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1
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Lucas-Ruiz F, Fernández-Nogales M, Valiente-Soriano FJ, Herrera M, Nadal-Nicolás FM, Agudo-Barriuso M, Herrera E. Restorative potential of ciliary body cells in a retinal ganglion cell degeneration model. Sci Rep 2025; 15:15503. [PMID: 40319064 PMCID: PMC12049432 DOI: 10.1038/s41598-025-00283-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Accepted: 04/28/2025] [Indexed: 05/07/2025] Open
Abstract
The ciliary body (CB) has been proposed as a niche of neural stem cells because, in vitro, cells from this area are able to form neurospheres, proliferate and differentiate. Here, we explore the potential of CB cells to differentiate and replace degenerated retinal ganglion cells (RGCs) in vivo. CB cells and cells from the subventricular zone (SVZ) were isolated from adult or postnatal C57BL/6Tg(CAG-EGFP) mice, respectively, and intravitreally injected into intact retinas, immediately after optic nerve crush or 45 days after the lesion of adult C57/BL/6 mice. Retinas were analysed in whole mounts or cross sections at different time points. Controls were matched untreated retinas. Neither cell type caused gliosis or toxicity when injected into intact retinas. When CB or SVZ cells were injected right after axotomy, they formed an epimembrane without integrating in the retina. However, when CB cells were administered in retinas depleted of RGCs, they integrated into the ganglion cell layer and expressed RGC and neuronal markers. Although SVZ cells were also able to integrate into RGC depleted retinas they did so more slowly than CB cells. These results shed light in the long-standing question of whether cells in the CB have the potential to transdifferentiate in vivo and point to the CB as a suitable source of cells that could be used in cell-replacement therapies for neurodegenerative diseases of the retina.
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Affiliation(s)
- Fernando Lucas-Ruiz
- Grupo de Investigación Oftalmología Experimental, Departamento de Oftalmología, Otorrinolaringología y Anatomía Patológica, Facultad de Medicina, Universidad de Murcia, Instituto Murciano de Investigación Biosanitaria (IMIB), Campus de Ciencias de la Salud, Optometría, Murcia, 30120, Spain
| | - Marta Fernández-Nogales
- Instituto de Neurociencias de Alicante (Consejo Superior de Investigaciones Científicas, Universidad Miguel Hernández, CSIC-UMH), Av. Santiago Ramón y Cajal s/n. Sant Joan d'Alacant 03550, Alicante, Spain
| | - Francisco J Valiente-Soriano
- Grupo de Investigación Oftalmología Experimental, Departamento de Oftalmología, Otorrinolaringología y Anatomía Patológica, Facultad de Medicina, Universidad de Murcia, Instituto Murciano de Investigación Biosanitaria (IMIB), Campus de Ciencias de la Salud, Optometría, Murcia, 30120, Spain
| | - Macarena Herrera
- Instituto de Neurociencias de Alicante (Consejo Superior de Investigaciones Científicas, Universidad Miguel Hernández, CSIC-UMH), Av. Santiago Ramón y Cajal s/n. Sant Joan d'Alacant 03550, Alicante, Spain
| | - Francisco M Nadal-Nicolás
- Grupo de Investigación Oftalmología Experimental, Departamento de Oftalmología, Otorrinolaringología y Anatomía Patológica, Facultad de Medicina, Universidad de Murcia, Instituto Murciano de Investigación Biosanitaria (IMIB), Campus de Ciencias de la Salud, Optometría, Murcia, 30120, Spain
| | - Marta Agudo-Barriuso
- Grupo de Investigación Oftalmología Experimental, Departamento de Oftalmología, Otorrinolaringología y Anatomía Patológica, Facultad de Medicina, Universidad de Murcia, Instituto Murciano de Investigación Biosanitaria (IMIB), Campus de Ciencias de la Salud, Optometría, Murcia, 30120, Spain.
| | - Eloisa Herrera
- Instituto de Neurociencias de Alicante (Consejo Superior de Investigaciones Científicas, Universidad Miguel Hernández, CSIC-UMH), Av. Santiago Ramón y Cajal s/n. Sant Joan d'Alacant 03550, Alicante, Spain.
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2
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Sheveleva O, Protasova E, Grigor’eva E, Butorina N, Kuziaeva V, Antonov D, Melnikova V, Medvedev S, Lyadova I. The Generation of Genetically Engineered Human Induced Pluripotent Stem Cells Overexpressing IFN-β for Future Experimental and Clinically Oriented Studies. Int J Mol Sci 2024; 25:12456. [PMID: 39596521 PMCID: PMC11595023 DOI: 10.3390/ijms252212456] [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: 09/30/2024] [Revised: 11/06/2024] [Accepted: 11/12/2024] [Indexed: 11/28/2024] Open
Abstract
Induced pluripotent stem cells (iPSCs) can be generated from various adult cells, genetically modified and differentiated into diverse cell populations. Type I interferons (IFN-Is) have multiple immunotherapeutic applications; however, their systemic administration can lead to severe adverse outcomes. One way of overcoming the limitation is to introduce cells able to enter the site of pathology and to produce IFN-Is locally. As a first step towards the generation of such cells, here, we aimed to generate human iPSCs overexpressing interferon-beta (IFNB, IFNB-iPSCs). IFNB-iPSCs were obtained by CRISPR/Cas9 editing of the previously generated iPSC line K7-4Lf. IFNB-iPSCs overexpressed IFNB RNA and produced a functionally active IFN-β. The cells displayed typical iPSC morphology and expressed pluripotency markers. Following spontaneous differentiation, IFNB-iPSCs formed embryoid bodies and upregulated endoderm, mesoderm, and some ectoderm markers. However, an upregulation of key neuroectoderm markers, PAX6 and LHX2, was compromised. A negative effect of IFN-β on iPSC neuroectoderm differentiation was confirmed in parental iPSCs differentiated in the presence of a recombinant IFN-β. The study describes new IFN-β-producing iPSC lines suitable for the generation of various types of IFN-β-producing cells for future experimental and clinical applications, and it unravels an inhibitory effect of IFN-β on stem cell neuroectoderm differentiation.
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Affiliation(s)
- Olga Sheveleva
- Laboratory of Cellular and Molecular Basis of Histogenesis, Koltzov Institute of Developmental Biology of the Russian Academy of Sciences, Moscow 119334, Russia; (E.P.); (N.B.); (V.K.); (D.A.)
| | - Elena Protasova
- Laboratory of Cellular and Molecular Basis of Histogenesis, Koltzov Institute of Developmental Biology of the Russian Academy of Sciences, Moscow 119334, Russia; (E.P.); (N.B.); (V.K.); (D.A.)
| | - Elena Grigor’eva
- Laboratory of Developmental Epigenetics, Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences, Novosibirsk 630090, Russia; (E.G.); (S.M.)
| | - Nina Butorina
- Laboratory of Cellular and Molecular Basis of Histogenesis, Koltzov Institute of Developmental Biology of the Russian Academy of Sciences, Moscow 119334, Russia; (E.P.); (N.B.); (V.K.); (D.A.)
| | - Valeriia Kuziaeva
- Laboratory of Cellular and Molecular Basis of Histogenesis, Koltzov Institute of Developmental Biology of the Russian Academy of Sciences, Moscow 119334, Russia; (E.P.); (N.B.); (V.K.); (D.A.)
| | - Daniil Antonov
- Laboratory of Cellular and Molecular Basis of Histogenesis, Koltzov Institute of Developmental Biology of the Russian Academy of Sciences, Moscow 119334, Russia; (E.P.); (N.B.); (V.K.); (D.A.)
| | - Victoria Melnikova
- Laboratory of Comparative Developmental Physiology, Koltzov Institute of Developmental Biology of the Russian Academy of Sciences, Moscow 119334, Russia;
| | - Sergey Medvedev
- Laboratory of Developmental Epigenetics, Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences, Novosibirsk 630090, Russia; (E.G.); (S.M.)
| | - Irina Lyadova
- Laboratory of Cellular and Molecular Basis of Histogenesis, Koltzov Institute of Developmental Biology of the Russian Academy of Sciences, Moscow 119334, Russia; (E.P.); (N.B.); (V.K.); (D.A.)
