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Yu P, Liu B, Dong C, Chang Y. Induced Pluripotent Stem Cells-Based Regenerative Therapies in Treating Human Aging-Related Functional Decline and Diseases. Cells 2025; 14:619. [PMID: 40277944 PMCID: PMC12025799 DOI: 10.3390/cells14080619] [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: 03/11/2025] [Revised: 04/15/2025] [Accepted: 04/17/2025] [Indexed: 04/26/2025] Open
Abstract
A significant increase in life expectancy worldwide has resulted in a growing aging population, accompanied by a rise in aging-related diseases that pose substantial societal, economic, and medical challenges. This trend has prompted extensive efforts within many scientific and medical communities to develop and enhance therapies aimed at delaying aging processes, mitigating aging-related functional decline, and addressing aging-associated diseases to extend health span. Research in aging biology has focused on unraveling various biochemical and genetic pathways contributing to aging-related changes, including genomic instability, telomere shortening, and cellular senescence. The advent of induced pluripotent stem cells (iPSCs), derived through reprogramming human somatic cells, has revolutionized disease modeling and understanding in humans by addressing the limitations of conventional animal models and primary human cells. iPSCs offer significant advantages over other pluripotent stem cells, such as embryonic stem cells, as they can be obtained without the need for embryo destruction and are not restricted by the availability of healthy donors or patients. These attributes position iPSC technology as a promising avenue for modeling and deciphering mechanisms that underlie aging and associated diseases, as well as for studying drug effects. Moreover, iPSCs exhibit remarkable versatility in differentiating into diverse cell types, making them a promising tool for personalized regenerative therapies aimed at replacing aged or damaged cells with healthy, functional equivalents. This review explores the breadth of research in iPSC-based regenerative therapies and their potential applications in addressing a spectrum of aging-related conditions.
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Affiliation(s)
- Peijie Yu
- Department of Biomedical Engineering, The Hong Kong Polytechnic University, Hunghom, Hong Kong 999077, China; (P.Y.); (B.L.)
- The Hong Kong Polytechnic University Shenzhen Research Institute, Shenzhen 518057, China
| | - Bin Liu
- Department of Biomedical Engineering, The Hong Kong Polytechnic University, Hunghom, Hong Kong 999077, China; (P.Y.); (B.L.)
- The Hong Kong Polytechnic University Shenzhen Research Institute, Shenzhen 518057, China
| | - Cheng Dong
- Department of Biomedical Engineering, The Hong Kong Polytechnic University, Hunghom, Hong Kong 999077, China; (P.Y.); (B.L.)
- The Hong Kong Polytechnic University Shenzhen Research Institute, Shenzhen 518057, China
| | - Yun Chang
- Department of Biomedical Engineering, The Hong Kong Polytechnic University, Hunghom, Hong Kong 999077, China; (P.Y.); (B.L.)
- The Hong Kong Polytechnic University Shenzhen Research Institute, Shenzhen 518057, China
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Choudhery MS, Arif T, Mahmood R, Mushtaq A, Niaz A, Hassan Z, Zahid H, Nayab P, Arshad I, Arif M, Majid M, Harris DT. Induced Mesenchymal Stem Cells: An Emerging Source for Regenerative Medicine Applications. J Clin Med 2025; 14:2053. [PMID: 40142860 PMCID: PMC11943107 DOI: 10.3390/jcm14062053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2025] [Revised: 03/07/2025] [Accepted: 03/10/2025] [Indexed: 03/28/2025] Open
Abstract
Regenerative medicine is gaining interest in the medical field due to the limitations of conventional treatments, which often fail to address the underlying cause of disease. In recent years, stem cell-based therapies have evolved as a promising alternative approach to treat those diseases that cannot be cured using conventional medicine. Adult stem cells, particularly the mesenchymal stem cells (MSCs), have attracted a lot of attention due to their ability to regenerate and repair human tissues and organs. MSCs isolated from adult tissues are well characterized and are currently the most common type of cells for use in regenerative medicine. However, their low number in adult donor tissues, donor-age and cell-source related heterogeneity, limited proliferative and differentiation potential, and early senescence in in vitro cultures, negatively affect MSC regenerative potential. These factors restrict MSC use for research as well as for clinical applications. To overcome these problems, MSCs with superior regenerative potential are required. Induced MSCs (iMSCs) are obtained from induced pluripotent stem cells (iPSCs). These cells are patient-specific, readily available, and have relatively superior regenerative potential and, therefore, can overcome the problems associated with the use of primary MSCs. In this review, the authors aim to discuss the characteristics, regenerative potential, and limitations of MSCs for regenerative medicine applications. The main methods to generate iMSCs from iPSCs have been discussed in detail. In addition, the proposed criteria for their molecular characterization, applications of iMSCs for disease modeling and drug discovery, as well as potential use in regenerative medicine have been explored in detail.
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Affiliation(s)
- Mahmood S. Choudhery
- Department of Human Genetics & Molecular Biology, University of Health Sciences, Lahore 50161, Pakistan; (M.S.C.); (T.A.); (A.M.); (A.N.); (Z.H.); (H.Z.); (P.N.); (I.A.); (M.A.); (M.M.)
| | - Taqdees Arif
- Department of Human Genetics & Molecular Biology, University of Health Sciences, Lahore 50161, Pakistan; (M.S.C.); (T.A.); (A.M.); (A.N.); (Z.H.); (H.Z.); (P.N.); (I.A.); (M.A.); (M.M.)
| | - Ruhma Mahmood
- Department of Pediatric Surgery, Allama Iqbal Medical College, Jinnah Hospital, Lahore 54700, Pakistan;
| | - Asad Mushtaq
- Department of Human Genetics & Molecular Biology, University of Health Sciences, Lahore 50161, Pakistan; (M.S.C.); (T.A.); (A.M.); (A.N.); (Z.H.); (H.Z.); (P.N.); (I.A.); (M.A.); (M.M.)
| | - Ahmad Niaz
- Department of Human Genetics & Molecular Biology, University of Health Sciences, Lahore 50161, Pakistan; (M.S.C.); (T.A.); (A.M.); (A.N.); (Z.H.); (H.Z.); (P.N.); (I.A.); (M.A.); (M.M.)
| | - Zaeema Hassan
- Department of Human Genetics & Molecular Biology, University of Health Sciences, Lahore 50161, Pakistan; (M.S.C.); (T.A.); (A.M.); (A.N.); (Z.H.); (H.Z.); (P.N.); (I.A.); (M.A.); (M.M.)
| | - Hamda Zahid
- Department of Human Genetics & Molecular Biology, University of Health Sciences, Lahore 50161, Pakistan; (M.S.C.); (T.A.); (A.M.); (A.N.); (Z.H.); (H.Z.); (P.N.); (I.A.); (M.A.); (M.M.)
| | - Pakeeza Nayab
- Department of Human Genetics & Molecular Biology, University of Health Sciences, Lahore 50161, Pakistan; (M.S.C.); (T.A.); (A.M.); (A.N.); (Z.H.); (H.Z.); (P.N.); (I.A.); (M.A.); (M.M.)
| | - Iqra Arshad
- Department of Human Genetics & Molecular Biology, University of Health Sciences, Lahore 50161, Pakistan; (M.S.C.); (T.A.); (A.M.); (A.N.); (Z.H.); (H.Z.); (P.N.); (I.A.); (M.A.); (M.M.)
| | - Mehak Arif
- Department of Human Genetics & Molecular Biology, University of Health Sciences, Lahore 50161, Pakistan; (M.S.C.); (T.A.); (A.M.); (A.N.); (Z.H.); (H.Z.); (P.N.); (I.A.); (M.A.); (M.M.)
| | - Mashaim Majid
- Department of Human Genetics & Molecular Biology, University of Health Sciences, Lahore 50161, Pakistan; (M.S.C.); (T.A.); (A.M.); (A.N.); (Z.H.); (H.Z.); (P.N.); (I.A.); (M.A.); (M.M.)
