nanjing Jiangsu China
| | - Chunming Wang
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences University of Macau Taipa Macau SAR China
| | - Xiaolong Qi
- CHESS Center, Institute of Portal Hypertension The First Hospital of Lanzhou University Lanzhou Gansu China
| | - Jordi Gracia‐Sancho
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital University of Bern Bern Switzerland
- Liver Vascular Biology Research Group IDIBAPS Research Institute, CIBEREHD Barcelona Spain
| | - Lei Dong
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences Nanjing University Nanjing Jiangsu China
- Chemistry and Biomedicine Innovative Center Nanjing University Nanjing Jiangsu China
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17
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Majood M, Garg P, Chaurasia R, Agarwal A, Mohanty S, Mukherjee M. Carbon Quantum Dots for Stem Cell Imaging and Deciding the Fate of Stem Cell Differentiation. ACS OMEGA 2022; 7:28685-28693. [PMID: 36033677 PMCID: PMC9404166 DOI: 10.1021/acsomega.2c03285] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Accepted: 08/01/2022] [Indexed: 05/12/2023]
Abstract
Nanotechnology advancements and applications have paved the way for new possibilities in regenerative medicine and tissue engineering. It is a relatively new field that has the potential to improve stem cell differentiation and therapy greatly. Numerous studies have demonstrated that nanomaterials can function as a physiological niche for the formation and differentiation of stem cells. However, quantum dots (QDs), such as carbon quantum dots (CQDs) and graphene quantum dots (GQDs), have shown considerable promise in the field of regenerative medicine. To date, most research has focused on stem cell tracking and imaging using CQDs. However, their interaction with stem cells and the associated possibility for differentiation by selectively focusing chemical signals to a particular lineage has received scant attention. In this mini-review, we attempt to categorize a few pathways linked with the role of CQDs in stem cell differentiation.
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Affiliation(s)
- Misba Majood
- Amity
Institute of Click Chemistry Research and Studies, Amity University Uttar Pradeshs, Noida 201313, India
| | - Piyush Garg
- Amity
Institute of Click Chemistry Research and Studies, Amity University Uttar Pradeshs, Noida 201313, India
| | - Radhika Chaurasia
- Amity
Institute of Click Chemistry Research and Studies, Amity University Uttar Pradeshs, Noida 201313, India
| | - Aakanksha Agarwal
- Amity
Institute of Click Chemistry Research and Studies, Amity University Uttar Pradeshs, Noida 201313, India
| | - Sujata Mohanty
- Stem
Cells Facility, DBT-Centre of Excellence, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Monalisa Mukherjee
- Amity
Institute of Click Chemistry Research and Studies, Amity University Uttar Pradeshs, Noida 201313, India
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Zhang Z, Zhao X, Wang C, Huang Y, Han Y, Guo B. Injectable conductive micro-cryogel as a muscle stem cell carrier improves myogenic proliferation, differentiation and in situ skeletal muscle regeneration. Acta Biomater 2022; 151:197-209. [PMID: 36002125 DOI: 10.1016/j.actbio.2022.08.036] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2022] [Revised: 08/12/2022] [Accepted: 08/16/2022] [Indexed: 11/16/2022]
Abstract
Volumetric muscle loss (VML) results in the impediment of skeletal muscle function, and there were still great challenges in cell delivery approach with the minimally invasive operation to repair muscle defects. To deliver cells to the VML defects site efficiently, the injectable conductive porous nanocomposite microcryogels based on gelatin (GT) and reduced graphene oxide (rGO) were designed and prepared. The microcryogels were loaded with myoblasts to form an injectable cell delivery system and show the ability to protect cells during injection. Conductive microcryogel with 4 mg/mL rGO (GT/rGO4) enhanced C2C12 cell proliferation and myogenic differentiation during 3D culture compared with pure gelatin microcryogel. In a mice VML model, injection of microcryogel loaded with muscle-derived stem cells into the injury site significantly improved the generation of new muscle fibers and blood vessels, and anti-inflammatory properties. The results show that injectable biodegradable conductive microcryogel can be used as myoblast cell carriers with the potential to maintain cell activity and deliver cells to defective sites, thereby in situ enhancing skeletal muscle regeneration. STATEMENT OF SIGNIFICANCE: Volumetric muscle loss overwhelms the regenerative capacity of skeletal muscle, which results in severe damage to muscle tissues. In the treatment of volumetric muscle loss, conductive niche and muscle stem cells are needed to alleviate excessive scar formation and inflammation to improve muscle regeneration. Injectable gelatin/reduced graphene oxide based nanocomposite microcryogel can enhance the differentiation of seeded muscle stem cells. The improved repair of volumetric muscle loss was achieved via reducing collagen deposition and inflammation in the injected region through the microcryogel cell-delivery therapy, suggesting great potential of the injectable microcryogel as a cell carrier in soft tissue repair.
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Affiliation(s)
- Zhiyi Zhang
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an 710049, China; State Key Laboratory for Mechanical Behavior of Materials, and Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, 710049, China
| | - Xin Zhao
- State Key Laboratory for Mechanical Behavior of Materials, and Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, 710049, China
| | - Chunbo Wang
- State Key Laboratory for Mechanical Behavior of Materials, and Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, 710049, China
| | - Ying Huang
- State Key Laboratory for Mechanical Behavior of Materials, and Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, 710049, China
| | - Yong Han
- State Key Laboratory for Mechanical Behavior of Materials, and Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, 710049, China
| | - Baolin Guo
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an 710049, China; State Key Laboratory for Mechanical Behavior of Materials, and Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, 710049, China.
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Ranamalla SR, Porfire AS, Tomuță I, Banciu M. An Overview of the Supramolecular Systems for Gene and Drug Delivery in Tissue Regeneration. Pharmaceutics 2022; 14:pharmaceutics14081733. [PMID: 36015356 PMCID: PMC9412871 DOI: 10.3390/pharmaceutics14081733] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 07/31/2022] [Accepted: 08/03/2022] [Indexed: 12/03/2022] Open
Abstract
Tissue regeneration is a prominent area of research, developing biomaterials aimed to be tunable, mechanistic scaffolds that mimic the physiological environment of the tissue. These biomaterials are projected to effectively possess similar chemical and biological properties, while at the same time are required to be safely and quickly degradable in the body once the desired restoration is achieved. Supramolecular systems composed of reversible, non-covalently connected, self-assembly units that respond to biological stimuli and signal cells have efficiently been developed as preferred biomaterials. Their biocompatibility and the ability to engineer the functionality have led to promising results in regenerative therapy. This review was intended to illuminate those who wish to envisage the niche translational research in regenerative therapy by summarizing the various explored types, chemistry, mechanisms, stimuli receptivity, and other advancements of supramolecular systems.
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Affiliation(s)
- Saketh Reddy Ranamalla
- Department of Pharmaceutical Technology and Bio Pharmacy, Faculty of Pharmacy, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400010 Cluj-Napoca, Romania
- Doctoral School in Integrative Biology, Faculty of Biology and Geology, “Babeș-Bolyai” University, 400015 Cluj-Napoca, Romania
| | - Alina Silvia Porfire
- Department of Pharmaceutical Technology and Bio Pharmacy, Faculty of Pharmacy, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400010 Cluj-Napoca, Romania
- Correspondence:
| | - Ioan Tomuță
- Department of Pharmaceutical Technology and Bio Pharmacy, Faculty of Pharmacy, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400010 Cluj-Napoca, Romania
| | - Manuela Banciu
- Department of Molecular Biology and Biotechnology, Center of Systems Biology, Biodiversity and Bioresources, Faculty of Biology and Geology, “Babeș-Bolyai” University, 400015 Cluj-Napoca, Romania
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20
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Wu X, Guo H, Jia Y, Wang Q, Wang J, Sun X, Wang J. Adipose mesenchymal stem cell-based tissue engineering mesh with sustained bFGF release to enhance tissue repair. Biomater Sci 2022; 10:3110-3121. [PMID: 35543346 DOI: 10.1039/d1bm01893k] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Pelvic organ prolapse (POP) harms the quality of life of elderly patients. Transvaginal polypropylene mesh repair for POP was a frequently reported complication and was banned by the FDA in 2019. New therapeutic strategies are urgently required, and tissue engineering technology could be a novel therapy. Here, we developed a tissue engineering mesh out of three components: silk fibroin (SF) knitted mesh loaded with basic fibroblast growth factor (bFGF) and adipose-derived stem cells (ADSCs). We used coaxial electrospinning technology to achieve local bFGF release to promote regeneration. Additionally, ADSCs were loaded to demonstrate their paracrine ability of immune regulation and angiogenesis. Meanwhile, knitted silk fibroin mesh provided mechanical support. In vitro, SF/bFGF/ADSC tissue engineering mesh can stably release bFGF and has good biocompatibility, promoting cell proliferation and extracellular matrix synthesis. Six months after the SF/bFGF/ADSC tissue engineering mesh was implanted in a SD rat model, extracellular matrix reorganization, angiogenesis, and immunomodulatory effect, as well as mechanical properties of the implanting position were improved. Hence, SF/bFGF/ADSC tissue engineering mesh could be regarded as a promising option with excellent collagen synthesis, low foreign body response, and early angiogenic ability, providing potential ideas for POP treatment.