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3
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Gheitasi M, Safdel S, Kumar Patra S, Zandvakili R, Nemati M, Saha B, Jafarzadeh A. Generation of immune cells from induced pluripotent stem cells (iPSCs): Their potential for adoptive cell therapy. Hum Immunol 2024; 85:110836. [PMID: 38981248 DOI: 10.1016/j.humimm.2024.110836] [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: 12/01/2023] [Revised: 06/03/2024] [Accepted: 06/24/2024] [Indexed: 07/11/2024]
Abstract
Advances in human stem cell technologies enable induced pluripotent stem cells (iPSCs) to be explored as potent candidates for treating various diseases, such as malignancies, autoimmunity, immunodeficiencies, and allergic reactions. iPSCs with infinite self-renewal ability can be derived from different types of somatic cells without the ethical issues associated with embryonic stem cells. To date, numerous cell types, including various immune cell subsets [CD4+ and CD8+ T cells, gamma delta T (γδ T) cells, regulatory T cells, dendritic cells, natural killer cells, macrophages, and neutrophils] have successfully been generated from iPSCs paving the way for effective adoptive cell transfer therapy, drug development, and disease modeling. Herein, we review various iPSC-derived immune cells and their possible application in immunotherapy.
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Affiliation(s)
- Mahsa Gheitasi
- Department of Immunology, School of Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Sepeher Safdel
- Department of Immunology, School of Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | | | - Raziyeh Zandvakili
- Department of Immunology, School of Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Maryam Nemati
- Department of Hematology and Laboratory Sciences, School of Para-Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Bhaskar Saha
- National Centre for Cell Science, Ganeshkhind, Pune 411007, India
| | - Abdollah Jafarzadeh
- Department of Immunology, School of Medicine, Kerman University of Medical Sciences, Kerman, Iran; Applied Cellular and Molecular Research Center, Kerman University of Medical Sciences, Kerman, Iran.
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Della Rocca Y, Diomede F, Konstantinidou F, Gatta V, Stuppia L, Benedetto U, Zimarino M, Lanuti P, Trubiani O, Pizzicannella J. Autologous hGMSC-Derived iPS: A New Proposal for Tissue Regeneration. Int J Mol Sci 2024; 25:9169. [PMID: 39273117 PMCID: PMC11395260 DOI: 10.3390/ijms25179169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Revised: 08/19/2024] [Accepted: 08/20/2024] [Indexed: 09/15/2024] Open
Abstract
The high mortality in the global population due to chronic diseases highlights the urgency to identify effective alternative therapies. Regenerative medicine provides promising new approaches for this purpose, particularly in the use of induced pluripotent stem cells (iPSCs). The aim of the work is to establish a new pluripotency cell line obtained for the first time by reprogramming human gingival mesenchymal stem cells (hGMSCs) by a non-integrating method. The hGMSC-derived iPS line characterization is performed through morphological analysis with optical and electron scanning microscopy and through the pluripotency markers expression evaluation in cytofluorimetry, immunofluorescence, and RT-PCR. To confirm the pluripotency of new hGMSC-derived iPS, the formation of embryoid bodies (EBs), as an alternative to the teratoma formation test, is studied in morphological analysis and through three germ layers' markers' expression in immunofluorescence and RT-PCR. At the end, a comparative study between parental hGMSCs and derived iPS cells is performed also for the extracellular vesicles (EVs) and their miRNA content. The new hGMSC-derived iPS line demonstrated to be pluripotent in all aspects, thus representing an innovative dynamic platform for personalized tissue regeneration.
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Affiliation(s)
- Ylenia Della Rocca
- Department of Innovative Technologies in Medicine & Dentistry, "G. d'Annunzio" University of Chieti-Pescara, Via dei Vestini, 31, 66100 Chieti, Italy
| | - Francesca Diomede
- Department of Innovative Technologies in Medicine & Dentistry, "G. d'Annunzio" University of Chieti-Pescara, Via dei Vestini, 31, 66100 Chieti, Italy
| | - Fanì Konstantinidou
- Department of Psychological Health and Territorial Sciences, "G. d'Annunzio" University of Chieti-Pescara, Via dei Vestini, 31, 66100 Chieti, Italy
- Center for Advanced Studies and Technology (CAST), "G. d'Annunzio" University of Chieti-Pescara, Via Luigi Polacchi 11, 66100 Chieti, Italy
| | - Valentina Gatta
- Department of Psychological Health and Territorial Sciences, "G. d'Annunzio" University of Chieti-Pescara, Via dei Vestini, 31, 66100 Chieti, Italy
- Center for Advanced Studies and Technology (CAST), "G. d'Annunzio" University of Chieti-Pescara, Via Luigi Polacchi 11, 66100 Chieti, Italy
| | - Liborio Stuppia
- Department of Psychological Health and Territorial Sciences, "G. d'Annunzio" University of Chieti-Pescara, Via dei Vestini, 31, 66100 Chieti, Italy
- Center for Advanced Studies and Technology (CAST), "G. d'Annunzio" University of Chieti-Pescara, Via Luigi Polacchi 11, 66100 Chieti, Italy
| | - Umberto Benedetto
- Department of Cardiac Surgery, "S.S. Annunziata" Hospital, ASL 2 Abruzzo, Via dei Vestini, 66100 Chieti, Italy
- Department of Neuroscience, Imaging and Clinical Sciences, "G. d'Annunzio" University of Chieti-Pescara, Via Luigi Polacchi 11, 66100 Chieti, Italy
| | - Marco Zimarino
- Department of Cardiology, "S.S. Annunziata" Hospital, ASL 2 Abruzzo, Via dei Vestini, 66100 Chieti, Italy
| | - Paola Lanuti
- Center for Advanced Studies and Technology (CAST), "G. d'Annunzio" University of Chieti-Pescara, Via Luigi Polacchi 11, 66100 Chieti, Italy
- Department of Medicine and Aging Science, "G. d'Annunzio" University of Chieti-Pescara, Via dei Vestini, 66100 Chieti, Italy
| | - Oriana Trubiani
- Department of Innovative Technologies in Medicine & Dentistry, "G. d'Annunzio" University of Chieti-Pescara, Via dei Vestini, 31, 66100 Chieti, Italy
| | - Jacopo Pizzicannella
- Department of Engineering and Geology, "G. d'Annunzio" University of Chieti-Pescara, Viale Pindaro, 42, 65127 Pescara, Italy
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Pierantoni M, Grassilli S, Brugnoli F, Dell'Aira M, Bertagnolo V. Insights into the development of insulin-producing cells: Precursors correlated involvement of microRNA panels. Life Sci 2024; 350:122762. [PMID: 38843994 DOI: 10.1016/j.lfs.2024.122762] [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: 04/11/2024] [Revised: 05/23/2024] [Accepted: 05/27/2024] [Indexed: 06/10/2024]
Abstract
Type 1 diabetes (T1D) is a chronic autoimmune condition characterized by the destruction of pancreatic β cells, recently estimated to affect approximately 8.75 million individuals worldwide. At variance with conventional management of T1D, which relies on exogenous insulin replacement and insulinotropic drugs, emerging therapeutic strategies include transplantation of insulin-producing cells (IPCs) derived from stem cells or fully reprogrammed differentiated cells. Through the in-depth analysis of the microRNAs (miRNAs) involved in the differentiation of human embryonic stem cells (ESCs), mesenchymal stem cells (MSCs), and induced pluripotent stem cells (iPSCs), into insulin-producing cells, this review provides a comprehensive overview of the molecular mechanisms orchestrating the transformation of precursors to cells producing insulin. In addition to miR-375, involved in all differentiation processes, and to miR-7, mir-145 and miR-9, common to the generation of insulin-producing cells from at least two different sources, the literature reveals panels of miRNAs closely related to precursor cells and associated with specific events of the physiological β cell maturation. Since the forced modulation of miRNAs can direct cells development towards insulin-producing cells or modify their fate, a more comprehensive knowledge of the miRNAs involved in the cellular events leading to obtain efficient β cells could improve the diagnostic, prognostic, and therapeutic approaches to diabetes.
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Affiliation(s)
- Marina Pierantoni
- Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy.
| | - Silvia Grassilli
- Department of Environmental and Prevention Sciences and LTTA Centre, University of Ferrara, 44121 Ferrara, Italy.
| | - Federica Brugnoli
- Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy.
| | - Marcello Dell'Aira
- Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy.
| | - Valeria Bertagnolo
- Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy.
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Yu G, Ye Z, Yuan Y, Wang X, Li T, Wang Y, Wang Y, Yan J. Recent Advancements in Biomaterials for Chimeric Antigen Receptor T Cell Immunotherapy. Biomater Res 2024; 28:0045. [PMID: 39011521 PMCID: PMC11246982 DOI: 10.34133/bmr.0045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Accepted: 05/13/2024] [Indexed: 07/17/2024] Open
Abstract
Cellular immunotherapy is an innovative cancer treatment method that utilizes the patient's own immune system to combat tumor cells effectively. Currently, the mainstream therapeutic approaches include chimeric antigen receptor T cell (CAR-T) therapy, T cell receptor gene-modified T cell therapy and chimeric antigen receptor natural killer-cell therapy with CAR-T therapy mostly advanced. Nonetheless, the conventional manufacturing process of this therapy has shortcomings in each step that call for improvement. Marked efforts have been invested for its enhancement while notable progresses achieved in the realm of biomaterials application. With CAR-T therapy as a prime example, the aim of this review is to comprehensively discuss the various biomaterials used in cell immunotherapy, their roles in regulating immune cells, and their potential for breakthroughs in cancer treatment from gene transduction to efficacy enhancement. This article additionally addressed widely adopted animal models for efficacy evaluating.