| | - David T. Harris
- Department of Immunobiology, University of Arizona Health Sciences Biorepository, College of Medicine, University of Arizona, Tucson, AZ 85721, USA
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Cardoso D, Guilbert S, Guigue P, Carabalona A, Harhouri K, Peccate C, Tournois J, Guesmia Z, Ferreira L, Bartoli C, Levy N, Colleaux L, Nissan X, Muchir A. Inhibition of poly(ADP-Ribosyl)ation reduced vascular smooth muscle cells loss and improves aortic disease in a mouse model of human accelerated aging syndrome. Cell Death Dis 2024; 15:723. [PMID: 39353941 PMCID: PMC11448498 DOI: 10.1038/s41419-024-07078-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Revised: 09/09/2024] [Accepted: 09/13/2024] [Indexed: 10/03/2024]
Abstract
Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare genetic disorder associated with features of accelerated aging. HGPS is an autosomal dominant disease caused by a de novo mutation of LMNA gene, encoding A-type lamins, resulting in the truncated form of pre-lamin A called progerin. While asymptomatic at birth, patients develop symptoms within the first year of life when they begin to display accelerated aging and suffer from growth retardation, and severe cardiovascular complications including loss of vascular smooth muscle cells (VSMCs). Recent works reported the loss of VSMCs as a major factor triggering atherosclerosis in HGPS. Here, we investigated the mechanisms by which progerin expression leads to massive VSMCs loss. Using aorta tissue and primary cultures of murine VSMCs from a mouse model of HGPS, we showed increased VSMCs death associated with increased poly(ADP-Ribosyl)ation. Poly(ADP-Ribosyl)ation is recognized as a post-translational protein modification that coordinates the repair at DNA damage sites. Poly-ADP-ribose polymerase (PARP) catalyzes protein poly(ADP-Ribosyl)ation by utilizing nicotinamide adenine dinucleotide (NAD+). Our results provided the first demonstration linking progerin accumulation, augmented poly(ADP-Ribosyl)ation and decreased nicotinamide adenine dinucleotide (NAD+) level in VSMCs. Using high-throughput screening on VSMCs differentiated from iPSCs from HGPS patients, we identified a new compound, trifluridine able to increase NAD+ levels through decrease of PARP-1 activity. Lastly, we demonstrate that trifluridine treatment in vivo was able to alleviate aortic VSMCs loss and clinical sign of progeria, suggesting a novel therapeutic approach of cardiovascular disease in progeria.
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MESH Headings
- Animals
- Muscle, Smooth, Vascular/metabolism
- Muscle, Smooth, Vascular/pathology
- Muscle, Smooth, Vascular/drug effects
- Disease Models, Animal
- Progeria/pathology
- Progeria/genetics
- Progeria/metabolism
- Mice
- Humans
- Myocytes, Smooth Muscle/metabolism
- Myocytes, Smooth Muscle/drug effects
- Myocytes, Smooth Muscle/pathology
- Lamin Type A/metabolism
- Lamin Type A/genetics
- Aorta/pathology
- Aorta/drug effects
- Aorta/metabolism
- Poly ADP Ribosylation
- Mice, Inbred C57BL
- Poly(ADP-ribose) Polymerase Inhibitors/pharmacology
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Affiliation(s)
- Déborah Cardoso
- Sorbonne Université, UPMC Paris 06, INSERM UMRS974, Center of Research in Myology, Institut de Myologie, Paris, France
| | - Solenn Guilbert
- Université Paris-Saclay, Université d'Evry, Inserm, IStem UMR861, Corbeil-Essonnes, France
- IStem, CECS, Corbeil-Essonnes, France
| | - Philippe Guigue
- Aix Marseille Université, INSERM, MMG, U1251 Faculté de Médecine Timone, Marseille, France
| | - Aurélie Carabalona
- Aix Marseille Université, INSERM, MMG, U1251 Faculté de Médecine Timone, Marseille, France
| | - Karim Harhouri
- Aix Marseille Université, INSERM, MMG, U1251 Faculté de Médecine Timone, Marseille, France
| | - Cécile Peccate
- Sorbonne Université, UPMC Paris 06, INSERM UMRS974, Center of Research in Myology, Institut de Myologie, Paris, France
| | - Johana Tournois
- Université Paris-Saclay, Université d'Evry, Inserm, IStem UMR861, Corbeil-Essonnes, France
- IStem, CECS, Corbeil-Essonnes, France
| | - Zoheir Guesmia
- Sorbonne Université, UPMC Paris 06, INSERM UMRS974, Center of Research in Myology, Institut de Myologie, Paris, France
| | - Lino Ferreira
- Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
- Faculty of Medicine, University of Coimbra, Coimbra, Portugal
| | - Catherine Bartoli
- Aix Marseille Université, INSERM, MMG, U1251 Faculté de Médecine Timone, Marseille, France
| | - Nicolas Levy
- Aix Marseille Université, INSERM, MMG, U1251 Faculté de Médecine Timone, Marseille, France
| | - Laurence Colleaux
- Aix Marseille Université, INSERM, MMG, U1251 Faculté de Médecine Timone, Marseille, France
| | - Xavier Nissan
- Université Paris-Saclay, Université d'Evry, Inserm, IStem UMR861, Corbeil-Essonnes, France
- IStem, CECS, Corbeil-Essonnes, France
| | - Antoine Muchir
- Sorbonne Université, UPMC Paris 06, INSERM UMRS974, Center of Research in Myology, Institut de Myologie, Paris, France.
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Shi X, Zhang K, Yu F, Qi Q, Cai X, Zhang Y. Advancements and Innovative Strategies in Induced Pluripotent Stem Cell-Derived Mesenchymal Stem Cell Therapy: A Comprehensive Review. Stem Cells Int 2024; 2024:4073485. [PMID: 39377039 PMCID: PMC11458320 DOI: 10.1155/2024/4073485] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Revised: 06/24/2024] [Accepted: 09/04/2024] [Indexed: 10/09/2024] Open
Abstract
The effectiveness and safety of mesenchymal stem cell (MSC) therapy have been substantiated across various diseases. Nevertheless, challenges such as the restricted in vitro expansion capacity of tissue-derived MSCs and the clinical instability due to the high heterogeneity of isolated cells require urgent resolution. The induced pluripotent stem cell-derived MSCs (iPSC-MSCs), which is differentiated from iPSCs via specific experimental pathways, holds considerable potential as a substitute for tissue derived MSCs. Multiple studies have demonstrated that iPSCs can be differentiated into iPSC-MSCs through diverse differentiation strategies. Research suggests that iPSC-MSCs, when compared to tissue derived MSCs, exhibit superior characteristics in terms of proliferation ability, immune modulation capacity, and biological efficiency. In this review, we meticulously described and summarized the experimental methods of iPSC differentiation into iPSC-MSCs, the application of iPSC-MSCs in various disease models, the latest advancements in clinically relevant iPSC-derived cell products, and the development strategies for the next generation of iPSC-derived therapy products (not only cell products but also their derivatives).