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Affiliation(s)
- Xiaotong Wu
- Department of Obstetrics and Gynecology, Peking University People's Hospital, Beijing, China. .,Beijing Key Laboratory of Female Pelvic Floor Disorders, Beijing, China
| | - Hong Guo
- Donghua University College of Textiles, Shanghai, China
| | - Yuanyuan Jia
- Department of Obstetrics and Gynecology, Peking University People's Hospital, Beijing, China. .,Beijing Key Laboratory of Female Pelvic Floor Disorders, Beijing, China
| | - Qing Wang
- Department of Obstetrics and Gynecology, Peking University People's Hospital, Beijing, China. .,Beijing Key Laboratory of Female Pelvic Floor Disorders, Beijing, China
| | - Jiaqi Wang
- Department of Obstetrics and Gynecology, Peking University People's Hospital, Beijing, China. .,Beijing Key Laboratory of Female Pelvic Floor Disorders, Beijing, China
| | - Xiuli Sun
- Department of Obstetrics and Gynecology, Peking University People's Hospital, Beijing, China. .,Beijing Key Laboratory of Female Pelvic Floor Disorders, Beijing, China
| | - Jianliu Wang
- Department of Obstetrics and Gynecology, Peking University People's Hospital, Beijing, China. .,Beijing Key Laboratory of Female Pelvic Floor Disorders, Beijing, China
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Holtzer L, Wesseling-Rozendaal Y, Verhaegh W, van de Stolpe A. Measurement of activity of developmental signal transduction pathways to quantify stem cell pluripotency and phenotypically characterize differentiated cells. Stem Cell Res 2022; 61:102748. [PMID: 35325817 DOI: 10.1016/j.scr.2022.102748] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Revised: 02/28/2022] [Accepted: 03/11/2022] [Indexed: 10/18/2022] Open
Abstract
Important challenges in stem cell research and regenerative medicine are reliable assessment of pluripotency state and purity of differentiated cell populations. Pluripotency and differentiation are regulated and determined by activity of developmental signal transduction pathways (STPs). To date activity of these STPs could not be directly measured on a cell sample. Here we validate a novel assay platform for measurement of activity of developmental STPs (STP) for use in stem cells and stem cell derivatives. In addition to previously developed STP assays, we report development of an additional STP assay for the MAPK-AP1 pathway. Subsequently, activity of Notch, Hedgehog, TGFβ, Wnt, PI3K, MAPK-AP1, and NFκB signaling pathways was calculated from Affymetrix transcriptome data of human pluripotent embryonic (hES) and iPS cell lines under different culture conditions, organ-derived multipotent stem cells, and differentiated cell types, to generate quantitative STP activity profiles. Results show that the STP assay technology enables reliable and quantitative measurement of multiple STP activities simultaneously on any individual cell sample. Using the technology, we found that culture conditions dominantly influence the pluripotent stem cell STP activity profile, while the origin of the stem cell line was a minor variable. A pluripotency STP activity profile (Pluripotency qPAP) was defined (active PI3K, MAPK, Hedgehog, Notch, TGFβ, and NFκB pathway, inactive Wnt pathway). Differentiation of hES cells to intestinal progenitor cells resulted in an STP activity profile characterized by active PI3K, Wnt and Notch pathways, comparable to the STP activity profile measured on primary intestinal crypt stem cells. Quantitative STP activity measurement is expected to improve experimental reproducibility and standardization of pluripotent and multipotent stem cell culture/differentiation, and enable controlled manipulation of pluripotency/differentiation state using pathway targeting compounds.
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Affiliation(s)
- Laurent Holtzer
- Molecular Pathway Diagnostics, Philips, Eindhoven, The Netherlands.
| | | | - Wim Verhaegh
- Molecular Pathway Diagnostics, Philips, Eindhoven, The Netherlands.
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22
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The Hematology of Tomorrow Is Here-Preclinical Models Are Not: Cell Therapy for Hematological Malignancies. Cancers (Basel) 2022; 14:cancers14030580. [PMID: 35158848 PMCID: PMC8833715 DOI: 10.3390/cancers14030580] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 01/13/2022] [Accepted: 01/21/2022] [Indexed: 02/04/2023] Open
Abstract
Simple Summary Cell therapy is revolutionizing the prospect of deadly hematological malignancies such as high-risk acute myeloid leukemia. Stem cell therapy of allogeneic source from compatible human leukocyte antigen donor has exceptional success promoting durable remissions, but the rate of relapse is currently still high and there is transplant-related mortality. This review presents the current knowledge on the clinical use of mesenchymal stromal cells to improve outcomes in hematopoietic stem cell transplants. As an alternative or adjuvant approach to prevent relapse, we summarize the status of the promising forms of cellular immunotherapy aimed at targeting not only the bulk but also the cells of origin of leukemia. Finally, we discuss the available in vivo models for disease modelling and treatment efficacy prediction in these contexts. Abstract The purpose of this review is to present the current knowledge on the clinical use of several forms of cell therapy in hematological malignancies and the preclinical models available for their study. In the context of allogeneic hematopoietic stem cell transplants, mesenchymal stromal cells are pursued to help stem cell engraftment and expansion, and control graft versus host disease. We further summarize the status of promising forms of cellular immunotherapy including CAR T cell and CAR NK cell therapy aimed at eradicating the cells of origin of leukemia, i.e., leukemia stem cells. Updates on other forms of cellular immunotherapy, such as NK cells, CIK cells and CAR CIK cells, show encouraging results in AML. The considerations in available in vivo models for disease modelling and treatment efficacy prediction are discussed, with a particular focus on their strengths and weaknesses for the study of healthy and diseased hematopoietic stem cell reconstitution, graft versus host disease and immunotherapy. Despite current limitations, cell therapy is a rapidly evolving field that holds the promise of improved cure rates, soon. As a result, we may be witnessing the birth of the hematology of tomorrow. To further support its development, improved preclinical models including humanized microenvironments in mice are urgently needed.
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23
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Minardi S. Editorial: Nano-Biomaterials for the Delivery of Therapeutic and Biological Cues for Regenerative Medicine. Front Bioeng Biotechnol 2022; 9:832487. [PMID: 35096803 PMCID: PMC8792963 DOI: 10.3389/fbioe.2021.832487] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Accepted: 12/10/2021] [Indexed: 11/13/2022] Open
Affiliation(s)
- Silvia Minardi
- Department of Orthopaedic Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
- Simpson Querrey Institute of BioNanotechnology, Northwestern University, Chicago, IL, United States
- *Correspondence: Silvia Minardi,
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24
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Abstract
In his prominent book Regeneration (1901), T.H. Morgan's collected and synthesized theoretical and experimental findings from a diverse array of regenerating animals and plants. Through his endeavor, he introduced a new way to study regeneration and its evolution, setting a conceptual framework that still guides today's research and that embraces the contemporary evolutionary and developmental approaches.In the first part of the chapter, we summarize Morgan's major tenets and use it as a narrative thread to advocate interpreting regenerative biology through the theoretical tools provided by evolution and developmental biology, but also to highlight potential caveats resulting from the rapid proliferation of comparative studies and from the expansion of experimental laboratory models. In the second part, we review some experimental evo-devo approaches, highlighting their power and some of their interpretative dangers. Finally, in order to further understand the evolution of regenerative abilities, we portray an adaptive perspective on the evolution of regeneration and suggest a framework for investigating the adaptive nature of regeneration.
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Affiliation(s)
| | - Alexandre Alié
- Sorbonne Université, CNRS, Laboratoire de Biologie du Développement de Villefranche-sur-Mer (LBDV), Villefranche-sur-Mer, France
| | - Stefano Tiozzo
- Sorbonne Université, CNRS, Laboratoire de Biologie du Développement de Villefranche-sur-Mer (LBDV), Villefranche-sur-Mer, France.