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Affiliation(s)
- Gaoyu Yu
- School of Medicine,
Zhejiang University, Hangzhou 310028, China
| | - Zhichao Ye
- Department of General Surgery, Sir Run Run Shaw Hospital Affiliated to School of Medicine,
Zhejiang University, Hangzhou 310016, China
- National Engineering Research Center of Innovation and Application of Minimally Invasive Instruments, Sir Run Run Shaw Hospital, School of Medicine,
Zhejiang University, Hangzhou 310028, China
| | - Yuyang Yuan
- Department of General Surgery, Sir Run Run Shaw Hospital Affiliated to School of Medicine,
Zhejiang University, Hangzhou 310016, China
- National Engineering Research Center of Innovation and Application of Minimally Invasive Instruments, Sir Run Run Shaw Hospital, School of Medicine,
Zhejiang University, Hangzhou 310028, China
- Department of Translational Medicine & Clinical Research, Sir Run Run Shaw Hospital, School of Medicine,
Zhejiang University, Hangzhou 310028, China
| | - Xiaofeng Wang
- Department of Plastic Surgery, Sir Run Run Shaw Hospital,
Zhejiang University School of Medicine, Hangzhou, 310016, Zhejiang Province, China
| | - Tianyu Li
- National Engineering Research Center of Innovation and Application of Minimally Invasive Instruments, Sir Run Run Shaw Hospital, School of Medicine,
Zhejiang University, Hangzhou 310028, China
- Department of Translational Medicine & Clinical Research, Sir Run Run Shaw Hospital, School of Medicine,
Zhejiang University, Hangzhou 310028, China
| | - Yi Wang
- National Engineering Research Center of Innovation and Application of Minimally Invasive Instruments, Sir Run Run Shaw Hospital, School of Medicine,
Zhejiang University, Hangzhou 310028, China
| | - Yifan Wang
- Department of General Surgery, Sir Run Run Shaw Hospital Affiliated to School of Medicine,
Zhejiang University, Hangzhou 310016, China
- National Engineering Research Center of Innovation and Application of Minimally Invasive Instruments, Sir Run Run Shaw Hospital, School of Medicine,
Zhejiang University, Hangzhou 310028, China
- Department of Translational Medicine & Clinical Research, Sir Run Run Shaw Hospital, School of Medicine,
Zhejiang University, Hangzhou 310028, China
| | - Jianing Yan
- Department of General Surgery, Sir Run Run Shaw Hospital Affiliated to School of Medicine,
Zhejiang University, Hangzhou 310016, China
- National Engineering Research Center of Innovation and Application of Minimally Invasive Instruments, Sir Run Run Shaw Hospital, School of Medicine,
Zhejiang University, Hangzhou 310028, China
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7
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Li C, Luo Y, Li S. The roles of neural stem cells in myelin regeneration and repair therapy after spinal cord injury. Stem Cell Res Ther 2024; 15:204. [PMID: 38978125 PMCID: PMC11232222 DOI: 10.1186/s13287-024-03825-x] [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: 02/12/2024] [Accepted: 07/02/2024] [Indexed: 07/10/2024] Open
Abstract
Spinal cord injury (SCI) is a complex tissue injury that results in a wide range of physical deficits, including permanent or progressive disabilities of sensory, motor and autonomic functions. To date, limitations in current clinical treatment options can leave SCI patients with lifelong disabilities. There is an urgent need to develop new therapies for reconstructing the damaged spinal cord neuron-glia network and restoring connectivity with the supraspinal pathways. Neural stem cells (NSCs) possess the ability to self-renew and differentiate into neurons and neuroglia, including oligodendrocytes, which are cells responsible for the formation and maintenance of the myelin sheath and the regeneration of demyelinated axons. For these properties, NSCs are considered to be a promising cell source for rebuilding damaged neural circuits and promoting myelin regeneration. Over the past decade, transplantation of NSCs has been extensively tested in a variety of preclinical models of SCI. This review aims to highlight the pathophysiology of SCI and promote the understanding of the role of NSCs in SCI repair therapy and the current advances in pathological mechanism, pre-clinical studies, as well as clinical trials of SCI via NSC transplantation therapeutic strategy. Understanding and mastering these frontier updates will pave the way for establishing novel therapeutic strategies to improve the quality of recovery from SCI.
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Affiliation(s)
- Chun Li
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Department of Neurology, Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China
- Tongji University Cancer Center, Shanghai Tenth People's Hospital of Tongji University, Tongji University School of Medicine, Shanghai, 200092, China
| | - Yuping Luo
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Department of Neurology, Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China
- Stem Cell Translational Research Center, Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China
| | - Siguang Li
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Department of Neurology, Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China.
- Stem Cell Translational Research Center, Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China.
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Sun Y, Zhao H, Yang S, Wang G, Zhu L, Sun C, An Y. Urine-derived stem cells: Promising advancements and applications in regenerative medicine and beyond. Heliyon 2024; 10:e27306. [PMID: 38509987 PMCID: PMC10951541 DOI: 10.1016/j.heliyon.2024.e27306] [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: 09/23/2023] [Revised: 02/27/2024] [Accepted: 02/27/2024] [Indexed: 03/22/2024] Open
Abstract
Currently, stem cells are a prominent focus of regenerative engineering research. However, due to the limitations of commonly used stem cell sources, their application in therapy is often restricted to the experimental stage and constrained by ethical considerations. In contrast, urine-derived stem cells (USCs) offer promising advantages for clinical trials and applications. The noninvasive nature of the collection process allows for repeated retrieval within a short period, making it a more feasible option. Moreover, studies have shown that USCs have a protective effect on organs, promoting vascular regeneration, inhibiting oxidative stress, and reducing inflammation in various acute and chronic organ dysfunctions. The application of USCs has also been enhanced by advancements in biomaterials technology, enabling better targeting and controlled release capabilities. This review aims to summarize the current state of research on USCs, providing insights for future applications in basic and clinical settings.
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Affiliation(s)
| | | | - Shuguang Yang
- Department of Critical Care Medicine, Peking University People's Hospital, PR China
| | - Guangjie Wang
- Department of Critical Care Medicine, Peking University People's Hospital, PR China
| | - Leijie Zhu
- Department of Critical Care Medicine, Peking University People's Hospital, PR China
| | - Chang Sun
- Department of Critical Care Medicine, Peking University People's Hospital, PR China
| | - Youzhong An
- Department of Critical Care Medicine, Peking University People's Hospital, PR China
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9
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Setiawan J, Rizal DM, Sofyantoro F, Priyono DS, Septriani NI, Mafiroh WU, Kotani T, Matozaki T, Putri WA. Bibliometric analysis of organoids in regenerative medicine-related research worldwide over two decades (2002-2022). Regen Med 2024; 19:119-133. [PMID: 38449425 DOI: 10.2217/rme-2023-0176] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/08/2024] Open
Abstract
Aim: This study aimed to evaluate the trends in organoid culture research within the field of regenerative medicine from 2002 to 2022. Methods: The worldwide distribution of organoid research in regenerative medicine articles indexed in the Scopus database was analyzed. Result: A total of 840 documents were analyzed, averaging 42 publications annually. The USA (n = 296) led in publications, followed by China (n = 127), Japan (n = 91) and the UK (n = 75). Since 2011, research has surged, particularly in China, which emerged as a prominent center. Conclusion: The findings highlight significant growth in organoid research, promising future organ transplantation. Research trends integrate tissue engineering, gene modification and induced pluripotent stem cell technologies, reflecting a move toward personalized medicine.