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Affiliation(s)
- Xiaoyu Shi
- State Industrial Base for Stem Cell Engineering Products, Tianjin 300384, China
| | - Kun Zhang
- State Industrial Base for Stem Cell Engineering Products, Tianjin 300384, China
| | - Fengshi Yu
- State Industrial Base for Stem Cell Engineering Products, Tianjin 300384, China
| | - Qi Qi
- State Industrial Base for Stem Cell Engineering Products, Tianjin 300384, China
| | - Xiaoyu Cai
- State Industrial Base for Stem Cell Engineering Products, Tianjin 300384, China
| | - Yu Zhang
- VCANBIO Cell and Gene Engineering Corp. Ltd., Tianjin, China
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Chiou SH, Ong HKA, Chou SJ, Aldoghachi AF, Loh JK, Verusingam ND, Yang YP, Chien Y. Current trends and promising clinical utility of IPSC-derived MSC (iMSC). PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2023; 199:131-154. [PMID: 37678969 DOI: 10.1016/bs.pmbts.2023.04.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/09/2023]
Abstract
Mesenchymal stem cells (MSCs) differentiated from human induced pluripotent stem cells (iPSC) or induced MSC (iMSCs) are expected to address issues of scalability and safety as well as the difficulty in producing homogenous clinical grade MSCs as demonstrated by the promising outcomes from preclinical and clinical trials, currently ongoing. The assessment of iMSCs based in vitro and in vivo studies have thus far showed more superior performance as compared to that of the primary or native human MSCs, in terms of cell proliferation, expansion capacity, immunomodulation properties as well as the influence of paracrine signaling and exosomal influence in cell-cell interaction. In this chapter, an overview of current well-established methods in generating a sustainable source of iMSCs involving well defined culture media is discussed followed by the properties of iMSC as compared to that of MSC and its promising prospects for continuous development into potential clinical grade applications.
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Affiliation(s)
- Shih-Hwa Chiou
- Institute of Pharmacology, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; Department of Medical Research, Taipei Veteran General Hospital, Taipei, Taiwan
| | - Han Kiat Alan Ong
- Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Cheras, Malaysia
| | - Shih-Jie Chou
- Institute of Pharmacology, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; Department of Medical Research, Taipei Veteran General Hospital, Taipei, Taiwan
| | - A F Aldoghachi
- Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Cheras, Malaysia
| | - Jit Kai Loh
- Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Cheras, Malaysia
| | - Nalini Devi Verusingam
- Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Cheras, Malaysia
| | - Yi-Ping Yang
- Department of Medical Research, Taipei Veteran General Hospital, Taipei, Taiwan.
| | - Yueh Chien
- Department of Medical Research, Taipei Veteran General Hospital, Taipei, Taiwan
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Abdelrahman A, Nielsen MMW, Stage MH, Arnspang EC. Nuclear envelope morphology change upon repetitive treatment with modified antisense oligonucleotides targeting Hutchinson-Gilford Progeria Syndrome. Biochem Biophys Rep 2022; 33:101411. [PMID: 36632198 PMCID: PMC9827026 DOI: 10.1016/j.bbrep.2022.101411] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 12/05/2022] [Accepted: 12/13/2022] [Indexed: 12/29/2022] Open
Abstract
We present the influence of treating progeroid fibroblasts with two modified antisense oligonucleotides (ONs) on the nuclear envelope. Two modified ONs were designed to block ribosome binding during translation and spliceosome binding at the cryptic splice site. We analysed the changes in the nuclear morphology of progeria cell nuclei after repetitive transfection with modified ONs as a physical analysis tool for estimating alteration of the gene expression at the protein level. Confocal microscopy was used to image the nuclei, and the nuclear lobulations were quantified to study the changes in the morphology of the nuclear envelope upon treatment. PCR was used to identify the changes in the expression of lamin A and progerin after antisense treatment at the RNA level. We found a significant decrease in the number of nuclear envelope lobulations and a lower progerin expression in progeria cells after transfection with modified ONs.
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Affiliation(s)
- Asmaa Abdelrahman
- Department of Green Technology, Faculty of Engineering, University of Southern Denmark, Odense, Denmark,Department of Photochemistry, National Research Centre, Dokki, Giza, Egypt
| | - Mette-Marie Wendelboe Nielsen
- Department of Green Technology, Faculty of Engineering, University of Southern Denmark, Odense, Denmark,Department of Mechanical and Electrical Engineering, Faculty of Engineering University of Southern Denmark, Sønderborg, Denmark
| | - Mette Halkjær Stage
- Department of Green Technology, Faculty of Engineering, University of Southern Denmark, Odense, Denmark,Department of Food Science, Faculty of Science, Copenhagen University, Copenhagen, Denmark
| | - Eva Christensen Arnspang
- Department of Green Technology, Faculty of Engineering, University of Southern Denmark, Odense, Denmark,Corresponding author.
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Wang G, Xu Y, Wang Q, Chai Y, Sun X, Yang F, Zhang J, Wu M, Liao X, Yu X, Sheng X, Liu Z, Zhang J. Rare and undiagnosed diseases: From disease-causing gene identification to mechanism elucidation. FUNDAMENTAL RESEARCH 2022; 2:918-928. [PMID: 38933382 PMCID: PMC11197726 DOI: 10.1016/j.fmre.2022.09.002] [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: 07/16/2022] [Revised: 09/04/2022] [Accepted: 09/05/2022] [Indexed: 11/27/2022] Open
Abstract
Rare and undiagnosed diseases substantially decrease patient quality of life and have increasingly become a heavy burden on healthcare systems. Because of the challenges in disease-causing gene identification and mechanism elucidation, patients are often confronted with difficulty obtaining a precise diagnosis and treatment. Due to advances in sequencing and multiomics analysis approaches combined with patient-derived iPSC models and gene-editing platforms, substantial progress has been made in the diagnosis and treatment of rare and undiagnosed diseases. The aforementioned techniques also provide an operational basis for future precision medicine studies. In this review, we summarize recent progress in identifying disease-causing genes based on GWAS/WES/WGS-guided multiomics analysis approaches. In addition, we discuss recent advances in the elucidation of pathogenic mechanisms and treatment of diseases with state-of-the-art iPSC and organoid models, which are improved by cell maturation level and gene editing technology. The comprehensive strategies described above will generate a new paradigm of disease classification that will significantly promote the precision and efficiency of diagnosis and treatment for rare and undiagnosed diseases.
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Affiliation(s)
- Gang Wang
- Zhejiang Laboratory for Systems & Precision Medicine, Zhejiang University Medical Center, Hangzhou 311121, China
- Zhejiang University School of Medicine, Hangzhou 310058, China
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, Jiangsu 210002, China
| | - Yuyan Xu
- Zhejiang Laboratory for Systems & Precision Medicine, Zhejiang University Medical Center, Hangzhou 311121, China
- Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Qintao Wang
- Zhejiang Laboratory for Systems & Precision Medicine, Zhejiang University Medical Center, Hangzhou 311121, China
- Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Yi Chai
- Zhejiang Laboratory for Systems & Precision Medicine, Zhejiang University Medical Center, Hangzhou 311121, China
- Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Xiangwei Sun
- Zhejiang Laboratory for Systems & Precision Medicine, Zhejiang University Medical Center, Hangzhou 311121, China
- Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Fan Yang
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, Jiangsu 210002, China
| | - Jian Zhang
- Zhejiang Laboratory for Systems & Precision Medicine, Zhejiang University Medical Center, Hangzhou 311121, China
- Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Mengchen Wu
- Zhejiang Laboratory for Systems & Precision Medicine, Zhejiang University Medical Center, Hangzhou 311121, China
- Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Xufeng Liao
- Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Xiaomin Yu
- Zhejiang Laboratory for Systems & Precision Medicine, Zhejiang University Medical Center, Hangzhou 311121, China
- Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Xin Sheng
- Zhejiang Laboratory for Systems & Precision Medicine, Zhejiang University Medical Center, Hangzhou 311121, China
- Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Zhihong Liu
- Zhejiang Laboratory for Systems & Precision Medicine, Zhejiang University Medical Center, Hangzhou 311121, China
- Zhejiang University School of Medicine, Hangzhou 310058, China
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, Jiangsu 210002, China
| | - Jin Zhang
- Zhejiang Laboratory for Systems & Precision Medicine, Zhejiang University Medical Center, Hangzhou 311121, China
- Center for Stem Cell and Regenerative Medicine, Department of Basic Medical Sciences, The First Affiliated Hospital, Zhejiang University School of Medicine; Center of Gene/Cell Engineering and Genome Medicine of Zhejiang Province, Hangzhou 310058, China
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8
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Skeletal Muscle Cells Derived from Induced Pluripotent Stem Cells: A Platform for Limb Girdle Muscular Dystrophies. Biomedicines 2022; 10:biomedicines10061428. [PMID: 35740450 PMCID: PMC9220148 DOI: 10.3390/biomedicines10061428] [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: 04/28/2022] [Revised: 05/27/2022] [Accepted: 06/09/2022] [Indexed: 11/16/2022] Open
Abstract
Limb girdle muscular dystrophies (LGMD), caused by mutations in 29 different genes, are the fourth most prevalent group of genetic muscle diseases. Although the link between LGMD and its genetic origins has been determined, LGMD still represent an unmet medical need. Here, we describe a platform for modeling LGMD based on the use of human induced pluripotent stem cells (hiPSC). Thanks to the self-renewing and pluripotency properties of hiPSC, this platform provides a renewable and an alternative source of skeletal muscle cells (skMC) to primary, immortalized, or overexpressing cells. We report that skMC derived from hiPSC express the majority of the genes and proteins that cause LGMD. As a proof of concept, we demonstrate the importance of this cellular model for studying LGMDR9 by evaluating disease-specific phenotypes in skMC derived from hiPSC obtained from four patients.