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25
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Chen J, Zhou H, Xie D, Niu Y. Bletilla striata polysaccharide cryogel scaffold for spatial control of foreign-body reaction. Chin Med 2021; 16:131. [PMID: 34863224 PMCID: PMC8642900 DOI: 10.1186/s13020-021-00526-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Accepted: 10/29/2021] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND Implantation of a biomaterial may induce the foreign-body reaction to the host tissue that determines the outcome of the integration and the biological performance of the implants. The foreign-body reaction can be modulated by control of the material properties of the implants. METHODS First, we synthesized methacrylated Bletilla striata Polysaccharide (BSP-MA) and constructed a series of open porous cryogels utilizing this material via the freezing-thawing treatment of solvent-precursors systems. Second, Pore size and modulus were measured to characterize the properties of BSP cryogels. Live/dead staining of cells and CCK-8 were performed to test the cytocompatibility of the scaffolds. In addition, the Real-Time qPCR experiments were carried for the tests. Finally, the BSP scaffolds were implanted subcutaneously to verify the foreign-body reaction between host tissue and materials. RESULTS Our data demonstrated that cryogels with different pore sizes and modulus can be fabricated by just adjusting the concentration. Besides, the cryogels showed well cytocompatibility in the in vitro experiments and exhibited upregulated expression levels of pro-inflammation-related genes (Tnfa and Il1b) with the increase of pore size. In vivo experiments further proved that with the increase of pore size, more immune cells infiltrated into the inner zone of materials. The foreign-body reaction and the distribution of immune-regulatory cells could be modulated by tuning the material microstructure. CONCLUSIONS Collectively, our findings revealed Bletilla striata polysaccharide cryogel scaffold with different pore sizes can spatially control foreign-body reaction. The microstructure of cryogels could differentially guide the distribution of inflammatory cells, affect the formation of blood vessels and fibrous capsules, which eventually influence the material-tissue integration. This work demonstrates a practical strategy to regulate foreign body reaction and promote the performance of medical devices.
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Affiliation(s)
- Jiaxi Chen
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Avenida da Universidade, Macau SAR, China
| | - Huiqun Zhou
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Avenida da Universidade, Macau SAR, China
| | - Daping Xie
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Avenida da Universidade, Macau SAR, China
| | - Yiming Niu
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Avenida da Universidade, Macau SAR, China.
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26
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Xu S, Qiu Y, Tao J. The challenges and optimization of cell-based therapy for cardiovascular disease. J Transl Int Med 2021; 9:234-238. [PMID: 35136722 PMCID: PMC8802397 DOI: 10.2478/jtim-2021-0017] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
With the hope of achieving real cardiovascular repair, cell-based therapy raised as a promising strategy for the treatment of cardiovascular disease (CVD) in the past two decades. Various types of cells have been studied for their reparative potential for CVD in the ensuing years. Despite the exciting results from animal experiments, the outcome of clinical trials is unsatisfactory and the development of cell-based therapy for CVD has hit a plateau nowadays. Thus, it is important to summarize the obstacles we are facing in this field in order to explore possible solutions for optimizing cell-based therapy and achieving real clinical application.
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Affiliation(s)
- Shiyue Xu
- Department of Hypertension and Vascular Disease, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou510080, Guangdong Province, China
- Department of Biomedical Engineering, Molecular Cardiology Program, School of Medicine and School of Engineering, University of Alabama at BirminghamBirminghamUnited States
| | - Yumin Qiu
- Department of Hypertension and Vascular Disease, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou510080, Guangdong Province, China
| | - Jun Tao
- Department of Hypertension and Vascular Disease, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou510080, Guangdong Province, China
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27
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Fang WH, Agrawal DK, Thankam FG. "Smart Exosomes": A Smart Approach for Tendon Regeneration. TISSUE ENGINEERING PART B-REVIEWS 2021; 28:613-625. [PMID: 34074136 DOI: 10.1089/ten.teb.2021.0075] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Shoulder tendon injuries are the common musculoskeletal disorder resulting in significant pain and disability. These injuries are characterized by chronic inflammation and tissue degeneration. Tendon pathology exhibits poor innate healing ability, enhanced inflammation, disorganized collagen fibers, calcification, and scar tissue formation affecting the normal healing process. Extracellular vesicle, especially exosomes, treatment has been emerging as a potential regenerative strategy improving the outcomes and biomechanical properties, accelerating tenocyte proliferation and migration, reducing inflammation, and facilitating the healing at tendon-bone interface. In this article, we critically reviewed the potential role of exosomes in tendon regeneration and their applications to accelerate the healing response following injury. In addition, the article provides novel insights on the concept of "Smart Exosomes" by programming/manipulating the secretome contents and functions of exosomes in the management of shoulder tendon injury.
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Affiliation(s)
- William H Fang
- Department of Translational Research, Western University of Health Sciences, Pomona, California, USA
| | - Devendra K Agrawal
- Department of Translational Research, Western University of Health Sciences, Pomona, California, USA
| | - Finosh G Thankam
- Department of Translational Research, Western University of Health Sciences, Pomona, California, USA
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28
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Sevari SP, Ansari S, Moshaverinia A. A narrative overview of utilizing biomaterials to recapitulate the salient regenerative features of dental-derived mesenchymal stem cells. Int J Oral Sci 2021; 13:22. [PMID: 34193832 PMCID: PMC8245503 DOI: 10.1038/s41368-021-00126-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 05/26/2021] [Accepted: 06/03/2021] [Indexed: 02/06/2023] Open
Abstract
Tissue engineering approaches have emerged recently to circumvent many limitations associated with current clinical practices. This elegant approach utilizes a natural/synthetic biomaterial with optimized physiomechanical properties to serve as a vehicle for delivery of exogenous stem cells and bioactive factors or induce local recruitment of endogenous cells for in situ tissue regeneration. Inspired by the natural microenvironment, biomaterials could act as a biomimetic three-dimensional (3D) structure to help the cells establish their natural interactions. Such a strategy should not only employ a biocompatible biomaterial to induce new tissue formation but also benefit from an easily accessible and abundant source of stem cells with potent tissue regenerative potential. The human teeth and oral cavity harbor various populations of mesenchymal stem cells (MSCs) with self-renewing and multilineage differentiation capabilities. In the current review article, we seek to highlight recent progress and future opportunities in dental MSC-mediated therapeutic strategies for tissue regeneration using two possible approaches, cell transplantation and cell homing. Altogether, this paper develops a general picture of current innovative strategies to employ dental-derived MSCs combined with biomaterials and bioactive factors for regenerating the lost or defective tissues and offers information regarding the available scientific data and possible applications.
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Affiliation(s)
- Sevda Pouraghaei Sevari
- Weintraub Center for Reconstructive Biotechnology, Division of Advanced Prosthodontics, School of Dentistry, University of California, Los Angeles, Los Angeles, CA, USA
| | - Sahar Ansari
- Weintraub Center for Reconstructive Biotechnology, Division of Advanced Prosthodontics, School of Dentistry, University of California, Los Angeles, Los Angeles, CA, USA
| | - Alireza Moshaverinia
- Weintraub Center for Reconstructive Biotechnology, Division of Advanced Prosthodontics, School of Dentistry, University of California, Los Angeles, Los Angeles, CA, USA.
- California NanoSystems Institute, University of California, Los Angeles, Los Angeles, CA, USA.
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29
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Lv Q, Wang L, Luo X, Chen X. Adult stem cells in endometrial regeneration: Molecular insights and clinical applications. Mol Reprod Dev 2021; 88:379-394. [PMID: 34014590 PMCID: PMC8362170 DOI: 10.1002/mrd.23476] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 03/23/2021] [Accepted: 04/22/2021] [Indexed: 02/06/2023]
Abstract
Endometrial damage is an important cause of female reproductive problems, manifested as menstrual abnormalities, infertility, recurrent pregnancy loss, and other complications. These conditions are collectively termed "Asherman syndrome" (AS) and are typically associated with recurrent induced pregnancy terminations, repeated diagnostic curettage and intrauterine infections. Cancer treatment also has unexpected detrimental side effects on endometrial function in survivors independently of ovarian effects. Endometrial stem cells act in the regeneration of the endometrium and in repair through direct differentiation or paracrine effects. Nonendometrial adult stem cells, such as bone marrow-derived mesenchymal stem cells and umbilical cord-derived mesenchymal stem cells, with autologous and allogenic applications, can also repair injured endometrial tissue in animal models of AS and in human studies. However, there remains a lack of research on the repair of the damaged endometrium after the reversal of tumors, especially endometrial cancers. Here, we review the biological mechanisms of endometrial regeneration, and research progress and challenges for adult stem cell therapy for damaged endometrium, and discuss the potential applications of their use for endometrial repair after cancer remission, especially in endometrial cancers. Successful application of such cells will improve reproductive parameters in patients with AS or cancer. Significance: The endometrium is the fertile ground for embryos, but damage to the endometrium will greatly impair female fertility. Adult stem cells combined with tissue engineering scaffold materials or not have made great progress in repairing the injured endometrium due to benign lesions. However, due to the lack of research on the repair of the damaged endometrium caused by malignant tumors or tumor therapies, the safety and effectiveness of such stem cell-based therapies need to be further explored. This review focuses on the molecular insights and clinical application potential of adult stem cells in endometrial regeneration and discusses the possible challenges or difficulties that need to be overcome in stem cell-based therapies for tumor survivors. The development of adult stem cell-related new programs will help repair damaged endometrium safely and effectively and meet fertility needs in tumor survivors.