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Affiliation(s)
- Jajar Setiawan
- Department of Physiology, Faculty of Medicine, Public Health, and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia
| | - Dicky Moch Rizal
- Department of Physiology, Faculty of Medicine, Public Health, and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia
| | - Fajar Sofyantoro
- Department of Tropical Biology, Faculty of Biology, Universitas Gadjah Mada, Yogyakarta, Indonesia
| | - Dwi Sendi Priyono
- Department of Tropical Biology, Faculty of Biology, Universitas Gadjah Mada, Yogyakarta, Indonesia
| | - Nur Indah Septriani
- Department of Tropical Biology, Faculty of Biology, Universitas Gadjah Mada, Yogyakarta, Indonesia
| | - Wulan Usfi Mafiroh
- Department of Tropical Biology, Faculty of Biology, Universitas Gadjah Mada, Yogyakarta, Indonesia
| | - Takenori Kotani
- Division of Molecular and Cellular Signaling, Department of Biochemistry & Molecular Biology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Takashi Matozaki
- Division of Molecular and Cellular Signaling, Department of Biochemistry & Molecular Biology, Kobe University Graduate School of Medicine, Kobe, Japan
- Division of Biosignal Regulation, Department of Biochemistry & Molecular Biology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Wahyu Aristyaning Putri
- Department of Tropical Biology, Faculty of Biology, Universitas Gadjah Mada, Yogyakarta, Indonesia
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10
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Chehelgerdi M, Behdarvand Dehkordi F, Chehelgerdi M, Kabiri H, Salehian-Dehkordi H, Abdolvand M, Salmanizadeh S, Rashidi M, Niazmand A, Ahmadi S, Feizbakhshan S, Kabiri S, Vatandoost N, Ranjbarnejad T. Exploring the promising potential of induced pluripotent stem cells in cancer research and therapy. Mol Cancer 2023; 22:189. [PMID: 38017433 PMCID: PMC10683363 DOI: 10.1186/s12943-023-01873-0] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Accepted: 09/27/2023] [Indexed: 11/30/2023] Open
Abstract
The advent of iPSCs has brought about a significant transformation in stem cell research, opening up promising avenues for advancing cancer treatment. The formation of cancer is a multifaceted process influenced by genetic, epigenetic, and environmental factors. iPSCs offer a distinctive platform for investigating the origin of cancer, paving the way for novel approaches to cancer treatment, drug testing, and tailored medical interventions. This review article will provide an overview of the science behind iPSCs, the current limitations and challenges in iPSC-based cancer therapy, the ethical and social implications, and the comparative analysis with other stem cell types for cancer treatment. The article will also discuss the applications of iPSCs in tumorigenesis, the future of iPSCs in tumorigenesis research, and highlight successful case studies utilizing iPSCs in tumorigenesis research. The conclusion will summarize the advancements made in iPSC-based tumorigenesis research and the importance of continued investment in iPSC research to unlock the full potential of these cells.
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Affiliation(s)
- Matin Chehelgerdi
- Novin Genome (NG) Lab, Research and Development Center for Biotechnology, Shahrekord, Iran
- Young Researchers and Elite Club, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran
| | - Fereshteh Behdarvand Dehkordi
- Novin Genome (NG) Lab, Research and Development Center for Biotechnology, Shahrekord, Iran
- Young Researchers and Elite Club, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran
| | - Mohammad Chehelgerdi
- Novin Genome (NG) Lab, Research and Development Center for Biotechnology, Shahrekord, Iran.
- Young Researchers and Elite Club, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran.
| | - Hamidreza Kabiri
- Novin Genome (NG) Lab, Research and Development Center for Biotechnology, Shahrekord, Iran
- Young Researchers and Elite Club, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran
| | | | - Mohammad Abdolvand
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Science, Isfahan, Iran
| | - Sharareh Salmanizadeh
- Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Hezar-Jereeb Street, Isfahan, 81746-73441, Iran
| | - Mohsen Rashidi
- Department Pharmacology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
- The Health of Plant and Livestock Products Research Center, Mazandaran University of Medical Sciences, Sari, Iran
| | - Anoosha Niazmand
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Science, Isfahan, Iran
| | - Saba Ahmadi
- Department of Molecular and Medical Genetics, Tbilisi State Medical University, Tbilisi, Georgia
| | - Sara Feizbakhshan
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Science, Isfahan, Iran
| | - Saber Kabiri
- Novin Genome (NG) Lab, Research and Development Center for Biotechnology, Shahrekord, Iran
- Young Researchers and Elite Club, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran
| | - Nasimeh Vatandoost
- Pediatric Inherited Diseases Research Center, Research Institute for Primordial Prevention of Non-Communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Tayebeh Ranjbarnejad
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Science, Isfahan, Iran
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11
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Chen Y, Zhu Y, Kramer A, Fang Y, Wilson M, Li YR, Yang L. Genetic engineering strategies to enhance antitumor reactivity and reduce alloreactivity for allogeneic cell-based cancer therapy. Front Med (Lausanne) 2023; 10:1135468. [PMID: 37064017 PMCID: PMC10090359 DOI: 10.3389/fmed.2023.1135468] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Accepted: 03/09/2023] [Indexed: 03/31/2023] Open
Abstract
The realm of cell-based immunotherapy holds untapped potential for the development of next-generation cancer treatment through genetic engineering of chimeric antigen receptor (CAR)-engineered T (CAR-T) cell therapies for targeted eradication of cancerous malignancies. Such allogeneic "off-the-shelf" cell products can be advantageously manufactured in large quantities, stored for extended periods, and easily distributed to treat an exponential number of cancer patients. At current, patient risk of graft-versus-host disease (GvHD) and host-versus-graft (HvG) allorejection severely restrict the development of allogeneic CAR-T cell products. To address these limitations, a variety of genetic engineering strategies have been implemented to enhance antitumor efficacy, reduce GvHD and HvG onset, and improve the overall safety profile of T-cell based immunotherapies. In this review, we summarize these genetic engineering strategies and discuss the challenges and prospects these approaches provide to expedite progression of translational and clinical studies for adoption of a universal cell-based cancer immunotherapy.
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Affiliation(s)
- Yuning Chen
- Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, United States
| | - Yichen Zhu
- Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, United States
| | - Adam Kramer
- Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, United States
| | - Ying Fang
- Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, United States
| | - Matthew Wilson
- Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, United States
| | - Yan-Ruide Li
- Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, United States
| | - Lili Yang
- Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, United States
- Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA, United States
- Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
- Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, United States
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12
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Han H, Rim YA, Ju JH. Recent updates of stem cell-based erythropoiesis. Hum Cell 2023; 36:894-907. [PMID: 36754940 PMCID: PMC9908308 DOI: 10.1007/s13577-023-00872-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2022] [Accepted: 01/28/2023] [Indexed: 02/10/2023]
Abstract
Blood transfusions are now an essential part of modern medicine. Transfusable red blood cells (RBCs) are employed in various therapeutic strategies; however, the processes of blood donation, collection, and administration still involve many limitations. Notably, a lack of donors, the risk of transfusion-transmitted disease, and recent pandemics such as COVID-19 have prompted us to search for alternative therapeutics to replace this resource. Originally, RBC production was attempted via the ex vivo differentiation of stem cells. However, a more approachable and effective cell source is now required for broader applications. As a viable alternative, pluripotent stem cells have been actively used in recent research. In this review, we discuss the basic concepts related to erythropoiesis, as well as early research using hematopoietic stem cells ex vivo, and discuss the current trend of in vitro erythropoiesis using human-induced pluripotent stem cells.
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Affiliation(s)
- Heeju Han
- Department of Biomedicine and Health Sciences, College of Medicine, The Catholic University of Korea, , Seoul, Republic of Korea ,Catholic iPSC Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Yeri Alice Rim
- Catholic iPSC Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
| | - Ji Hyeon Ju
- Catholic iPSC Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea. .,Division of Rheumatology, Department of Internal Medicine, Institute of Medical Science, College of Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Republic of Korea.
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13
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Wang S, Chen K, Jiang Y, Zhao G, Wang C, Fang H, Tang Q, Sun C, Zhang L, Wu H, Zhang LF, Li N. Breaking boundaries: Current progress of anticancer NK cell-based drug development. Drug Discov Today 2023; 28:103436. [PMID: 36370993 DOI: 10.1016/j.drudis.2022.103436] [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: 10/12/2022] [Revised: 10/14/2022] [Accepted: 11/07/2022] [Indexed: 11/11/2022]
Abstract
Natural killer (NK) cell therapy is emerging as a cancer treatment. NK cells are innate cytotoxic lymphocytes that act as first-line responders to kill target cells without prior encounters. NK cells recognize cancer cells, virus-infected cells, and other types of stressed cell through a reservoir of germline-encoded receptors. NK cells are safe for allogeneic applications. Therefore, they are the ideal off-the-shelf cell, which overcome the low efficiency issue caused by the patient-by-patient nature of autologous cell therapy. Unlike T cells, NK cells cannot form a strong immune memory; therefore, they suffer from short in vivo persistence. However, different from T cells, NK cells have a reservoir of innate immune receptors targeting a variety of malignant cells. In addition, they can utilize antibody guidance in target recognition. With suitable engineering, NK cells can function as universal anticancer drugs that are not restricted to HLA and cancer types, which will benefit the large cohort of patients with rare cancer types and patients with no convenient drug targets for precision and personalized medicine. Here, we summarize and discuss the designs of current anticancer NK cell therapies.