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9
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Liu TM. Application of mesenchymal stem cells derived from human pluripotent stem cells in regenerative medicine. World J Stem Cells 2021; 13:1826-1844. [PMID: 35069985 PMCID: PMC8727229 DOI: 10.4252/wjsc.v13.i12.1826] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 06/29/2021] [Accepted: 11/30/2021] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem cells (MSCs) represent the most clinically used stem cells in regenerative medicine. However, due to the disadvantages with primary MSCs, such as limited cell proliferative capacity and rarity in the tissues leading to limited MSCs, gradual loss of differentiation during in vitro expansion reducing the efficacy of MSC application, and variation among donors increasing the uncertainty of MSC efficacy, the clinical application of MSCs has been greatly hampered. MSCs derived from human pluripotent stem cells (hPSC-MSCs) can circumvent these problems associated with primary MSCs. Due to the infinite self-renewal of hPSCs and their differentiation potential towards MSCs, hPSC-MSCs are emerging as an attractive alternative for regenerative medicine. This review summarizes the progress on derivation of MSCs from human pluripotent stem cells, disease modelling and drug screening using hPSC-MSCs, and various applications of hPSC-MSCs in regenerative medicine. In the end, the challenges and concerns with hPSC-MSC applications are also discussed.
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Affiliation(s)
- Tong-Ming Liu
- Agency for Science, Technology and Research, Institute of Molecular and Cell Biology, Singapore 138648, Singapore.
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Zhang J, Chen M, Liao J, Chang C, Liu Y, Padhiar AA, Zhou Y, Zhou G. Induced Pluripotent Stem Cell-Derived Mesenchymal Stem Cells Hold Lower Heterogeneity and Great Promise in Biological Research and Clinical Applications. Front Cell Dev Biol 2021; 9:716907. [PMID: 34660579 PMCID: PMC8514743 DOI: 10.3389/fcell.2021.716907] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2021] [Accepted: 09/03/2021] [Indexed: 01/14/2023] Open
Abstract
Mesenchymal stem cells (MSC) isolated from different tissue sources exhibit multiple biological effects and have shown promising therapeutic effects in a broad range of diseases. In order to fulfill their clinical applications in context of precision medicine, however, more detailed molecular characterization of diverse subgroups and standardized scalable production of certain functional subgroups would be highly desired. Thus far, the generation of induced pluripotent stem cell (iPSC)-derived MSC (iMSC) seems to provide the unique opportunity to solve most obstacles that currently exist to prevent the broad application of MSC as an advanced medicinal product. The features of iMSC include their single cell clone origins, and defined and controllable cultural conditions for their derivation and proliferation. Still, comprehensive research of the molecular and functional heterogeneity of iMSC, just like MSC from any other tissue types, would be required. Furthered on previous efforts on iMSC differentiation and expansion platform and transcriptomic studies, advantages of single cell multi-omics analysis and other up-to-dated technologies would be taken in order to elucidate the molecular origin and regulation of heterogeneity and to obtain iMSC subgroups homogeneous enough for particular clinical conditions. In this perspective, the current obstacles in MSC applications, the advantages of iMSC over MSC and their implications for biological research and clinical applications will be discussed.
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Affiliation(s)
- Juan Zhang
- Guangdong Key Laboratory of Genomic Stability and Disease Prevention, Shenzhen Key Laboratory of Anti-Aging and Regenerative Medicine, Shenzhen Engineering Laboratory of Regenerative Technologies for Orthopedic Diseases, Department of Medical Cell Biology and Genetics, Health Science Center, Shenzhen University, Shenzhen, China.,Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Shenzhen University Health Science Center, Shenzhen, China
| | - Mingzhuang Chen
- Guangdong Key Laboratory of Genomic Stability and Disease Prevention, Shenzhen Key Laboratory of Anti-Aging and Regenerative Medicine, Shenzhen Engineering Laboratory of Regenerative Technologies for Orthopedic Diseases, Department of Medical Cell Biology and Genetics, Health Science Center, Shenzhen University, Shenzhen, China.,Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Shenzhen University Health Science Center, Shenzhen, China.,Shenzhen University General Hospital, Shenzhen, China
| | | | | | - Yuqing Liu
- Cheerland Danlun Biopharma Co., Ltd., Shenzhen, China
| | | | - Yan Zhou
- Lungene Biotech Ltd., Shenzhen, China
| | - Guangqian Zhou
- Guangdong Key Laboratory of Genomic Stability and Disease Prevention, Shenzhen Key Laboratory of Anti-Aging and Regenerative Medicine, Shenzhen Engineering Laboratory of Regenerative Technologies for Orthopedic Diseases, Department of Medical Cell Biology and Genetics, Health Science Center, Shenzhen University, Shenzhen, China.,Senotherapeutics Ltd., Hangzhou, China.,Central Laboratory, Longgang District People's Hospital of Shenzhen and The Third Affiliated Hospital (Provisional) of The Chinese University of Hong Kong, Shenzhen, China
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11
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Infante A, Rodríguez CI. Cell and Cell-Free Therapies to Counteract Human Premature and Physiological Aging: MSCs Come to Light. J Pers Med 2021; 11:1043. [PMID: 34683184 PMCID: PMC8541473 DOI: 10.3390/jpm11101043] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Revised: 10/13/2021] [Accepted: 10/14/2021] [Indexed: 12/13/2022] Open
Abstract
The progressive loss of the regenerative potential of tissues is one of the most obvious consequences of aging, driven by altered intercellular communication, cell senescence and niche-specific stem cell exhaustion, among other drivers. Mesenchymal tissues, such as bone, cartilage and fat, which originate from mesenchymal stem cell (MSC) differentiation, are especially affected by aging. Senescent MSCs show limited proliferative capacity and impairment in key defining features: their multipotent differentiation and secretory abilities, leading to diminished function and deleterious consequences for tissue homeostasis. In the past few years, several interventions to improve human healthspan by counteracting the cellular and molecular consequences of aging have moved closer to the clinic. Taking into account the MSC exhaustion occurring in aging, advanced therapies based on the potential use of young allogeneic MSCs and derivatives, such as extracellular vesicles (EVs), are gaining attention. Based on encouraging pre-clinical and clinical data, this review assesses the strong potential of MSC-based (cell and cell-free) therapies to counteract age-related consequences in both physiological and premature aging scenarios. We also discuss the mechanisms of action of these therapies and the possibility of enhancing their clinical potential by exposing MSCs to niche-relevant signals.