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Affiliation(s)
- Qiaoying Lv
- Department of GynecologyObstetrics and Gynecology Hospital of Fudan UniversityShanghaiChina
| | - Lulu Wang
- Department of GynecologyObstetrics and Gynecology Hospital of Fudan UniversityShanghaiChina
| | - Xuezhen Luo
- Department of GynecologyObstetrics and Gynecology Hospital of Fudan UniversityShanghaiChina
| | - Xiaojun Chen
- Department of GynecologyObstetrics and Gynecology Hospital of Fudan UniversityShanghaiChina
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30
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Ji Y, Li YM, Seo JG, Jang TS, Knowles JC, Song SH, Lee JH. Biological Potential of Polyethylene Glycol (PEG)-Functionalized Graphene Quantum Dots in In Vitro Neural Stem/Progenitor Cells. NANOMATERIALS (BASEL, SWITZERLAND) 2021; 11:1446. [PMID: 34072613 PMCID: PMC8226482 DOI: 10.3390/nano11061446] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 05/24/2021] [Accepted: 05/26/2021] [Indexed: 02/07/2023]
Abstract
Stem cell therapy is one of the novel and prospective fields. The ability of stem cells to differentiate into different lineages makes them attractive candidates for several therapies. It is essential to understand the cell fate, distribution, and function of transplanted cells in the local microenvironment before their applications. Therefore, it is necessary to develop an accurate and reliable labeling method of stem cells for imaging techniques to track their translocation after transplantation. The graphitic quantum dots (GQDs) are selected among various stem cell labeling and tracking strategies which have high photoluminescence ability, photostability, relatively low cytotoxicity, tunable surface functional groups, and delivering capacity. Since GQDs interact easily with the cell and interfere with cell behavior through surface functional groups, an appropriate surface modification needs to be considered to get close to the ideal labeling nanoprobes. In this study, polyethylene glycol (PEG) is used to improve biocompatibility while simultaneously maintaining the photoluminescent potentials of GQDs. The biochemically inert PEG successfully covered the surface of GQDs. The PEG-GQDs composites show adequate bioimaging capabilities when internalized into neural stem/progenitor cells (NSPCs). Furthermore, the bio-inertness of the PEG-GQDs is confirmed. Herein, we introduce the PEG-GQDs as a valuable tool for stem cell labeling and tracking for biomedical therapies in the field of neural regeneration.
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Affiliation(s)
- Yunseong Ji
- Institute of Tissue Regeneration Engineering (ITREN), Dankook University, 119 Dandae-ro, Cheonan 31116, Korea; (Y.J.); (Y.-M.L.)
- Department of Nanobiomedical Science & BK21 PLUS NBM Global Research Center for Regenerative Medicine, Dankook University, 119 Dandae-ro, Cheonan 31116, Korea
| | - Yu-Meng Li
- Institute of Tissue Regeneration Engineering (ITREN), Dankook University, 119 Dandae-ro, Cheonan 31116, Korea; (Y.J.); (Y.-M.L.)
- Department of Nanobiomedical Science & BK21 PLUS NBM Global Research Center for Regenerative Medicine, Dankook University, 119 Dandae-ro, Cheonan 31116, Korea
| | - Jin Gwan Seo
- Division of Advanced Materials Engineering, Kongju National University, Cheonan 32588, Korea;
| | - Tae-Su Jang
- Department of Pre-medi, College of Medicine, Dankook University, Cheonan 31116, Korea;
| | - Jonathan Campbell Knowles
- UCL Eastman-Korea Dental Medicine Innovation Centre, Dankook University, 119 Dandae-ro, Cheonan 31116, Korea;
- Division of Biomaterials and Tissue Engineering, Eastman Dental Institute, University College London, London WC1E 6HH, UK
- The Discoveries Centre for Regenerative and Precision Medicine, Eastman Dental Institute, University College London, London WC1E 6HH, UK
| | - Sung Ho Song
- Division of Advanced Materials Engineering, Kongju National University, Cheonan 32588, Korea;
| | - Jung-Hwan Lee
- Institute of Tissue Regeneration Engineering (ITREN), Dankook University, 119 Dandae-ro, Cheonan 31116, Korea; (Y.J.); (Y.-M.L.)
- Department of Nanobiomedical Science & BK21 PLUS NBM Global Research Center for Regenerative Medicine, Dankook University, 119 Dandae-ro, Cheonan 31116, Korea
- Department of Regenerative Dental Medicine, College of Dentistry, Dankook University, Cheonan 31116, Korea
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31
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Amaral AJR, Gaspar VM, Lavrador P, Mano JF. Double network laminarin-boronic/alginate dynamic bioink for 3D bioprinting cell-laden constructs. Biofabrication 2021; 13. [PMID: 34075894 DOI: 10.1088/1758-5090/abfd79] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Accepted: 04/30/2021] [Indexed: 12/12/2022]
Abstract
The design of dynamically crosslinked hydrogel bioinks for three-dimensional (3D) bioprinting is emerging as a valuable strategy to advance the fabrication of mechanically tuneable cell-laden constructs for 3Din vitrodisease modelling and tissue engineering applications. Herein, a dynamic bioink comprising boronic acid-functionalised laminarin and alginate is explored for bioprinting 3D constructs under physiologically relevant conditions. The formulated bioink takes advantage of a double crosslinked network that combines covalent but reversible boronate ester bonds and ionic gelation via divalent cations. Moreover, it exhibits suitable rheological properties and improved mechanical features owing to its modular crosslinking chemistry, yielding stable constructs with user-programmable architecture. We explored such dynamic bioink as a supporting matrix for different cell classes, namely osteoblast precursors, fibroblasts and breast cancer cells. The resulting cell-laden bioprinted hydrogels display a homogeneous cell distribution post-printing and exceptional cell viability (>90%) that can be maintained for prolonged time periods in culture (14 days) for all cell lines. This simple and chemically versatile approach is envisaged to accelerate the development of multifunctional bioinks and contribute towards the fabrication of biomimetic 3D scaffolds with applicability in a wide range of predictive or exploratory biomedical platforms.
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Affiliation(s)
- Adérito J R Amaral
- CICECO-Aveiro Institute of Materials, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal
| | - Vítor M Gaspar
- CICECO-Aveiro Institute of Materials, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal
| | - Pedro Lavrador
- CICECO-Aveiro Institute of Materials, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal
| | - João F Mano
- CICECO-Aveiro Institute of Materials, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal
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32
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Key Markers and Epigenetic Modifications of Dental-Derived Mesenchymal Stromal Cells. Stem Cells Int 2021; 2021:5521715. [PMID: 34046069 PMCID: PMC8128613 DOI: 10.1155/2021/5521715] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 04/08/2021] [Accepted: 04/17/2021] [Indexed: 12/13/2022] Open
Abstract
As a novel research hotspot in tissue regeneration, dental-derived mesenchymal stromal cells (MSCs) are famous for their accessibility, multipotent differentiation ability, and high proliferation. However, cellular heterogeneity is a major obstacle to the clinical application of dental-derived MSCs. Here, we reviewed the heterogeneity of dental-derived MSCs firstly and then discussed the key markers and epigenetic modifications related to the proliferation, differentiation, immunomodulation, and aging of dental-derived MSCs. These messages help to control the composition and function of dental-derived MSCs and thus accelerate the translation of cell therapy into clinical practice.
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33
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Arenas Gómez CM, Echeverri K. Salamanders: The molecular basis of tissue regeneration and its relevance to human disease. Curr Top Dev Biol 2021; 145:235-275. [PMID: 34074531 PMCID: PMC8186737 DOI: 10.1016/bs.ctdb.2020.11.009] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Salamanders are recognized for their ability to regenerate a broad range of tissues. They have also have been used for hundreds of years for classical developmental biology studies because of their large accessible embryos. The range of tissues these animals can regenerate is fascinating, from full limbs to parts of the brain or heart, a potential that is missing in humans. Many promising research efforts are working to decipher the molecular blueprints shared across the organisms that naturally have the capacity to regenerate different tissues and organs. Salamanders are an excellent example of a vertebrate that can functionally regenerate a wide range of tissue types. In this review, we outline some of the significant insights that have been made that are aiding in understanding the cellular and molecular mechanisms of tissue regeneration in salamanders and discuss why salamanders are a worthy model in which to study regenerative biology and how this may benefit research fields like regenerative medicine to develop therapies for humans in the future.
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Affiliation(s)
- Claudia Marcela Arenas Gómez
- Marine Biological Laboratory, Eugene Bell Center for Regenerative Biology and Tissue Engineering, University of Chicago, Woods Hole, MA, United States
| | - Karen Echeverri
- Marine Biological Laboratory, Eugene Bell Center for Regenerative Biology and Tissue Engineering, University of Chicago, Woods Hole, MA, United States.
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34
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Challenges and advances in clinical applications of mesenchymal stromal cells. J Hematol Oncol 2021; 14:24. [PMID: 33579329 PMCID: PMC7880217 DOI: 10.1186/s13045-021-01037-x] [Citation(s) in RCA: 379] [Impact Index Per Article: 94.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Accepted: 01/26/2021] [Indexed: 12/12/2022] Open
Abstract
Mesenchymal stromal cells (MSCs), also known as mesenchymal stem cells, have been intensely investigated for clinical applications within the last decades. However, the majority of registered clinical trials applying MSC therapy for diverse human diseases have fallen short of expectations, despite the encouraging pre-clinical outcomes in varied animal disease models. This can be attributable to inconsistent criteria for MSCs identity across studies and their inherited heterogeneity. Nowadays, with the emergence of advanced biological techniques and substantial improvements in bio-engineered materials, strategies have been developed to overcome clinical challenges in MSC application. Here in this review, we will discuss the major challenges of MSC therapies in clinical application, the factors impacting the diversity of MSCs, the potential approaches that modify MSC products with the highest therapeutic potential, and finally the usage of MSCs for COVID-19 pandemic disease.