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Affiliation(s)
- Shuhang Wang
- Clinical Trial Center, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Kun Chen
- Guizhou Provincial People's Hospital, Guiyang, China
| | - Yale Jiang
- Clinical Trial Center, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Guo Zhao
- Clinical Trial Center, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Caie Wang
- Department of Pharmacy, the First Affiliated Hospital of Henan University of Science and Technology, Luoyang, Henan, China
| | - Hong Fang
- Clinical Trial Center, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Qiyu Tang
- Clinical Trial Center, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Chao Sun
- Clinical Trial Center, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | | | - Haiyang Wu
- TCRCure Biological Technology Co Ltd, Guangdong, China
| | - Li-Feng Zhang
- TCRCure Biological Technology Co Ltd, Guangdong, China.
| | - Ning Li
- Clinical Trial Center, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
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14
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Damkham N, Issaragrisil S, Lorthongpanich C. Role of YAP as a Mechanosensing Molecule in Stem Cells and Stem Cell-Derived Hematopoietic Cells. Int J Mol Sci 2022; 23:14634. [PMID: 36498961 PMCID: PMC9737411 DOI: 10.3390/ijms232314634] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Revised: 11/11/2022] [Accepted: 11/20/2022] [Indexed: 11/25/2022] Open
Abstract
Yes-associated protein (YAP) and WW domain-containing transcription regulator protein 1 (WWTR1, also known as TAZ) are transcriptional coactivators in the Hippo signaling pathway. Both are well-known regulators of cell proliferation and organ size control, and they have significant roles in promoting cell proliferation and differentiation. The roles of YAP and TAZ in stem cell pluripotency and differentiation have been extensively studied. However, the upstream mediators of YAP and TAZ are not well understood. Recently, a novel role of YAP in mechanosensing and mechanotransduction has been reported. The present review updates information on the regulation of YAP by mechanical cues such as extracellular matrix stiffness, fluid shear stress, and actin cytoskeleton tension in stem cell behaviors and differentiation. The review explores mesenchymal stem cell fate decisions, pluripotent stem cells (PSCs), self-renewal, pluripotency, and differentiation to blood products. Understanding how cells sense their microenvironment or niche and mimic those microenvironments in vitro could improve the efficiency of producing stem cell products and the efficacy of the products.
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Affiliation(s)
- Nattaya Damkham
- Siriraj Center of Excellence for Stem cell Research, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Surapol Issaragrisil
- Siriraj Center of Excellence for Stem cell Research, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
- Division of Hematology, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
- Bangkok Hematology Center, Wattanosoth Hospital, BDMS Center of Excellence for Cancer, Bangkok 10310, Thailand
| | - Chanchao Lorthongpanich
- Siriraj Center of Excellence for Stem cell Research, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
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15
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Thanaskody K, Jusop AS, Tye GJ, Wan Kamarul Zaman WS, Dass SA, Nordin F. MSCs vs. iPSCs: Potential in therapeutic applications. Front Cell Dev Biol 2022; 10:1005926. [PMID: 36407112 PMCID: PMC9666898 DOI: 10.3389/fcell.2022.1005926] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Accepted: 10/21/2022] [Indexed: 01/24/2023] Open
Abstract
Over the past 2 decades, mesenchymal stem cells (MSCs) have attracted a lot of interest as a unique therapeutic approach for a variety of diseases. MSCs are capable of self-renewal and multilineage differentiation capacity, immunomodulatory, and anti-inflammatory properties allowing it to play a role in regenerative medicine. Furthermore, MSCs are low in tumorigenicity and immune privileged, which permits the use of allogeneic MSCs for therapies that eliminate the need to collect MSCs directly from patients. Induced pluripotent stem cells (iPSCs) can be generated from adult cells through gene reprogramming with ectopic expression of specific pluripotency factors. Advancement in iPS technology avoids the destruction of embryos to make pluripotent cells, making it free of ethical concerns. iPSCs can self-renew and develop into a plethora of specialized cells making it a useful resource for regenerative medicine as they may be created from any human source. MSCs have also been used to treat individuals infected with the SARS-CoV-2 virus. MSCs have undergone more clinical trials than iPSCs due to high tumorigenicity, which can trigger oncogenic transformation. In this review, we discussed the overview of mesenchymal stem cells and induced pluripotent stem cells. We briefly present therapeutic approaches and COVID-19-related diseases using MSCs and iPSCs.
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Affiliation(s)
- Kalaiselvaan Thanaskody
- Centre for Tissue Engineering and Regenerative Medicine (CTERM), Faculty of Medicine, University Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Amirah Syamimi Jusop
- Centre for Tissue Engineering and Regenerative Medicine (CTERM), Faculty of Medicine, University Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Gee Jun Tye
- Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia, Gelugor, Malaysia
| | - Wan Safwani Wan Kamarul Zaman
- Department of Biomedical Engineering, Faculty of Engineering, Universiti Malaya, Kuala Lumpur, Malaysia,Centre for Innovation in Medical Engineering (CIME), Department of Biomedical Engineering, Faculty of Engineering, Universiti Malaya, Kuala Lumpur, Malaysia
| | - Sylvia Annabel Dass
- Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia, Gelugor, Malaysia
| | - Fazlina Nordin
- Centre for Tissue Engineering and Regenerative Medicine (CTERM), Faculty of Medicine, University Kebangsaan Malaysia, Kuala Lumpur, Malaysia,*Correspondence: Fazlina Nordin,
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16
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Asai A, Tsuchimoto Y, Ohama H, Nishikawa H, Chopra A, Higuchi K. CD34+CD10+CD19− Cells in Patients with Unhealthy Alcohol Use Stimulate the M2b Monocyte Polarization. Cells 2022; 11:cells11172703. [PMID: 36078108 PMCID: PMC9454773 DOI: 10.3390/cells11172703] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 08/15/2022] [Accepted: 08/27/2022] [Indexed: 11/26/2022] Open
Abstract
M2b monocytes commonly isolated from patients with unhealthy alcohol use (Alc) have been described as cells that make the host susceptible to opportunistic infections. CD34+CD10+CD19− cells are multilineage progenitors of CD19+ cells, and we show that the effect of these cells from the peripheral blood on M2b monocyte polarization differed between healthy donors and Alc in this study. In healthy donors, these cells consistently differentiated into high-mobility group box-1 (HMGB1)-nonproducing cells (CD19+ cells) in response to retinoic acid (RA). However, owing to the lack of expression of RA receptor (RAR), these cells from Alc failed to differentiate into CD19+ cells under the same RA stimulation. Conditioned medium (CM) of these cells from Alc induced the polarization of M2b monocytes, which increases the susceptibility of hosts to opportunistic infections in Alc. When the alcoholic individuals were subjected to 2 weeks of abstinence from alcohol, these cells from Alc recovered their RAR expression and differentiated into CD19+ cells. Moreover, the CM of these cells from Alc after abstinence lost its ability to induce M2b monocyte polarization. These results indicate that these cells from Alc have different properties from those of healthy donors. In Alc, these cells without RAR stimulate M2b monocyte polarization through the production of HMGB1.
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Affiliation(s)
- Akira Asai
- 2nd Department of Internal Medicine, Osaka Medical and Pharmaceutical University, Takatsuki 569-8686, Japan
- Correspondence: ; Tel.: +81-(726)-83-1221
| | - Yusuke Tsuchimoto
- 2nd Department of Internal Medicine, Osaka Medical and Pharmaceutical University, Takatsuki 569-8686, Japan
| | - Hideko Ohama
- 2nd Department of Internal Medicine, Osaka Medical and Pharmaceutical University, Takatsuki 569-8686, Japan
| | - Hiroki Nishikawa
- 2nd Department of Internal Medicine, Osaka Medical and Pharmaceutical University, Takatsuki 569-8686, Japan
| | - Ashok Chopra
- Department of Microbiology and Immunology, The University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Kazuhide Higuchi
- 2nd Department of Internal Medicine, Osaka Medical and Pharmaceutical University, Takatsuki 569-8686, Japan
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17
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Bai C, Ren Q, Liu H, Li X, Guan W, Gao Y. miR-212/132-Enriched Extracellular Vesicles Promote Differentiation of Induced Pluripotent Stem Cells Into Pancreatic Beta Cells. Front Cell Dev Biol 2021; 9:673231. [PMID: 34055806 PMCID: PMC8155495 DOI: 10.3389/fcell.2021.673231] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Accepted: 04/22/2021] [Indexed: 01/08/2023] Open
Abstract
Pancreatic beta cell transplantation is the ideal method for treatment of type 1 diabetes mellitus (T1DM), and the generation of beta cells from induced pluripotent stem cells (iPSCs) of patients is a promising strategy. In this study, we improved a previous strategy to produce beta cells using extracellular vesicles (EVs) derived from mature beta cells and differentiated beta cells from iPSCs (i-Beta cells), which secreted insulin under glucose stimulation in vitro and ameliorated hyperglycemia in vivo. Mechanistic analyses revealed that EV-carried microRNA (miR)-212/132 (EV-miR-212/132) directly bound to the 3' UTR of FBW7 to prevent its translation and FBW7 combined with NGN3 to accelerate its proteasomal degradation. EV-miR-212/132 stabilized NGN3 expression to promote differentiation of endocrine cells from induced iPSCs. Moreover, NGN3 bound to PDX1 to enhance transcription of endogenous miR-212/132 and formed a positive regulatory circuit that maintained the functions of mature pancreatic beta cells. CONCLUSION This study describes a novel approach for beta cell production and supports the use of iPSCs for cell replacement therapy of T1DM.