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Affiliation(s)
- Arantza Infante
- Stem Cells and Cell Therapy Laboratory, Biocruces Bizkaia Health Research Institute, Cruces University Hospital, 48903 Barakaldo, Spain
| | - Clara I Rodríguez
- Stem Cells and Cell Therapy Laboratory, Biocruces Bizkaia Health Research Institute, Cruces University Hospital, 48903 Barakaldo, Spain
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12
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Puttaraju M, Jackson M, Klein S, Shilo A, Bennett CF, Gordon L, Rigo F, Misteli T. Systematic screening identifies therapeutic antisense oligonucleotides for Hutchinson-Gilford progeria syndrome. Nat Med 2021; 27:526-535. [PMID: 33707772 PMCID: PMC10167920 DOI: 10.1038/s41591-021-01262-4] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Accepted: 01/25/2021] [Indexed: 11/09/2022]
Abstract
Hutchinson-Gilford progeria syndrome (HGPS) is a rare, invariably fatal childhood premature aging disorder caused by a pre-messenger RNA (mRNA) splicing defect in the LMNA gene. We used combined in vitro screening and in vivo validation to systematically explore the effects of target sequence, backbone chemistry and mechanism of action to identify optimized antisense oligonucleotides (ASOs) for therapeutic use in HGPS. In a library of 198 ASOs, the most potent ASOs targeted the LMNA exon 12 junction and acted via non-RNase H-mediated mechanisms. Treatment with an optimized lead candidate resulted in extension of lifespan in a mouse model of HGPS. Progerin mRNA levels were robustly reduced in vivo, but the extent of progerin protein reduction differed between tissues, suggesting a long half-life and tissue-specific turnover of progerin in vivo. These results identify a novel therapeutic agent for HGPS and provide insight into the HGPS disease mechanism.
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Affiliation(s)
- Madaiah Puttaraju
- National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | | | | | - Asaf Shilo
- National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | | | - Leslie Gordon
- Division of Genetics, Department of Pediatrics, Hasbro Children's Hospital and Warren Alpert Medical School of Brown University, Providence, RI, USA
- Department of Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA
| | - Frank Rigo
- Ionis Pharmaceuticals, Carlsbad, CA, USA
| | - Tom Misteli
- National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
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13
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Induced pluripotent stem cell-derived monocytic cell lines from a NOMID patient serve as a screening platform for modulating NLRP3 inflammasome activity. PLoS One 2020; 15:e0237030. [PMID: 32810141 PMCID: PMC7437452 DOI: 10.1371/journal.pone.0237030] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Accepted: 07/18/2020] [Indexed: 11/24/2022] Open
Abstract
Curative therapeutic options for a number of immunological disorders remain to be established, and approaches for identifying drug candidates are relatively limited. Furthermore, phenotypic screening methods using induced pluripotent stem cell (iPSC)-derived immune cells or hematopoietic cells need improvement. In the present study, using immortalized monocytic cell lines derived from iPSCs, we developed a high-throughput screening (HTS) system to detect compounds that inhibit IL-1β secretion and NLRP3 inflammasome activation from activated macrophages. The iPSCs were generated from a patient with neonatal onset multisystem inflammatory disease (NOMID) as a model of a constitutively activated NLRP3 inflammasome. HTS of 4,825 compounds including FDA-approved drugs and compounds with known bioactivity identified 7 compounds as predominantly IL-1β inhibitors. Since these compounds are known inflammasome inhibitors or derivatives of, these results prove the validity of our HTS system, which can be a versatile platform for identifying drug candidates for immunological disorders associated with monocytic lineage cells.
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14
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Proshkina E, Shaposhnikov M, Moskalev A. Genome-Protecting Compounds as Potential Geroprotectors. Int J Mol Sci 2020; 21:E4484. [PMID: 32599754 PMCID: PMC7350017 DOI: 10.3390/ijms21124484] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2020] [Revised: 06/18/2020] [Accepted: 06/19/2020] [Indexed: 02/06/2023] Open
Abstract
Throughout life, organisms are exposed to various exogenous and endogenous factors that cause DNA damages and somatic mutations provoking genomic instability. At a young age, compensatory mechanisms of genome protection are activated to prevent phenotypic and functional changes. However, the increasing stress and age-related deterioration in the functioning of these mechanisms result in damage accumulation, overcoming the functional threshold. This leads to aging and the development of age-related diseases. There are several ways to counteract these changes: 1) prevention of DNA damage through stimulation of antioxidant and detoxification systems, as well as transition metal chelation; 2) regulation of DNA methylation, chromatin structure, non-coding RNA activity and prevention of nuclear architecture alterations; 3) improving DNA damage response and repair; 4) selective removal of damaged non-functional and senescent cells. In the article, we have reviewed data about the effects of various trace elements, vitamins, polyphenols, terpenes, and other phytochemicals, as well as a number of synthetic pharmacological substances in these ways. Most of the compounds demonstrate the geroprotective potential and increase the lifespan in model organisms. However, their genome-protecting effects are non-selective and often are conditioned by hormesis. Consequently, the development of selective drugs targeting genome protection is an advanced direction.
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Affiliation(s)
- Ekaterina Proshkina
- Laboratory of Geroprotective and Radioprotective Technologies, Institute of Biology, Komi Science Centre, Ural Branch, Russian Academy of Sciences, 28 Kommunisticheskaya st., 167982 Syktyvkar, Russia; (E.P.); (M.S.)
| | - Mikhail Shaposhnikov
- Laboratory of Geroprotective and Radioprotective Technologies, Institute of Biology, Komi Science Centre, Ural Branch, Russian Academy of Sciences, 28 Kommunisticheskaya st., 167982 Syktyvkar, Russia; (E.P.); (M.S.)
| | - Alexey Moskalev
- Laboratory of Geroprotective and Radioprotective Technologies, Institute of Biology, Komi Science Centre, Ural Branch, Russian Academy of Sciences, 28 Kommunisticheskaya st., 167982 Syktyvkar, Russia; (E.P.); (M.S.)
- Pitirim Sorokin Syktyvkar State University, 55 Oktyabrsky prosp., 167001 Syktyvkar, Russia
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
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15
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Alcorta-Sevillano N, Macías I, Rodríguez CI, Infante A. Crucial Role of Lamin A/C in the Migration and Differentiation of MSCs in Bone. Cells 2020; 9:cells9061330. [PMID: 32466483 PMCID: PMC7348862 DOI: 10.3390/cells9061330] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 05/22/2020] [Accepted: 05/25/2020] [Indexed: 12/17/2022] Open
Abstract
Lamin A/C, intermediate filament proteins from the nuclear lamina encoded by the LMNA gene, play a central role in mediating the mechanosignaling of cytoskeletal forces into nucleus. In fact, this mechanotransduction process is essential to ensure the proper functioning of other tasks also mediated by lamin A/C: the structural support of the nucleus and the regulation of gene expression. In this way, lamin A/C is fundamental for the migration and differentiation of mesenchymal stem cells (MSCs), the progenitors of osteoblasts, thus affecting bone homeostasis. Bone formation is a complex process regulated by chemical and mechanical cues, coming from the surrounding extracellular matrix. MSCs respond to signals modulating the expression levels of lamin A/C, and therefore, adapting their nuclear shape and stiffness. To promote cell migration, MSCs need soft nuclei with low lamin A content. Conversely, during osteogenic differentiation, lamin A/C levels are known to be increased. Several LMNA mutations present a negative impact in the migration and osteogenesis of MSCs, affecting bone tissue homeostasis and leading to pathological conditions. This review aims to describe these concepts by discussing the latest state-of-the-art in this exciting area, focusing on the relationship between lamin A/C in MSCs' function and bone tissue from both, health and pathological points of view.