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35
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Chen Y, Pu Q, Ma Y, Zhang H, Ye T, Zhao C, Huang X, Ren Y, Qiao L, Liu HM, Esmon CT, Ding BS, Cao Z. Aging Reprograms the Hematopoietic-Vascular Niche to Impede Regeneration and Promote Fibrosis. Cell Metab 2021; 33:395-410.e4. [PMID: 33357457 DOI: 10.1016/j.cmet.2020.11.019] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2019] [Revised: 09/23/2020] [Accepted: 11/25/2020] [Indexed: 02/05/2023]
Abstract
Regenerative capacity is frequently impaired in aged organs. Stress to aged organs often causes scar formation (fibrosis) at the expense of regeneration. It remains to be defined how hematopoietic and vascular cells contribute to aging-induced regeneration to fibrotic transition. Here, we find that aging aberrantly reprograms the crosstalk between hematopoietic and vascular cells to impede the regenerative capacity and enhance fibrosis. In aged lung, liver, and kidney, induction of Neuropilin-1/hypoxia-inducible-factor 2α (HIF2α) suppresses anti-thrombotic and anti-inflammatory endothelial protein C receptor (EPCR) pathway, leading to formation of pro-fibrotic platelet-macrophage rosette. Activated platelets via supplying interleukin 1α synergize with endothelial-produced angiocrine chemokine to recruit fibrogenic TIMP1high macrophages. In mouse models, genetic targeting of endothelial Neuropilin-1-HIF2α, platelet interleukin 1α, or macrophage TIMP1 normalized the pro-fibrotic hematopoietic-vascular niche and restored the regenerative capacity of old organs. Targeting of aberrant endothelial node molecules might help propel "regeneration without scarring" in the repair of multiple organs.
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Affiliation(s)
- Yutian Chen
- Key Laboratory of Birth Defects of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu 610041, China
| | - Qiang Pu
- Department of Thoracic Surgery, National Frontier Center of Disease Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yongyuan Ma
- Key Laboratory of Birth Defects of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu 610041, China
| | - Hua Zhang
- Key Laboratory of Birth Defects of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu 610041, China
| | - Tinghong Ye
- Key Laboratory of Birth Defects of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu 610041, China
| | - Chengjian Zhao
- Key Laboratory of Birth Defects of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu 610041, China
| | - Xiaojuan Huang
- Key Laboratory of Birth Defects of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu 610041, China
| | - Yafeng Ren
- Key Laboratory of Birth Defects of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu 610041, China
| | - Lina Qiao
- Key Laboratory of Birth Defects of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu 610041, China
| | - Han-Min Liu
- Key Laboratory of Birth Defects of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu 610041, China
| | - Charles T Esmon
- Coagulation Biology Laboratory, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA
| | - Bi-Sen Ding
- Key Laboratory of Birth Defects of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu 610041, China; Fibrosis Research Center, Division of Pulmonary and Critical Care Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Division of Regenerative Medicine, Weill Cornell Medicine, New York, NY 10065, USA
| | - Zhongwei Cao
- Key Laboratory of Birth Defects of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu 610041, China.
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DeFrates KG, Franco D, Heber-Katz E, Messersmith PB. Unlocking mammalian regeneration through hypoxia inducible factor one alpha signaling. Biomaterials 2021; 269:120646. [PMID: 33493769 PMCID: PMC8279430 DOI: 10.1016/j.biomaterials.2020.120646] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Revised: 12/19/2020] [Accepted: 12/29/2020] [Indexed: 02/08/2023]
Abstract
Historically, the field of regenerative medicine has aimed to heal damaged tissue through the use of biomaterials scaffolds or delivery of foreign progenitor cells. Despite 30 years of research, however, translation and commercialization of these techniques has been limited. To enable mammalian regeneration, a more practical approach may instead be to develop therapies that evoke endogenous processes reminiscent of those seen in innate regenerators. Recently, investigations into tadpole tail regrowth, zebrafish limb restoration, and the super-healing Murphy Roths Large (MRL) mouse strain, have identified ancient oxygen-sensing pathways as a possible target to achieve this goal. Specifically, upregulation of the transcription factor, hypoxia-inducible factor one alpha (HIF-1α) has been shown to modulate cell metabolism and plasticity, as well as inflammation and tissue remodeling, possibly priming injuries for regeneration. Since HIF-1α signaling is conserved across species, environmental or pharmacological manipulation of oxygen-dependent pathways may elicit a regenerative response in non-healing mammals. In this review, we will explore the emerging role of HIF-1α in mammalian healing and regeneration, as well as attempts to modulate protein stability through hyperbaric oxygen treatment, intermittent hypoxia therapy, and pharmacological targeting. We believe that these therapies could breathe new life into the field of regenerative medicine.
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Affiliation(s)
- Kelsey G DeFrates
- Department of Bioengineering and Materials Science and Engineering, University of California, Berkeley, CA, USA.
| | - Daniela Franco
- Department of Bioengineering and Materials Science and Engineering, University of California, Berkeley, CA, USA.
| | - Ellen Heber-Katz
- Laboratory of Regenerative Medicine, Lankenau Institute for Medical Research, Wynnewood, PA, USA.
| | - Phillip B Messersmith
- Department of Bioengineering and Materials Science and Engineering, University of California, Berkeley, CA, USA; Materials Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.
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Rodríguez-Merchán EC. A Review of Recent Developments in the Molecular Mechanisms of Bone Healing. Int J Mol Sci 2021; 22:767. [PMID: 33466612 PMCID: PMC7828700 DOI: 10.3390/ijms22020767] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 01/08/2021] [Accepted: 01/12/2021] [Indexed: 02/06/2023] Open
Abstract
Between 5 and 10 percent of fractures do not heal, a condition known as nonunion. In clinical practice, stable fracture fixation associated with autologous iliac crest bone graft placement is the gold standard for treatment. However, some recalcitrant nonunions do not resolve satisfactorily with this technique. For these cases, biological alternatives are sought based on the molecular mechanisms of bone healing, whose most recent findings are reviewed in this article. The pro-osteogenic efficacy of morin (a pale yellow crystalline flavonoid pigment found in old fustic and osage orange trees) has recently been reported, and the combined use of bone morphogenetic protein-9 (BMP9) and leptin might improve fracture healing. Inhibition with methyl-piperidino-pyrazole of estrogen receptor alpha signaling delays bone regeneration. Smoking causes a chondrogenic disorder, aberrant activity of the skeleton's stem and progenitor cells, and an intense initial inflammatory response. Smoking cessation 4 weeks before surgery is therefore highly recommended. The delay in fracture consolidation in diabetic animals is related to BMP6 deficiency (35 kDa). The combination of bioceramics and expanded autologous human mesenchymal stem cells from bone marrow is a new and encouraging alternative for treating recalcitrant nonunions.
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Affiliation(s)
- Emerito Carlos Rodríguez-Merchán
- Osteoarticular Surgery Research, Hospital La Paz Institute for Health Research-IdiPAZ, La Paz University Hospital-Autonomous University of Madrid, 28046 Madrid, Spain
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Yeola A, Subramanian S, Oliver RA, Lucas CA, Thoms JAI, Yan F, Olivier J, Chacon D, Tursky ML, Srivastava P, Potas JR, Hung T, Power C, Hardy P, Ma DD, Kilian KA, McCarroll J, Kavallaris M, Hesson LB, Beck D, Curtis DJ, Wong JWH, Hardeman EC, Walsh WR, Mobbs R, Chandrakanthan V, Pimanda JE. Induction of muscle-regenerative multipotent stem cells from human adipocytes by PDGF-AB and 5-azacytidine. SCIENCE ADVANCES 2021; 7:7/3/eabd1929. [PMID: 33523875 PMCID: PMC7806226 DOI: 10.1126/sciadv.abd1929] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Accepted: 11/23/2020] [Indexed: 06/12/2023]
Abstract
Terminally differentiated murine osteocytes and adipocytes can be reprogrammed using platelet-derived growth factor-AB and 5-azacytidine into multipotent stem cells with stromal cell characteristics. We have now optimized culture conditions to reprogram human adipocytes into induced multipotent stem (iMS) cells and characterized their molecular and functional properties. Although the basal transcriptomes of adipocyte-derived iMS cells and adipose tissue-derived mesenchymal stem cells were similar, there were changes in histone modifications and CpG methylation at cis-regulatory regions consistent with an epigenetic landscape that was primed for tissue development and differentiation. In a non-specific tissue injury xenograft model, iMS cells contributed directly to muscle, bone, cartilage, and blood vessels, with no evidence of teratogenic potential. In a cardiotoxin muscle injury model, iMS cells contributed specifically to satellite cells and myofibers without ectopic tissue formation. Together, human adipocyte-derived iMS cells regenerate tissues in a context-dependent manner without ectopic or neoplastic growth.