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Affiliation(s)
- Chunyu Bai
- Institute of Precision Medicine, Jining Medical University, Jining, China
- Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing China
| | - Qiwei Ren
- College of Basic Medicine, Jining Medical University, Jining, China
| | - Haifeng Liu
- Department of Laboratory Medicine, Affiliated Hospital of Jining Medical University, Jining, China
| | - Xiangchen Li
- College of Animal Science and Technology, College of Veterinary Medicine, Zhejiang A&F University, Lin’an, China
| | - Weijun Guan
- Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing China
| | - Yuhua Gao
- Institute of Precision Medicine, Jining Medical University, Jining, China
- Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing China
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18
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Ke M, Chong CM, Zhu Q, Zhang K, Cai CZ, Lu JH, Qin D, Su H. Comprehensive Perspectives on Experimental Models for Parkinson's Disease. Aging Dis 2021; 12:223-246. [PMID: 33532138 PMCID: PMC7801282 DOI: 10.14336/ad.2020.0331] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Accepted: 03/31/2020] [Indexed: 11/19/2022] Open
Abstract
Parkinson’s disease (PD) ranks second among the most common neurodegenerative diseases, characterized by progressive and selective loss of dopaminergic neurons. Various cross-species preclinical models, including cellular models and animal models, have been established through the decades to study the etiology and mechanism of the disease from cell lines to nonhuman primates. These models are aimed at developing effective therapeutic strategies for the disease. None of the current models can replicate all major pathological and clinical phenotypes of PD. Selection of the model for PD largely relies on our interest of study. In this review, we systemically summarized experimental PD models, including cellular and animal models used in preclinical studies, to understand the pathogenesis of PD. This review is intended to provide current knowledge about the application of these different PD models, with focus on their strengths and limitations with respect to their contributions to the assessment of the molecular pathobiology of PD and identification of the therapeutic strategies for the disease.
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Affiliation(s)
- Minjing Ke
- 1State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China
| | - Cheong-Meng Chong
- 1State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China
| | - Qi Zhu
- 1State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China
| | - Ke Zhang
- 1State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China
| | - Cui-Zan Cai
- 1State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China
| | - Jia-Hong Lu
- 1State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China
| | - Dajiang Qin
- 2Guangzhou Regenerative Medicine and Health Guangdong Laboratory, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,3South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| | - Huanxing Su
- 1State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China
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Dubey SK, Alexander A, Sivaram M, Agrawal M, Singhvi G, Sharma S, Dayaramani R. Uncovering the Diversification of Tissue Engineering on the Emergent Areas of Stem Cells, Nanotechnology and Biomaterials. Curr Stem Cell Res Ther 2020; 15:187-201. [PMID: 31957615 DOI: 10.2174/1574888x15666200103124821] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2019] [Revised: 11/11/2019] [Accepted: 11/12/2019] [Indexed: 12/23/2022]
Abstract
Damaged or disabled tissue is life-threatening due to the lack of proper treatment. Many conventional transplantation methods like autograft, iso-graft and allograft are in existence for ages, but they are not sufficient to treat all types of tissue or organ damages. Stem cells, with their unique capabilities like self-renewal and differentiate into various cell types, can be a potential strategy for tissue regeneration. However, the challenges like reproducibility, uncontrolled propagation and differentiation, isolation of specific kinds of cell and tumorigenic nature made these stem cells away from clinical application. Today, various types of stem cells like embryonic, fetal or gestational tissue, mesenchymal and induced-pluripotent stem cells are under investigation for their clinical application. Tissue engineering helps in configuring the stem cells to develop into a desired viable tissue, to use them clinically as a substitute for the conventional method. The use of stem cell-derived Extracellular Vesicles (EVs) is being studied to replace the stem cells, which decreases the immunological complications associated with the direct administration of stem cells. Tissue engineering also investigates various biomaterials to use clinically, either to replace the bones or as a scaffold to support the growth of stemcells/ tissue. Depending upon the need, there are various biomaterials like bio-ceramics, natural and synthetic biodegradable polymers to support replacement or regeneration of tissue. Like the other fields of science, tissue engineering is also incorporating the nanotechnology to develop nano-scaffolds to provide and support the growth of stem cells with an environment mimicking the Extracellular matrix (ECM) of the desired tissue. Tissue engineering is also used in the modulation of the immune system by using patient-specific Mesenchymal Stem Cells (MSCs) and by modifying the physical features of scaffolds that may provoke the immune system. This review describes the use of various stem cells, biomaterials and the impact of nanotechnology in regenerative medicine.
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Affiliation(s)
- Sunil K Dubey
- Department of Pharmacy, Birla Institute of Technology and Science, Pilani (BITS-PILANI), Pilani Campus, Rajasthan 333031, India
| | - Amit Alexander
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER GUWAHATI), Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Govt. of India, NH 37, NITS Mirza, Kamrup-781125, Guwahati (Assam), India
| | - Munnangi Sivaram
- Department of Pharmacy, Birla Institute of Technology and Science, Pilani (BITS-PILANI), Pilani Campus, Rajasthan 333031, India
| | - Mukta Agrawal
- Rungta College of Pharmaceutical Sciences and Research, Kohka- Kurud Road, Bhilai, Chhattisgarh 490024, India
| | - Gautam Singhvi
- Department of Pharmacy, Birla Institute of Technology and Science, Pilani (BITS-PILANI), Pilani Campus, Rajasthan 333031, India
| | - Swapnil Sharma
- Department of Pharmacy, Banastahli Vidyapith, Tonk, Rajasthan 304022, India
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Farzaneh M, Anbiyaiee A, Khoshnam SE. Human Pluripotent Stem Cells for Spinal Cord Injury. Curr Stem Cell Res Ther 2020; 15:135-143. [PMID: 31656156 DOI: 10.2174/1574362414666191018121658] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2019] [Revised: 07/16/2019] [Accepted: 09/17/2019] [Indexed: 12/27/2022]
Abstract
Spinal cord injury (SCI) as a serious public health issue and neurological insult is one of the most severe cause of long-term disability. To date, a variety of techniques have been widely developed to treat central nervous system injury. Currently, clinical treatments are limited to surgical decompression and pharmacotherapy. Because of their negative effects and inefficiency, novel therapeutic approaches are required in the management of SCI. Improvement and innovation of stem cell-based therapies have a huge potential for biological and future clinical applications. Human pluripotent stem cells (hPSCs) including embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) are defined by their abilities to divide asymmetrically, self-renew and ultimately differentiate into various cell lineages. There are considerable research efforts to use various types of stem cells, such as ESCs, neural stem cells (NSCs), and mesenchymal stem cells (MSCs) in the treatment of patients with SCI. Moreover, the use of patient-specific iPSCs holds great potential as an unlimited cell source for generating in vivo models of SCI. In this review, we focused on the potential of hPSCs in treating SCI.