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16
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Guilbert SM, Cardoso D, Lévy N, Muchir A, Nissan X. Hutchinson-Gilford progeria syndrome: Rejuvenating old drugs to fight accelerated ageing. Methods 2020; 190:3-12. [PMID: 32278808 DOI: 10.1016/j.ymeth.2020.04.005] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2019] [Revised: 04/06/2020] [Accepted: 04/07/2020] [Indexed: 12/14/2022] Open
Abstract
What if the next generation of successful treatments was hidden in the current pharmacopoeia? Identifying new indications for existing drugs, also called the drug repurposing or drug rediscovery process, is a highly efficient and low-cost strategy. First reported almost a century ago, drug repurposing has emerged as a valuable therapeutic option for diseases that do not have specific treatments and rare diseases, in particular. This review focuses on Hutchinson-Gilford progeria syndrome (HGPS), a rare genetic disorder that induces accelerated and precocious aging, for which drug repurposing has led to the discovery of several potential treatments over the past decade.
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Affiliation(s)
- Solenn M Guilbert
- CECS, I-STEM AFM, Institute for Stem Cell Therapy and Exploration of Monogenic Diseases, 28 rue Henri Desbruères, 91100 Corbeil-Essonnes, France
| | - Déborah Cardoso
- Sorbonne Université, UPMC Paris 06, INSERM UMRS974, Center of Research in Myology, Institut de Myologie, F-75013 Paris, France
| | - Nicolas Lévy
- Aix-Marseille Université, UMRS910: Génétique médicale et Génomique fonctionnelle, Faculté de médecine Timone, Marseille, France
| | - Antoine Muchir
- Sorbonne Université, UPMC Paris 06, INSERM UMRS974, Center of Research in Myology, Institut de Myologie, F-75013 Paris, France
| | - Xavier Nissan
- CECS, I-STEM AFM, Institute for Stem Cell Therapy and Exploration of Monogenic Diseases, 28 rue Henri Desbruères, 91100 Corbeil-Essonnes, France.
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17
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Mitxitorena I, Infante A, Gener B, Rodríguez CI. Suitability and limitations of mesenchymal stem cells to elucidate human bone illness. World J Stem Cells 2019; 11:578-593. [PMID: 31616536 PMCID: PMC6789184 DOI: 10.4252/wjsc.v11.i9.578] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2019] [Revised: 07/31/2019] [Accepted: 08/27/2019] [Indexed: 02/06/2023] Open
Abstract
Functional impairment of mesenchymal stem cells (MSCs), osteoblast progenitor cells, has been proposed to be a pathological mechanism contributing to bone disorders, such as osteoporosis (the most common bone disease) and other rare inherited skeletal dysplasias. Pathological bone loss can be caused not only by an enhanced bone resorption activity but also by hampered osteogenic differentiation of MSCs. The majority of the current treatment options counteract bone loss, and therefore bone fragility by blocking bone resorption. These so-called antiresorptive treatments, in spite of being effective at reducing fracture risk, cannot be administered for extended periods due to security concerns. Therefore, there is a real need to develop osteoanabolic therapies to promote bone formation. Human MSCs emerge as a suitable tool to study the etiology of bone disorders at the cellular level as well as to be used for cell therapy purposes for bone diseases. This review will focus on the most relevant findings using human MSCs as an in vitro cell model to unravel pathological bone mechanisms and the application and outcomes of human MSCs in cell therapy clinical trials for bone disease.
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Affiliation(s)
- Izaskun Mitxitorena
- Stem Cells and Cell Therapy Laboratory, Biocruces Bizkaia Health Research Institute, Cruces University Hospital, Barakaldo 48903, Bizkaia, Spain
| | - Arantza Infante
- Stem Cells and Cell Therapy Laboratory, Biocruces Bizkaia Health Research Institute, Cruces University Hospital, Barakaldo 48903, Bizkaia, Spain
| | - Blanca Gener
- Stem Cells and Cell Therapy Laboratory, Biocruces Bizkaia Health Research Institute, Cruces University Hospital, Barakaldo 48903, Bizkaia, Spain
- Service of Genetics, Biocruces Bizkaia Health Research Institute, Cruces University Hospital, Barakaldo 48903, Bizkaia, Spain
- Centre for Biomedical Network Research on Rare Diseases, Instituto de Salud Carlos III, Madrid 28005, Spain
| | - Clara I Rodríguez
- Stem Cells and Cell Therapy Laboratory, Biocruces Bizkaia Health Research Institute, Cruces University Hospital, Barakaldo 48903, Bizkaia, Spain
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18
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Choi JY, Lai JK, Xiong ZM, Ren M, Moorer MC, Stains JP, Cao K. Diminished Canonical β-Catenin Signaling During Osteoblast Differentiation Contributes to Osteopenia in Progeria. J Bone Miner Res 2018; 33:2059-2070. [PMID: 30001457 PMCID: PMC7739562 DOI: 10.1002/jbmr.3549] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2018] [Revised: 06/25/2018] [Accepted: 06/30/2018] [Indexed: 12/31/2022]
Abstract
Patients with Hutchinson-Gilford progeria syndrome (HGPS) have low bone mass and an atypical skeletal geometry that manifests in a high risk of fractures. Using both in vitro and in vivo models of HGPS, we demonstrate that defects in the canonical WNT/β-catenin pathway, seemingly at the level of the efficiency of nuclear import of β-catenin, impair osteoblast differentiation and that restoring β-catenin activity rescues osteoblast differentiation and significantly improves bone mass. Specifically, we show that HGPS patient-derived iPSCs display defects in osteoblast differentiation, characterized by a decreased alkaline phosphatase activity and mineralizing capacity. We demonstrate that the canonical WNT/β-catenin pathway, a major signaling cascade involved in skeletal homeostasis, is impaired by progerin, causing a reduction in the active β-catenin in the nucleus and thus decreased transcriptional activity, and its reciprocal cytoplasmic accumulation. Blocking farnesylation of progerin restores active β-catenin accumulation in the nucleus, increasing signaling, and ameliorates the defective osteogenesis. Moreover, in vivo analysis of the Zmpste24-/- HGPS mouse model demonstrates that treatment with a sclerostin-neutralizing antibody (SclAb), which targets an antagonist of canonical WNT/β-catenin signaling pathway, fully rescues the low bone mass phenotype to wild-type levels. Together, this study reveals that the β-catenin signaling cascade is a therapeutic target for restoring defective skeletal microarchitecture in HGPS. © 2018 American Society for Bone and Mineral Research.
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Affiliation(s)
- Ji Young Choi
- Department of Cell Biology and Molecular Genetics, University of Maryland College Park, MD 20742
| | - Jim K Lai
- Department of Orthopedics, University of Maryland School of Medicine, Baltimore, MD 21201
| | - Zheng-Mei Xiong
- Department of Cell Biology and Molecular Genetics, University of Maryland College Park, MD 20742
| | - Margaret Ren
- Department of Cell Biology and Molecular Genetics, University of Maryland College Park, MD 20742
| | - Megan C Moorer
- Department of Orthopedics, University of Maryland School of Medicine, Baltimore, MD 21201
| | - Joseph P Stains
- Department of Orthopedics, University of Maryland School of Medicine, Baltimore, MD 21201
| | - Kan Cao
- Department of Cell Biology and Molecular Genetics, University of Maryland College Park, MD 20742
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19
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Abstract
Aging is a high risk factor for the development of osteoporosis, a multifactorial age-related progressive disease characterized by reduced bone mass and increased risk of fractures. At the cellular level, the mesenchymal stem cell pool in the bone marrow niche shows a biased differentiation into adipogenesis at the cost of osteogenesis. This differentiation shift leads to decreased bone formation, contributing to the etiology of osteoporosis. This review will focus on the most recent/relevant molecular findings driving this functional impairment of mesenchymal stem cells in the aging process.
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Affiliation(s)
- Arantza Infante
- Stem Cells and Cell Therapy Laboratory, BioCruces Bizkaia Health Research Institute, Cruces University Hospital, 48903, Barakaldo, Spain
| | - Clara I Rodríguez
- Stem Cells and Cell Therapy Laboratory, BioCruces Bizkaia Health Research Institute, Cruces University Hospital, 48903, Barakaldo, Spain.