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Affiliation(s)
- Avani Yeola
- Adult Cancer Program, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW 2052, Australia
- School of Medical Sciences, Faculty of Medicine, UNSW Sydney, Sydney, NSW 2052, Australia
| | - Shruthi Subramanian
- Adult Cancer Program, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW 2052, Australia
- Prince of Wales Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW 2052, Australia
| | - Rema A Oliver
- Surgical and Orthopaedic Research Laboratories, Prince of Wales Clinical School, UNSW Sydney, Sydney, NSW 2052, Australia
| | - Christine A Lucas
- Cellular and Genetic Medicine Unit, School of Medical Sciences, UNSW Sydney, Sydney, NSW 2052, Australia
| | - Julie A I Thoms
- Adult Cancer Program, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW 2052, Australia
- School of Medical Sciences, Faculty of Medicine, UNSW Sydney, Sydney, NSW 2052, Australia
| | - Feng Yan
- Australian Centre for Blood Diseases, Central Clinical School, Monash University, Melbourne, VIC, Australia
| | - Jake Olivier
- School of Mathematics and Statistics, UNSW Sydney, Sydney, NSW 2052, Australia
| | - Diego Chacon
- School of Biomedical Engineering, University of Technology Sydney, Sydney, NSW 2007, Australia
| | - Melinda L Tursky
- St. Vincent's Centre for Applied Medical Research, St Vincent's Hospital Sydney and St Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW 2010, Australia
| | - Pallavi Srivastava
- School of Material Sciences and Engineering, School of Chemistry, Australian Centre for Nanomedicine, UNSW Sydney, Sydney, NSW 2052, Australia
| | - Jason R Potas
- Translational Neuroscience Facility, School of Medical Sciences, UNSW Sydney, Sydney, NSW 2052, Australia
| | - Tzongtyng Hung
- Biological Resources Imaging Laboratory, Mark Wainwright Analytical Centre, UNSW Sydney, Sydney, NSW 2052, Australia
| | - Carl Power
- Biological Resources Imaging Laboratory, Mark Wainwright Analytical Centre, UNSW Sydney, Sydney, NSW 2052, Australia
| | | | - David D Ma
- St. Vincent's Centre for Applied Medical Research, St Vincent's Hospital Sydney and St Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW 2010, Australia
| | - Kristopher A Kilian
- School of Material Sciences and Engineering, School of Chemistry, Australian Centre for Nanomedicine, UNSW Sydney, Sydney, NSW 2052, Australia
| | - Joshua McCarroll
- Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales Sydney, Sydney, NSW, Australia
| | - Maria Kavallaris
- Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales Sydney, Sydney, NSW, Australia
- ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Australian Centre for Nanomedicine, UNSW Sydney, Sydney, NSW 2052, Australia
- School of Women's and Children's Health, Faculty of Medicine, UNSW Sydney, Sydney, NSW 2052, Australia
| | - Luke B Hesson
- Prince of Wales Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW 2052, Australia
- Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia
| | - Dominik Beck
- School of Biomedical Engineering, University of Technology Sydney, Sydney, NSW 2007, Australia
| | - David J Curtis
- Australian Centre for Blood Diseases, Central Clinical School, Monash University, Melbourne, VIC, Australia
- Department of Clinical Haematology, Alfred Health, Melbourne, VIC, Australia
| | - Jason W H Wong
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region
| | - Edna C Hardeman
- Cellular and Genetic Medicine Unit, School of Medical Sciences, UNSW Sydney, Sydney, NSW 2052, Australia
| | - William R Walsh
- Surgical and Orthopaedic Research Laboratories, Prince of Wales Clinical School, UNSW Sydney, Sydney, NSW 2052, Australia
| | - Ralph Mobbs
- Surgical and Orthopaedic Research Laboratories, Prince of Wales Clinical School, UNSW Sydney, Sydney, NSW 2052, Australia
- Department of Neurosurgery, Prince of Wales Hospital, Randwick, NSW 2031, Australia
| | - Vashe Chandrakanthan
- Adult Cancer Program, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW 2052, Australia.
- School of Medical Sciences, Faculty of Medicine, UNSW Sydney, Sydney, NSW 2052, Australia
| | - John E Pimanda
- Adult Cancer Program, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW 2052, Australia.
- School of Medical Sciences, Faculty of Medicine, UNSW Sydney, Sydney, NSW 2052, Australia
- Prince of Wales Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW 2052, Australia
- Department of Haematology, Prince of Wales Hospital, Randwick, NSW 2031, Australia
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de la Torre P, Flores AI. Current Status and Future Prospects of Perinatal Stem Cells. Genes (Basel) 2020; 12:6. [PMID: 33374593 PMCID: PMC7822425 DOI: 10.3390/genes12010006] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 12/18/2020] [Accepted: 12/20/2020] [Indexed: 02/05/2023] Open
Abstract
The placenta is a temporary organ that is discarded after birth and is one of the most promising sources of various cells and tissues for use in regenerative medicine and tissue engineering, both in experimental and clinical settings. The placenta has unique, intrinsic features because it plays many roles during gestation: it is formed by cells from two individuals (mother and fetus), contributes to the development and growth of an allogeneic fetus, and has two independent and interacting circulatory systems. Different stem and progenitor cell types can be isolated from the different perinatal tissues making them particularly interesting candidates for use in cell therapy and regenerative medicine. The primary source of perinatal stem cells is cord blood. Cord blood has been a well-known source of hematopoietic stem/progenitor cells since 1974. Biobanked cord blood has been used to treat different hematological and immunological disorders for over 30 years. Other perinatal tissues that are routinely discarded as medical waste contain non-hematopoietic cells with potential therapeutic value. Indeed, in advanced perinatal cell therapy trials, mesenchymal stromal cells are the most commonly used. Here, we review one by one the different perinatal tissues and the different perinatal stem cells isolated with their phenotypical characteristics and the preclinical uses of these cells in numerous pathologies. An overview of clinical applications of perinatal derived cells is also described with special emphasis on the clinical trials being carried out to treat COVID19 pneumonia. Furthermore, we describe the use of new technologies in the field of perinatal stem cells and the future directions and challenges of this fascinating and rapidly progressing field of perinatal cells and regenerative medicine.
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Affiliation(s)
| | - Ana I. Flores
- Grupo de Medicina Regenerativa, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Avda. Cordoba s/n, 28041 Madrid, Spain;
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Abstract
Compared with non-degradable materials, biodegradable biomaterials play an increasingly important role in the repairing of severe bone defects, and have attracted extensive attention from researchers. In the treatment of bone defects, scaffolds made of biodegradable materials can provide a crawling bridge for new bone tissue in the gap and a platform for cells and growth factors to play a physiological role, which will eventually be degraded and absorbed in the body and be replaced by the new bone tissue. Traditional biodegradable materials include polymers, ceramics and metals, which have been used in bone defect repairing for many years. Although these materials have more or fewer shortcomings, they are still the cornerstone of our development of a new generation of degradable materials. With the rapid development of modern science and technology, in the twenty-first century, more and more kinds of new biodegradable materials emerge in endlessly, such as new intelligent micro-nano materials and cell-based products. At the same time, there are many new fabrication technologies of improving biodegradable materials, such as modular fabrication, 3D and 4D printing, interface reinforcement and nanotechnology. This review will introduce various kinds of biodegradable materials commonly used in bone defect repairing, especially the newly emerging materials and their fabrication technology in recent years, and look forward to the future research direction, hoping to provide researchers in the field with some inspiration and reference.