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Affiliation(s)
- Maryam Farzaneh
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Amir Anbiyaiee
- Department of Obstetrics and Gynecology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz 61357-15794, Iran
| | - Seyed Esmaeil Khoshnam
- Physiology Research Center, Department of Physiology, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
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21
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Mashima H, Zhang R, Kobayashi T, Hagiya Y, Tsukamoto H, Liu T, Iwama T, Yamamoto M, Lin C, Nakatsuka R, Mishima Y, Watanabe N, Yamada T, Senju S, Kaneko S, Idiris A, Nakatsura T, Ohdan H, Uemura Y. Generation of GM-CSF-producing antigen-presenting cells that induce a cytotoxic T cell-mediated antitumor response. Oncoimmunology 2020; 9:1814620. [PMID: 33457097 PMCID: PMC7781730 DOI: 10.1080/2162402x.2020.1814620] [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] [Indexed: 12/12/2022] Open
Abstract
Immunotherapy using dendritic cells (DCs) is a promising treatment modality for cancer. However, the limited number of functional DCs from peripheral blood has been linked to the unsatisfactory clinical efficacies of current DC-based cancer immunotherapies. We previously generated proliferating antigen-presenting cells (APCs) by genetically engineering myeloid cells derived from induced pluripotent stem cells (iPSC-pMCs), which offer infinite functional APCs for broad applications in cancer therapy. Herein, we aimed to further enhance the antitumor effect of these cells by genetic modification. GM-CSF gene transfer did not affect the morphology, or surface phenotype of the original iPSC-pMCs, however, it did impart good viability to iPSC-pMCs. The resultant cells induced GM-CSF-dependent CD8+ T cell homeostatic proliferation, thereby enhancing antigen-specific T cell priming in vitro. Administration of the tumor antigen-loaded GM-CSF-producing iPSC-pMCs (GM-pMCs) efficiently stimulated antigen-specific T cells and promoted effector cell infiltration of the tumor tissues, leading to an augmented antitumor effect. To address the potential tumorigenicity of iPSC-derived products, irradiation was applied and found to restrict the proliferation of GM-pMCs, while retaining their T cell-stimulatory capacity. Furthermore, the irradiated cells exerted an antitumor effect equivalent to that of bone marrow-derived DCs obtained from immunocompetent mice. Additionally, combination with immune checkpoint inhibitors increased the infiltration of CD8+ or NK1.1+ effector cells and decreased CD11b+/Gr-1+ cells without causing adverse effects. Hence, although GM-pMCs have certain characteristics that differ from endogenous DCs, our findings suggest the applicability of these cells for broad clinical use and will provide an unlimited source of APCs with uniform quality.
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Affiliation(s)
- Hiroaki Mashima
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan.,Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
| | - Rong Zhang
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan
| | - Tsuyoshi Kobayashi
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
| | - Yuichiro Hagiya
- Biochemistry Team, Bio Science Division, Technology General Division, Materials Integration Laboratories, AGC Inc., Yokohama, Japan
| | - Hirotake Tsukamoto
- Department of Immunology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Tianyi Liu
- Key Laboratory of Cancer Center, Chinese PLA General Hospital, Beijing, China
| | - Tatsuaki Iwama
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan
| | - Masateru Yamamoto
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan.,Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
| | - Chiahsuan Lin
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan
| | - Ryusuke Nakatsuka
- Department of Stem Cell Biology and Regenerative Medicine, Graduate School of Medical Science, Kansai Medical University, Hirakata, Japan
| | - Yuta Mishima
- Shin Kaneko Laboratory, Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application (Cira), Kyoto University, Kyoto, Japan
| | - Noriko Watanabe
- Research & Early Development, Brightpath Biotherapeutics Co., Ltd., Kawasaki, Japan
| | - Takashi Yamada
- Research & Early Development, Brightpath Biotherapeutics Co., Ltd., Kawasaki, Japan
| | - Satoru Senju
- Department of Immunogenetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Shin Kaneko
- Shin Kaneko Laboratory, Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application (Cira), Kyoto University, Kyoto, Japan
| | - Alimjan Idiris
- Biochemistry Team, Bio Science Division, Technology General Division, Materials Integration Laboratories, AGC Inc., Yokohama, Japan
| | - Tetsuya Nakatsura
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan
| | - Hideki Ohdan
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
| | - Yasushi Uemura
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan
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22
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Branscome H, Paul S, Yin D, El-Hage N, Agbottah ET, Zadeh MA, Liotta LA, Kashanchi F. Use of Stem Cell Extracellular Vesicles as a "Holistic" Approach to CNS Repair. Front Cell Dev Biol 2020; 8:455. [PMID: 32587858 PMCID: PMC7298153 DOI: 10.3389/fcell.2020.00455] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Accepted: 05/15/2020] [Indexed: 12/20/2022] Open
Abstract
Neurodegeneration is a hallmark of many diseases and disorders of the central nervous system (CNS). High levels of neuroinflammation are often associated with irreparable damage to CNS cells due to the dysregulation of signaling cascades that are unable to restore a homeostatic balance. Due to the inherent complexity of the CNS, development of CNS-related therapeutics has met limited success. While stem cell therapy has been evaluated in the context of CNS repair, the mechanisms responsible for their functional properties have not been clearly defined. In recent years, there has been growing interest in the use of stem cell extracellular vesicles (EVs) for the treatment of various CNS pathologies as these vesicles are believed to mediate many of the functional effects associated with their donor stem cells. The potency of stem cell EVs is believed to be largely driven by their biological cargo which includes various types of RNAs, proteins, and cytokines. In this review, we describe the characteristic properties of stem cell EVs and summarize their reported neuroprotective and immunomodulatory functions. A special emphasis is placed on the identification of specific biological cargo, including proteins and non-coding RNA molecules, that have been found to be associated with stem cell EVs. Collectively, this review highlights the potential of stem cell EVs as an alternative to traditional stem cell therapy for the repair of cellular damage associated with diverse CNS pathologies.
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Affiliation(s)
- Heather Branscome
- Laboratory of Molecular Virology, School of Systems Biology, George Mason University, Manassas, VA, United States
- American Type Culture Collection (ATCC), Manassas, VA, United States
| | - Siddhartha Paul
- American Type Culture Collection (ATCC) Cell Systems, Gaithersburg, MD, United States
| | - Dezhong Yin
- American Type Culture Collection (ATCC) Cell Systems, Gaithersburg, MD, United States
| | - Nazira El-Hage
- Department of Immunology and Nano-Medicine, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, United States
| | - Emmanuel T. Agbottah
- Laboratory of Molecular Virology, School of Systems Biology, George Mason University, Manassas, VA, United States
| | - Mohammad Asad Zadeh
- Laboratory of Molecular Virology, School of Systems Biology, George Mason University, Manassas, VA, United States
| | - Lance A. Liotta
- Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA, United States
| | - Fatah Kashanchi
- Laboratory of Molecular Virology, School of Systems Biology, George Mason University, Manassas, VA, United States
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23
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Seetharaman R, Mahmood A, Kshatriya P, Patel D, Srivastava A. An Overview on Stem Cells in Tissue Regeneration. Curr Pharm Des 2020; 25:2086-2098. [PMID: 31298159 DOI: 10.2174/1381612825666190705211705] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Accepted: 06/19/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND Deteriorations in tissues and decline in organ functions, due to chronic diseases or with advancing age or sometimes due to infections or injuries, can severely compromise the quality of life of an individual. Regenerative medicine, a field of medical research focuses on replacing non-functional or dead cells or repairing or regenerating tissues and organs to restore normal functions of an impaired organ. Approaches used in regenerative therapy for achieving the objective employ a number of means which include soluble biomolecules, stem cell transplants, tissue engineering, gene therapy and reprogramming of cells according to target tissue types. Stem cells transplant and tissue regeneration methods for treating various diseases have rapidly grown in usage over the past decades or so. There are different types of stem cells such as mesenchymal, hematopoietic, embryonic, mammary, intestinal, endothelial, neural, olfactory, neural crest, testicular and induced pluripotent stem cells. METHODS This review covers the recent advances in tissue regeneration and highlights the application of stem cell transplants in treating many life-threatening diseases or in improving quality of life. RESULTS Remarkable progress in stem cell research has established that the cell-based therapy could be an option for treating diseases which could not be cured by conventional medical means till recent. Stem cells play major roles in regenerative medicine with its exceptional characteristics of self-renewal capacity and potential to differentiate into almost all types of cells of a body. CONCLUSION Vast number of reports on preclinical and clinical application of stem cells revealed its vital role in disease management and many pharmacological industries around the globe working to achieve effective stem cell based products.
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Affiliation(s)
| | | | | | | | - Anand Srivastava
- Global Institute of Stem Cell Therapy and Research, 4660 La Jolla Village Drive, San Diego, CA 92122, United States
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24
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Kim K, Abdal Dayem A, Gil M, Yang GM, Lee SB, Kwon OH, Choi S, Kang GH, Lim KM, Kim D, Cho SG. 3,2'-Dihydroxyflavone Improves the Proliferation and Survival of Human Pluripotent Stem Cells and Their Differentiation into Hematopoietic Progenitor Cells. J Clin Med 2020; 9:jcm9030669. [PMID: 32131506 PMCID: PMC7141312 DOI: 10.3390/jcm9030669] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Revised: 02/23/2020] [Accepted: 02/25/2020] [Indexed: 01/14/2023] Open
Abstract
Efficient maintenance of the undifferentiated status of human pluripotent stem cells (hiPSCs) is crucial for producing cells with improved proliferation, survival and differentiation, which can be successfully used for stem cell research and therapy. Here, we generated iPSCs from healthy donor peripheral blood mononuclear cells (PBMCs) and analyzed the proliferation and differentiation capacities of the generated iPSCs using single cell NGS-based 24-chromosome aneuploidy screening and RNA sequencing. In addition, we screened various natural compounds for molecules that could enhance the proliferation and differentiation potential of hiPSCs. Among the tested compounds, 3,2′-dihydroxyflavone (3,2′-DHF) significantly increased cell proliferation and expression of naïve stemness markers and decreased the dissociation-induced apoptosis of hiPSCs. Of note, 3,2′-DHF-treated hiPSCs showed upregulation of intracellular glutathione (GSH) and an increase in the percentage of GSH-high cells in an analysis with a FreSHtracer system. Interestingly, culture of the 3,2′-DHF-treated hiPSCs in differentiation media enhanced their mesodermal differentiation and differentiation into CD34+ CD45+ hematopoietic progenitor cells (HPC) and natural killer cells (NK) cells. Taken together, our results demonstrate that the natural compound 3,2′-DHF can improve the proliferation and differentiation capacities of hiPSCs and increase the efficiency of HPC and NK cell production from hiPSCs.