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20
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Generation and Applications of Induced Pluripotent Stem Cell-Derived Mesenchymal Stem Cells. Stem Cells Int 2018; 2018:9601623. [PMID: 30154868 PMCID: PMC6091255 DOI: 10.1155/2018/9601623] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2018] [Revised: 06/12/2018] [Accepted: 06/20/2018] [Indexed: 12/13/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are adult stem cells with fibroblast-like morphology and isolated from the bone marrow via plastic adhesion. Their multipotency and immunoregulatory properties make MSCs possible therapeutic agents, and an increasing number of publications and clinical trials have highlighted their potential in regenerative medicine. However, the finite proliferative capacity of MSCs limits their scalability and global dissemination as a standardized therapeutic product. Furthermore, adult tissue provenance could constrain accessibility, impinge on cellular potency, and incur greater exposure to disease-causing pathogens based on the donor. These issues could be circumvented by the derivation of MSCs from pluripotent stem cells. In this paper, we review methods that induce and characterize MSCs derived from induced pluripotent stem cells (iPSCs) and introduce MSC applications to disease modeling, pathogenic mechanisms, and drug discovery. We also discuss the potential applications of MSCs in regenerative medicine including cell-based therapies and issues that should be overcome before iPSC-derived MSC therapy will be applied in the clinic.
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21
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Finley J. Cellular stress and AMPK activation as a common mechanism of action linking the effects of metformin and diverse compounds that alleviate accelerated aging defects in Hutchinson-Gilford progeria syndrome. Med Hypotheses 2018; 118:151-162. [PMID: 30037605 DOI: 10.1016/j.mehy.2018.06.029] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2018] [Revised: 06/13/2018] [Accepted: 06/27/2018] [Indexed: 12/19/2022]
Abstract
Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder characterized by an accelerated aging phenotype that typically leads to death via stroke or myocardial infarction at approximately 14.6 years of age. Most cases of HGPS have been linked to the extensive use of a cryptic splice donor site located in the LMNA gene due to a de novo mutation, generating a truncated and toxic protein known as progerin. Progerin accumulation in the nuclear membrane and within the nucleus distorts the nuclear architecture and negatively effects nuclear processes including DNA replication and repair, leading to accelerated cellular aging and premature senescence. The serine-arginine rich splicing factor SRSF1 (also known as ASF/SF2) has recently been shown to modulate alternative splicing of the LMNA gene, with SRSF1 inhibition significantly reducing progerin at both the mRNA and protein levels. In 2014, we hypothesized for the first time that compounds including metformin that induce activation of AMP-activated protein kinase (AMPK), a master metabolic regulator activated by cellular stress (e.g. increases in intracellular calcium, reactive oxygen species, and/or an AMP(ADP)/ATP ratio increase, etc.), will beneficially alter gene splicing in progeria cells by inhibiting SRSF1, thus lowering progerin levels and altering the LMNA pre-mRNA splicing ratio. Recent evidence has substantiated this hypothesis, with metformin significantly reducing the mRNA and protein levels of both SRSF1 and progerin, activating AMPK, and alleviating pathological defects in HGPS cells. Metformin has also recently been shown to beneficially alter gene splicing in normal humans. Interestingly, several chemically distinct compounds, including rapamycin, methylene blue, all-trans retinoic acid, MG132, 1α,25-dihydroxyvitamin D3, sulforaphane, and oltipraz have each been shown to alleviate accelerated aging defects in patient-derived HGPS cells. Each of these compounds has also been independently shown to induce AMPK activation. Because these compounds improve accelerated aging defects in HGPS cells either by enhancing mitochondrial functionality, increasing Nrf2 activity, inducing autophagy, or by altering gene splicing and because AMPK activation beneficially modulates each of the aforementioned processes, it is our hypothesis that cellular stress-induced AMPK activation represents an indirect yet common mechanism of action linking such chemically diverse compounds with the beneficial effects of those compounds observed in HGPS cells. As normal humans also produce progerin at much lower levels through a similar mechanism, compounds that safely induce AMPK activation may have wide-ranging implications for both normal and pathological aging.
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22
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Pathological modelling of pigmentation disorders associated with Hutchinson-Gilford Progeria Syndrome (HGPS) revealed an impaired melanogenesis pathway in iPS-derived melanocytes. Sci Rep 2018; 8:9112. [PMID: 29904107 PMCID: PMC6002548 DOI: 10.1038/s41598-018-27165-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2018] [Accepted: 05/29/2018] [Indexed: 12/21/2022] Open
Abstract
Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare genetic disorder that leads to premature aging. In this study, we used induced pluripotent stem cells to investigate the hypopigmentation phenotypes observed in patients with progeria. Accordingly, two iPS cell lines were derived from cells from HGPS patients and differentiated into melanocytes. Measurements of melanin content revealed a lower synthesis of melanin in HGPS melanocytes as compared to non-pathologic cells. Analysis of the melanosome maturation process by electron microscopy revealed a lower percentage of mature, fully pigmented melanosomes. Finally, a functional rescue experiment revealed the direct role of progerin in the regulation of melanogenesis. Overall, these results report a new dysregulated pathway in HGPS and open up novel perspectives in the study of pigmentation phenotypes that are associated with normal and pathological aging.
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23
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Cho S, Abbas A, Irianto J, Ivanovska IL, Xia Y, Tewari M, Discher DE. Progerin phosphorylation in interphase is lower and less mechanosensitive than lamin-A,C in iPS-derived mesenchymal stem cells. Nucleus 2018; 9:230-245. [PMID: 29619860 PMCID: PMC5973135 DOI: 10.1080/19491034.2018.1460185] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Interphase phosphorylation of lamin-A,C depends dynamically on a cell's microenvironment, including the stiffness of extracellular matrix. However, phosphorylation dynamics is poorly understood for diseased forms such as progerin, a permanently farnesylated mutant of LMNA that accelerates aging of stiff and mechanically stressed tissues. Here, fine-excision alignment mass spectrometry (FEA-MS) is developed to quantify progerin and its phosphorylation levels in patient iPS cells differentiated to mesenchymal stem cells (MSCs). The stoichiometry of total A-type lamins (including progerin) versus B-type lamins measured for Progeria iPS-MSCs prove similar to that of normal MSCs, with total A-type lamins more abundant than B-type lamins. However, progerin behaves more like farnesylated B-type lamins in mechanically-induced segregation from nuclear blebs. Phosphorylation of progerin at multiple sites in iPS-MSCs cultured on rigid plastic is also lower than that of normal lamin-A and C. Reduction of nuclear tension upon i) cell rounding/detachment from plastic, ii) culture on soft gels, and iii) inhibition of actomyosin stress increases phosphorylation and degradation of lamin-C > lamin-A > progerin. Such mechano-sensitivity diminishes, however, with passage as progerin and DNA damage accumulate. Lastly, transcription-regulating retinoids exert equal effects on both diseased and normal A-type lamins, suggesting a differential mechano-responsiveness might best explain the stiff tissue defects in Progeria.