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Affiliation(s)
- Shuai Wei
- Tianjin Hospital, Tianjin University, No. 406 Jiefang South Road, Tianjin, 300211 China
| | - Jian-Xiong Ma
- Tianjin Hospital, Tianjin University, No. 406 Jiefang South Road, Tianjin, 300211 China
| | - Lai Xu
- Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Nantong University, No. 19 Qixiu Road, Chongchuan District, Nantong, 226001 China
| | - Xiao-Song Gu
- Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Nantong University, No. 19 Qixiu Road, Chongchuan District, Nantong, 226001 China
| | - Xin-Long Ma
- Tianjin Hospital, Tianjin University, No. 406 Jiefang South Road, Tianjin, 300211 China
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McElhinney JMWR, Hasan A, Sajini AA. The epitranscriptome landscape of small noncoding RNAs in stem cells. Stem Cells 2020; 38:1216-1228. [PMID: 32598085 PMCID: PMC7586957 DOI: 10.1002/stem.3233] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Revised: 05/04/2020] [Accepted: 05/11/2020] [Indexed: 12/14/2022]
Abstract
Stem cells (SCs) are unique cells that have an inherent ability to self‐renew or differentiate. Both fate decisions are strongly regulated at the molecular level via intricate signaling pathways. The regulation of signaling networks promoting self‐renewal or differentiation was thought to be largely governed by the action of transcription factors. However, small noncoding RNAs (ncRNAs), such as vault RNAs, and their post‐transcriptional modifications (the epitranscriptome) have emerged as additional regulatory layers with essential roles in SC fate decisions. RNA post‐transcriptional modifications often modulate RNA stability, splicing, processing, recognition, and translation. Furthermore, modifications on small ncRNAs allow for dual regulation of RNA activity, at both the level of biogenesis and RNA‐mediated actions. RNA post‐transcriptional modifications act through structural alterations and specialized RNA‐binding proteins (RBPs) called writers, readers, and erasers. It is through SC‐context RBPs that the epitranscriptome coordinates specific functional roles. Small ncRNA post‐transcriptional modifications are today exploited by different mechanisms to facilitate SC translational studies. One mechanism readily being studied is identifying how SC‐specific RBPs of small ncRNAs regulate fate decisions. Another common practice of using the epitranscriptome for regenerative applications is using naturally occurring post‐transcriptional modifications on synthetic RNA to generate induced pluripotent SCs. Here, we review exciting insights into how small ncRNA post‐transcriptional modifications control SC fate decisions in development and disease. We hope, by illustrating how essential the epitranscriptome and their associated proteome are in SCs, they would be considered as novel tools to propagate SCs for regenerative medicine.
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Affiliation(s)
- James M W R McElhinney
- Department of Biomedical Engineering, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates
| | - Ayesha Hasan
- Department of Biomedical Engineering, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates
| | - Abdulrahim A Sajini
- Department of Biomedical Engineering, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates
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Mesenchymal Stem/Progenitor Cells: The Prospect of Human Clinical Translation. Stem Cells Int 2020; 2020:8837654. [PMID: 33953753 PMCID: PMC8063852 DOI: 10.1155/2020/8837654] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Revised: 06/19/2020] [Accepted: 07/20/2020] [Indexed: 12/13/2022] Open
Abstract
Mesenchymal stem/progenitor cells (MSCs) are key players in regenerative medicine, relying principally on their differentiation/regeneration potential, immunomodulatory properties, paracrine effects, and potent homing ability with minimal if any ethical concerns. Even though multiple preclinical and clinical studies have demonstrated remarkable properties for MSCs, the clinical applicability of MSC-based therapies is still questionable. Several challenges exist that critically hinder a successful clinical translation of MSC-based therapies, including but not limited to heterogeneity of their populations, variability in their quality and quantity, donor-related factors, discrepancies in protocols for isolation, in vitro expansion and premodification, and variability in methods of cell delivery, dosing, and cell homing. Alterations of MSC viability, proliferation, properties, and/or function are also affected by various drugs and chemicals. Moreover, significant safety concerns exist due to possible teratogenic/neoplastic potential and transmission of infectious diseases. Through the current review, we aim to highlight the major challenges facing MSCs' human clinical translation and shed light on the undergoing strategies to overcome them.
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43
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Lu L. The "Salmon Spirit" of translational medical research. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:560. [PMID: 32775361 PMCID: PMC7347785 DOI: 10.21037/atm.2020.04.29] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Affiliation(s)
- Ling Lu
- Liver Transplantation Center, First Affiliated Hospital, Nanjing Medical University; Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing 210029, China.,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing 210029, China
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Bozorgmehr M, Gurung S, Darzi S, Nikoo S, Kazemnejad S, Zarnani AH, Gargett CE. Endometrial and Menstrual Blood Mesenchymal Stem/Stromal Cells: Biological Properties and Clinical Application. Front Cell Dev Biol 2020; 8:497. [PMID: 32742977 PMCID: PMC7364758 DOI: 10.3389/fcell.2020.00497] [Citation(s) in RCA: 118] [Impact Index Per Article: 23.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Accepted: 05/25/2020] [Indexed: 12/11/2022] Open
Abstract
A highly proliferative mesenchymal stem/stromal cell (MSC) population was recently discovered in the dynamic, cyclically regenerating human endometrium as clonogenic stromal cells that fulfilled the International Society for Cellular Therapy (ISCT) criteria. Specific surface markers enriching for clonogenic endometrial MSC (eMSC), CD140b and CD146 co-expression, and the single marker SUSD2, showed their perivascular identity in the endometrium, including the layer which sheds during menstruation. Indeed, cells with MSC properties have been identified in menstrual fluid and commonly termed menstrual blood stem/stromal cells (MenSC). MenSC are generally retrieved from menstrual fluid as plastic adherent cells, similar to bone marrow MSC (bmMSC). While eMSC and MenSC share several biological features with bmMSC, they also show some differences in immunophenotype, proliferation and differentiation capacities. Here we review the phenotype and functions of eMSC and MenSC, with a focus on recent studies. Similar to other MSC, eMSC and MenSC exert immunomodulatory and anti-inflammatory impacts on key cells of the innate and adaptive immune system. These include macrophages, T cells and NK cells, both in vitro and in small and large animal models. These properties suggest eMSC and MenSC as additional sources of MSC for cell therapies in regenerative medicine as well as immune-mediated disorders and inflammatory diseases. Their easy acquisition via an office-based biopsy or collected from menstrual effluent makes eMSC and MenSC attractive sources of MSC for clinical applications. In preparation for clinical translation, a serum-free culture protocol was established for eMSC which includes a small molecule TGFβ receptor inhibitor that prevents spontaneous differentiation, apoptosis, senescence, maintains the clonogenic SUSD2+ population and enhances their potency, suggesting potential for cell-therapies and regenerative medicine. However, standardization of MenSC isolation protocols and culture conditions are major issues requiring further research to maximize their potential for clinical application. Future research will also address crucial safety aspects of eMSC and MenSC to ensure these protocols produce cell products free from tumorigenicity and toxicity. Although a wealth of data on the biological properties of eMSC and MenSC has recently been published, it will be important to address their mechanism of action in preclinical models of human disease.
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Affiliation(s)
- Mahmood Bozorgmehr
- Reproductive Immunology Research Center, Avicenna Research Institute, Academic Center for Education, Culture and Research (ACECR), Tehran, Iran
- Oncopathology Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Shanti Gurung
- Centre for Reproductive Health, Hudson Institute of Medical Research, Melbourne, VIC, Australia
| | - Saeedeh Darzi
- The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, VIC, Australia
- Department of Obstetrics and Gynaecology, Monash University, Melbourne, VIC, Australia
| | - Shohreh Nikoo
- Immunology Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Somaieh Kazemnejad
- Nanobitechnology Research Center, Avicenna Research Institute, Academic Center for Education, Culture and Research (ACECR), Tehran, Iran
| | - Amir-Hassan Zarnani
- Reproductive Immunology Research Center, Avicenna Research Institute, Academic Center for Education, Culture and Research (ACECR), Tehran, Iran
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Caroline E. Gargett
- The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, VIC, Australia
- Department of Obstetrics and Gynaecology, Monash University, Melbourne, VIC, Australia
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Tiwari A, Kumar R, Shefi O, Randhawa JK. Fluorescent Mantle Carbon Coated Core–Shell SPIONs for Neuroengineering Applications. ACS APPLIED BIO MATERIALS 2020; 3:4665-4673. [DOI: 10.1021/acsabm.0c00582] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Ashish Tiwari
- School of Engineering, Indian Institute of Technology Mandi-175005, India
| | - Raj Kumar
- Bar-Ilan Institute for Nanotechnology and Advanced Materials (BINA) and Faculty of Engineering, Bar-Ilan University, Ramat Gan-52900, Israel
| | - Orit Shefi
- Bar-Ilan Institute for Nanotechnology and Advanced Materials (BINA) and Faculty of Engineering, Bar-Ilan University, Ramat Gan-52900, Israel
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Wang L, Wang C, Wang Z, Gan J, Liu C, Xia S, Niu Y, Chen D, Zhang J, Dong L. Transforming the spleen into a liver-like organ in vivo. SCIENCE ADVANCES 2020; 6:eaaz9974. [PMID: 32577515 PMCID: PMC7286668 DOI: 10.1126/sciadv.aaz9974] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/26/2019] [Accepted: 04/14/2020] [Indexed: 05/10/2023]
Abstract
Regenerating human organs remains an unmet medical challenge. Suitable transplants are scarce, while engineered tissues have a long way to go toward clinical use. Here, we demonstrate a different strategy that successfully transformed an existing, functionally dispensable organ to regenerate another functionally vital one in the body. Specifically, we injected a tumor extract into the mouse spleen to remodel its tissue structure into an immunosuppressive and proregenerative microenvironment. We implanted autologous, allogeneic, or xenogeneic liver cells (either primary or immortalized), which survived and proliferated in the remodeled spleen, without exerting adverse responses. Notably, the allografted primary liver cells exerted typical hepatic functions to rescue the host mice from severe liver damages including 90% hepatectomy. Our approach shows its competence in overcoming the key challenges in tissue regeneration, including insufficient transplants, immune rejection, and poor vascularization. It may be ready for translation into new therapies to regenerate large, complex human tissue/organs.