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Affiliation(s)
- Sangkyun Cho
- Molecular & Cell Biophysics Lab, University of Pennsylvania, Philadelphia, PA, USA
| | - Amal Abbas
- Molecular & Cell Biophysics Lab, University of Pennsylvania, Philadelphia, PA, USA
| | - Jerome Irianto
- Molecular & Cell Biophysics Lab, University of Pennsylvania, Philadelphia, PA, USA
| | - Irena L. Ivanovska
- Molecular & Cell Biophysics Lab, University of Pennsylvania, Philadelphia, PA, USA
| | - Yuntao Xia
- Molecular & Cell Biophysics Lab, University of Pennsylvania, Philadelphia, PA, USA
| | - Manu Tewari
- Molecular & Cell Biophysics Lab, University of Pennsylvania, Philadelphia, PA, USA
| | - Dennis E. Discher
- Molecular & Cell Biophysics Lab, University of Pennsylvania, Philadelphia, PA, USA,CONTACT Dennis E. Discher , University of Pennsylvania, 129 Towne Bldg, Philadelphia, PA 19104
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Infante A, Rodríguez CI. Secretome analysis of in vitro aged human mesenchymal stem cells reveals IGFBP7 as a putative factor for promoting osteogenesis. Sci Rep 2018; 8:4632. [PMID: 29545581 PMCID: PMC5854613 DOI: 10.1038/s41598-018-22855-z] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2017] [Accepted: 03/02/2018] [Indexed: 12/13/2022] Open
Abstract
Aging is a complex biological process, which involves multiple mechanisms with different levels of regulation. Senescent cells are known to secrete senescence-associated proteins, which exert negative influences on surrounding cells. Mesenchymal stem cells (MSCs), the common progenitors for bone, cartilage and adipose tissue (which are especially affected tissues in aging), are known to secrete a broad spectrum of biologically active proteins with both paracrine and autocrine functions in many biological processes. In this report, we have studied the secreted factors (secretome) from human MSCs (hMSCs) and hMSCs-derived adipocytes which were induced to accumulate prelamin A, the immature form of the nuclear lamina protein called Lamin A, known to induce premature aging syndromes in humans and in murine models. Proteomic analysis from two different techniques, antibody arrays and LS-MS, showed that prelamin A accumulation in hMSCs promotes the differential secretion of factors previously identified as secreted by hMSCs undergoing osteogenesis. Moreover, this secretome was able to modulate osteogenesis of normal hMSCs in vitro. Finally, we found that one of the overexpressed secreted factors of this human aging in vitro stem cell model, IGFBP-7, is an osteogenic factor, essential for the viability of hMSCs during osteogenesis.
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Affiliation(s)
- Arantza Infante
- Stem Cells and Cell Therapy Laboratory, BioCruces Health Research Institute, Cruces University Hospital, Barakaldo, 48903, Spain
| | - Clara I Rodríguez
- Stem Cells and Cell Therapy Laboratory, BioCruces Health Research Institute, Cruces University Hospital, Barakaldo, 48903, Spain.
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25
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Yener Ilce B, Cagin U, Yilmazer A. Cellular reprogramming: A new way to understand aging mechanisms. WILEY INTERDISCIPLINARY REVIEWS-DEVELOPMENTAL BIOLOGY 2018; 7. [PMID: 29350802 DOI: 10.1002/wdev.308] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/01/2017] [Revised: 09/29/2017] [Accepted: 10/13/2017] [Indexed: 12/11/2022]
Abstract
Increased life expectancy, due to the rise in life quality and the decline in mortality rates, is leading to a society in which the population aged 60 and over is growing more rapidly than the entire population. Although various models and model organisms have been employed to investigate the mechanism of aging, induced pluripotent stem cells (iPSCs) are useful candidates to study human aging and age-related human diseases. This work discusses how iPSCs can be used as an alternative to the model organisms such as yeast, Caenorhabditis elegans, Drosophila melanogaster, or the mouse. The main focus is the reprogramming technology of somatic cells which is thought to provide an important perspective for rejuvenation strategies. The effects and relationships between aging and cell reprogramming are discussed, and studies related to aging and cell reprogramming are critically reviewed. We believe that for future studies, different parameters and detailed quantitative experiments should be performed in order to clearly understand the effect of aging on human cell reprogramming with respect to programming efficiency and differentiation capacity. This way, new insights will be provided to prevent or even reverse the aging process. WIREs Dev Biol 2018, 7:e308. doi: 10.1002/wdev.308 This article is categorized under: Adult Stem Cells, Tissue Renewal, and Regeneration > Stem Cells and Aging Adult Stem Cells, Tissue Renewal, and Regeneration > Regeneration Adult Stem Cells, Tissue Renewal, and Regeneration > Stem Cells and Disease.
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Affiliation(s)
| | | | - Acelya Yilmazer
- Biomedical Engineering Department, Engineering Faculty, Ankara University, Ankara, Turkey.,Stem Cell Institute, Ankara University, Ankara, Turkey
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26
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Han X, Li X, Zhong G, Liu Z. Regulation of osteogenic differentiation by DNA methylation of the dishevelled gene in bone marrow mesenchymal stem cells. Am J Transl Res 2017; 9:4848-4855. [PMID: 29218084 PMCID: PMC5714770] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2017] [Accepted: 10/10/2017] [Indexed: 06/07/2023]
Abstract
Bone marrow mesenchymal stem cells (BMSCs) are stem cells with multidirectional differentiation potential, which can be used as seed cells to repair and reconstruct many types of tissues and organs following injury or disease. Osteogenic differentiation involves a variety of pathway and factors, including cytokines, growth factors, and hormones. In the present study, we investigated the potential role of Dishevelled in osteogenic differentiation of BMSCs in induction medium containing the methyltransferase inhibitor 5-aza-2'-deoxycytidine. The expression of Dishevelled was analyzed using the reverse transcriptase-polymerase chain reaction (RT-PCR) and a Western blot. The methylation degree of the CpG island in the promoter region of the Dishevelled gene was analyzed, and protein expression levels of Wnt, Glycogen synthase kinase-3 (GSK3), axin, Dishevelled, and β-catenin were increased after the addition of the methyltransferase inhibitor. The expression of Dishevelled increased in accordance with the differentiation of osteoblasts, and the degree of methylation of the promoter affected its expression level. In conclusion, regulating the methylation degree of the Dishevelled gene promoter region appears to influence the expression of Dishevelled and therefore the osteogenic differentiation of BMSCs.
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Affiliation(s)
- Xiaofeng Han
- Department of Orthopaedics, Renji Hospital, School of Medicine, Shanghai Jiao Tong UniversityShanghai 200127, China
- Department of Orthopaedics, Renji Hospital South Campus, School of Medicine, Shanghai Jiao Tong UniversityShanghai 201112, China
| | - Xinfeng Li
- Department of Orthopaedics, Renji Hospital, School of Medicine, Shanghai Jiao Tong UniversityShanghai 200127, China
| | - Guibin Zhong
- Department of Orthopaedics, Renji Hospital, School of Medicine, Shanghai Jiao Tong UniversityShanghai 200127, China
| | - Zude Liu
- Department of Orthopaedics, Renji Hospital, School of Medicine, Shanghai Jiao Tong UniversityShanghai 200127, China
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Pegoraro G, Misteli T. High-Throughput Imaging for the Discovery of Cellular Mechanisms of Disease. Trends Genet 2017; 33:604-615. [PMID: 28732598 DOI: 10.1016/j.tig.2017.06.005] [Citation(s) in RCA: 68] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2017] [Revised: 06/19/2017] [Accepted: 06/20/2017] [Indexed: 12/23/2022]
Abstract
High-throughput imaging (HTI) is a powerful tool in the discovery of cellular disease mechanisms. While traditional approaches to identify disease pathways often rely on knowledge of the causative genetic defect, HTI-based screens offer an unbiased discovery approach based on any morphological or functional defects of disease cells or tissues. In this review, we provide an overview of the use of HTI for the study of human disease mechanisms. We discuss key technical aspects of HTI and highlight representative examples of its practical applications for the discovery of molecular mechanisms of disease, focusing on infectious diseases and host-pathogen interactions, cancer, and rare genetic diseases. We also present some of the current challenges and possible solutions offered by novel cell culture systems and genome engineering approaches.
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Affiliation(s)
- Gianluca Pegoraro
- NCI High-Throughput Imaging Facility, Bethesda, MD 20892, USA; Center for Cancer Research, National Cancer Institute/NIH, Bethesda, MD 20892, USA.
| | - Tom Misteli
- Center for Cancer Research, National Cancer Institute/NIH, Bethesda, MD 20892, USA.
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