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Affiliation(s)
- Lintao Wang
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 163 Xianlin Avenue, Nanjing 210093, China
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macau SAR, China
| | - Chunming Wang
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macau SAR, China
- Corresponding author. (L.D.); (C.W.); (J.Z.)
| | - Zhenzhen Wang
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 163 Xianlin Avenue, Nanjing 210093, China
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macau SAR, China
| | - Jingjing Gan
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 163 Xianlin Avenue, Nanjing 210093, China
| | - Chunyan Liu
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 163 Xianlin Avenue, Nanjing 210093, China
| | - Suhua Xia
- Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Yiming Niu
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macau SAR, China
| | - Dianhua Chen
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 163 Xianlin Avenue, Nanjing 210093, China
| | - Junfeng Zhang
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 163 Xianlin Avenue, Nanjing 210093, China
- Corresponding author. (L.D.); (C.W.); (J.Z.)
| | - Lei Dong
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 163 Xianlin Avenue, Nanjing 210093, China
- Chemistry and Biomedicine Innovative Center, Nanjing University, 163 Xianlin Avenue, Nanjing 210093, China
- Corresponding author. (L.D.); (C.W.); (J.Z.)
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Lee JH, Luo J, Choi HK, Chueng STD, Lee KB, Choi JW. Functional nanoarrays for investigating stem cell fate and function. NANOSCALE 2020; 12:9306-9326. [PMID: 32090229 PMCID: PMC7671654 DOI: 10.1039/c9nr10963c] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/21/2023]
Abstract
Stem cells show excellent potential in the field of tissue engineering and regenerative medicine based on their excellent capability to not only self-renew but also differentiate into a specialized cell type of interest. However, the lack of a non-destructive monitoring system makes it challenging to identify and characterize differentiated cells before their transplantation without compromising cell viability. Thus, the development of a non-destructive monitoring method for analyzing cell function is highly desired and can significantly benefit stem cell-based therapies. Recently, nanomaterial-based scaffolds (e.g., nanoarrays) have made possible considerable advances in controlling the differentiation of stem cells and characterization of the differentiation status sensitively in real time. This review provides a selective overview of the recent progress in the synthesis methods of nanoarrays and their applications in controlling stem cell fate and monitoring live cell functions electrochemically. We believe that the topics discussed in this review can provide brief and concise guidelines for the development of novel nanoarrays and promote the interest in live cell study applications. A method which can not only control but also monitor stem cell fate and function will be a promising technology that can accelerate stem cell therapies.
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Affiliation(s)
- Jin-Ho Lee
- Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ 08854, USA.
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Chang HT, Heuer RA, Oleksijew AM, Coots KS, Roque CB, Nella KT, McGuire TL, Matsuoka AJ. An engineered three-dimensional stem cell niche in the inner ear by applying a nanofibrillar cellulose hydrogel with a sustained-release neurotrophic factor delivery system. Acta Biomater 2020; 108:111-127. [PMID: 32156626 PMCID: PMC7198367 DOI: 10.1016/j.actbio.2020.03.007] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Revised: 02/01/2020] [Accepted: 03/03/2020] [Indexed: 11/17/2022]
Abstract
Although the application of human embryonic stem cells (hESCs) in stem cell-replacement therapy remains promising, its potential is hindered by a low cell survival rate in post-transplantation within the inner ear. Here, we aim to enhance the in vitro and in vivo survival rate and neuronal differentiation of otic neuronal progenitors (ONPs) by generating an artificial stem cell niche consisting of three-dimensional (3D) hESC-derived ONP spheroids with a nanofibrillar cellulose hydrogel and a sustained-release brain-derivative neurotrophic factor delivery system. Our results demonstrated that the transplanted hESC-derived ONP spheroids survived and neuronally differentiated into otic neuronal lineages in vitro and in vivo and also extended neurites toward the bony wall of the cochlea 90 days after the transplantation without the use of immunosuppressant medication. Our data in vitro and in vivo presented here provide sufficient evidence that we have established a robust, reproducible protocol for in vivo transplantation of hESC-derived ONPs to the inner ear. Using our protocol to create an artificial stem cell niche in the inner ear, it is now possible to work on integrating transplanted hESC-derived ONPs further and also to work toward achieving functional auditory neurons generated from hESCs. Our findings suggest that the provision of an artificial stem cell niche can be a future approach to stem cell-replacement therapy for inner-ear regeneration. STATEMENT OF SIGNIFICANCE: Inner ear regeneration utilizing human embryonic stem cell-derived otic neuronal progenitors (hESC-derived ONPs) has remarkable potential for treating sensorineural hearing loss. However, the local environment of the inner ear requires a suitable stem cell niche to allow hESC-derived ONP engraftment as well as neuronal differentiation. To overcome this obstacle, we utilized three-dimensional spheroid formation (direct contact), nanofibrillar cellulose hydrogel (extracellular matrix), and a neurotrophic factor delivery system to artificially create a stem cell niche in vitro and in vivo. Our in vitro and in vivo data presented here provide sufficient evidence that we have established a robust, reproducible protocol for in vivo transplantation of hESC-derived ONPs to the inner ear.
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Affiliation(s)
- Hsiang-Tsun Chang
- Department of Otolaryngology and Head and Neck Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Rachel A Heuer
- Department of Otolaryngology and Head and Neck Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Andrew M Oleksijew
- Department of Otolaryngology and Head and Neck Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Kyle S Coots
- Department of Otolaryngology and Head and Neck Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Christian B Roque
- Department of Otolaryngology and Head and Neck Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Kevin T Nella
- Department of Otolaryngology and Head and Neck Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Tammy L McGuire
- Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago IL 60611, USA
| | - Akihiro J Matsuoka
- Department of Otolaryngology and Head and Neck Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; Department of Communication Sciences and Disorders, Northwestern University, Evanston, IL 60201, USA; Hugh Knowles Center for Hearing Research, Northwestern University, Evanston, IL 60201, USA.
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mRNA as a Tool for Gene Transfection in 3D Cell Culture for Future Regenerative Therapy. MICROMACHINES 2020; 11:mi11040426. [PMID: 32325734 PMCID: PMC7231348 DOI: 10.3390/mi11040426] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Revised: 04/14/2020] [Accepted: 04/16/2020] [Indexed: 01/31/2023]
Abstract
A combination of three-dimensional (3D) cell culturing and non-viral gene transfection is promising in improving outcomes of cell transplantation therapy. Herein, gene transfection profiles in 3D cell culture were compared between plasmid DNA (pDNA) and messenger RNA (mRNA) introduction, using mesenchymal stem cell (MSC) 3D spheroids. Green fluorescence protein (GFP) mRNA induced GFP protein expression in 77% of the cells in the spheroids, whereas only 34% of the cells became GFP positive following pDNA introduction. In mechanistic analyses, most of the cells in MSC spheroids were non-dividing, and pDNA failed to induce GFP expression in most of the non-dividing cells. In contrast, both dividing and non-dividing cells became GFP-positive after mRNA introduction, which led to a high overall percentage of GFP-positive cells in the spheroids. Consequently, mRNA encoding an osteogenic factor, runt-related transcription factor 2 (Runx2), allowed in vitro osteogenic differentiation of MSCs in spheroids more efficiently compared to Runx2 pDNA. Conclusively, mRNA exhibits high potential in gene transfection in 3D cell culture, in which the cell division rate is lower than that in monolayer culture, and the combination of mRNA introduction and 3D cell culture is a promising approach to improve outcomes of cell transplantation in future regenerative therapy.
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Injectable Therapeutic Organoids Using Sacrificial Hydrogels. iScience 2020; 23:101052. [PMID: 32353766 PMCID: PMC7191221 DOI: 10.1016/j.isci.2020.101052] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2020] [Revised: 03/11/2020] [Accepted: 04/03/2020] [Indexed: 12/28/2022] Open
Abstract
Organoids are becoming widespread in drug-screening technologies but have been used sparingly for cell therapy as current approaches for producing self-organized cell clusters lack scalability or reproducibility in size and cellular organization. We introduce a method of using hydrogels as sacrificial scaffolds, which allow cells to form self-organized clusters followed by gentle release, resulting in highly reproducible multicellular structures on a large scale. We demonstrated this strategy for endothelial cells and mesenchymal stem cells to self-organize into blood-vessel units, which were injected into mice, and rapidly formed perfusing vasculature. Moreover, in a mouse model of peripheral artery disease, intramuscular injections of blood-vessel units resulted in rapid restoration of vascular perfusion within seven days. As cell therapy transforms into a new class of therapeutic modality, this simple method—by making use of the dynamic nature of hydrogels—could offer high yields of self-organized multicellular aggregates with reproducible sizes and cellular architectures.
Therapeutic, prevascularized organoids were formed in a sacrificial scaffold The organoids are highly reproducible and grown in a high-throughput manner The organoids rapidly formed perfusing vasculature in healthy mice Therapeutic potential was assessed in a mouse model of peripheral artery disease
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