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Affiliation(s)
- Kyeongseok Kim
- Department of Stem Cell & Regenerative Biotechnology and Incurable Disease Animal Model and Stem Cell Institute (IDASI), Konkuk University, Seoul 05029, Korea; (K.K.); (A.A.D.); (M.G.); (G.-M.Y.); (S.B.L.); (S.C.); (G.-H.K.); (K.M.L.)
| | - Ahmed Abdal Dayem
- Department of Stem Cell & Regenerative Biotechnology and Incurable Disease Animal Model and Stem Cell Institute (IDASI), Konkuk University, Seoul 05029, Korea; (K.K.); (A.A.D.); (M.G.); (G.-M.Y.); (S.B.L.); (S.C.); (G.-H.K.); (K.M.L.)
| | - Minchan Gil
- Department of Stem Cell & Regenerative Biotechnology and Incurable Disease Animal Model and Stem Cell Institute (IDASI), Konkuk University, Seoul 05029, Korea; (K.K.); (A.A.D.); (M.G.); (G.-M.Y.); (S.B.L.); (S.C.); (G.-H.K.); (K.M.L.)
| | - Gwang-Mo Yang
- Department of Stem Cell & Regenerative Biotechnology and Incurable Disease Animal Model and Stem Cell Institute (IDASI), Konkuk University, Seoul 05029, Korea; (K.K.); (A.A.D.); (M.G.); (G.-M.Y.); (S.B.L.); (S.C.); (G.-H.K.); (K.M.L.)
| | - Soo Bin Lee
- Department of Stem Cell & Regenerative Biotechnology and Incurable Disease Animal Model and Stem Cell Institute (IDASI), Konkuk University, Seoul 05029, Korea; (K.K.); (A.A.D.); (M.G.); (G.-M.Y.); (S.B.L.); (S.C.); (G.-H.K.); (K.M.L.)
| | - Oh-Hyung Kwon
- Bio-Medical Science (BMS) Co., Ltd., Gimpo 10136, Korea; (O.-H.K.)
| | - Sangbaek Choi
- Department of Stem Cell & Regenerative Biotechnology and Incurable Disease Animal Model and Stem Cell Institute (IDASI), Konkuk University, Seoul 05029, Korea; (K.K.); (A.A.D.); (M.G.); (G.-M.Y.); (S.B.L.); (S.C.); (G.-H.K.); (K.M.L.)
| | - Geun-Ho Kang
- Department of Stem Cell & Regenerative Biotechnology and Incurable Disease Animal Model and Stem Cell Institute (IDASI), Konkuk University, Seoul 05029, Korea; (K.K.); (A.A.D.); (M.G.); (G.-M.Y.); (S.B.L.); (S.C.); (G.-H.K.); (K.M.L.)
| | - Kyung Min Lim
- Department of Stem Cell & Regenerative Biotechnology and Incurable Disease Animal Model and Stem Cell Institute (IDASI), Konkuk University, Seoul 05029, Korea; (K.K.); (A.A.D.); (M.G.); (G.-M.Y.); (S.B.L.); (S.C.); (G.-H.K.); (K.M.L.)
| | - Dongho Kim
- Bio-Medical Science (BMS) Co., Ltd., Gimpo 10136, Korea; (O.-H.K.)
| | - Ssang-Goo Cho
- Department of Stem Cell & Regenerative Biotechnology and Incurable Disease Animal Model and Stem Cell Institute (IDASI), Konkuk University, Seoul 05029, Korea; (K.K.); (A.A.D.); (M.G.); (G.-M.Y.); (S.B.L.); (S.C.); (G.-H.K.); (K.M.L.)
- Correspondence: ; Tel.: +82-2-450-4207
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25
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Li R, Hornberger K, Dutton JR, Hubel A. Cryopreservation of Human iPS Cell Aggregates in a DMSO-Free Solution-An Optimization and Comparative Study. Front Bioeng Biotechnol 2020; 8:1. [PMID: 32039188 PMCID: PMC6987262 DOI: 10.3389/fbioe.2020.00001] [Citation(s) in RCA: 150] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2019] [Accepted: 01/03/2020] [Indexed: 01/28/2023] Open
Abstract
Human induced pluripotent stem cells (hiPSCs) are an important cell source for regenerative medicine products. Effective methods of preservation are critical to their clinical and commercial applications. The use of a dimethyl sulfoxide (DMSO)-free solution containing all non-toxic molecules offers an effective alternative to the conventional DMSO and alleviates pain points associated with the use of DMSO in the cryopreservation of hiPSCs. Both hiPSCs and cells differentiated from them are commonly multicellular systems, which are more sensitive to stresses of freezing and thawing than single cells. In this investigation, low-temperature Raman spectroscopy visualized freezing behaviors of hiPSC aggregates in different solutions. These aggregates exhibited sensitivity to undercooling in DMSO-containing solutions. We demonstrated the ability to replace DMSO with non-toxic molecules, improve post-thaw cell survival, and reduce sensitivity to undercooling. An accelerated optimization process capitalized on the positive synergy among multiple DMSO-free molecules, which acted in concert to influence ice formation and protect cells during freezing and thawing. A differential evolution algorithm was used to optimize the multi-variable, DMSO-free preservation protocol in 8 experiments. hiPSC aggregates frozen in the optimized solution did not exhibit the same sensitivity to undercooling as those frozen in non-optimized solutions or DMSO, indicating superior adaptability of the optimized solution to different freezing modalities and unplanned deviations. This investigation shows the importance of optimization, explains the mechanisms and advantages of a DMSO-free solution, and enables not only improved cryopreservation of hiPSCs but potentially other cell types for translational regenerative medicine.
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Affiliation(s)
- Rui Li
- Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN, United States
| | - Kathlyn Hornberger
- Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN, United States
| | - James R. Dutton
- Stem Cell Institute, University of Minnesota, Minneapolis, MN, United States
- Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN, United States
| | - Allison Hubel
- Stem Cell Institute, University of Minnesota, Minneapolis, MN, United States
- Department of Mechanical Engineering, University of Minnesota, Minneapolis, MN, United States
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26
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Cota P, Helmi SA, Hsu C, Rancourt DE. Cytokine Directed Chondroblast Trans-Differentiation: JAK Inhibition Facilitates Direct Reprogramming of Fibroblasts to Chondroblasts. Cells 2020; 9:cells9010191. [PMID: 31940860 PMCID: PMC7017373 DOI: 10.3390/cells9010191] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Revised: 01/08/2020] [Accepted: 01/09/2020] [Indexed: 12/14/2022] Open
Abstract
Osteoarthritis (OA) is a degenerative disease of the hyaline articular cartilage. This disease is progressive and may lead to disability. Researchers proposed many regenerative approaches to treat osteoarthritis, including stem cells. Trans-differentiation of a fully differentiated cell state directly into another different differentiated cell state avoids the disadvantages of fully reprogramming cells to induced pluripotent stem cells (iPSCs) in terms of faster reprogramming of the needed cells. Trans-differentiation also reduces the risk of tumor formation by avoiding the iPSC state. OSKM factors (Oct4, Sox2, Klf4, and cMyc) accompanied by the JAK-STAT pathway inhibition, followed by the introduction of specific differentiation factors, directly reprogrammed mouse embryonic fibroblasts to chondroblasts. Our results showed the absence of intermediate induced pluripotent stem cell formation. The resulting aggregates showed clear hyaline and hypertrophic cartilage. Tumor formation was absent in sub-cutaneous capsules transplanted in SCID mice.
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Affiliation(s)
- Perla Cota
- Department of Biochemistry and Molecular Biology, University of Calgary, 3330 Hospital Dr. NW, Calgary, AB T2N 1N4, Canada; (P.C.); (S.A.H.); (C.H.)
- Institute of Diabetes and Regeneration Research, Helmholtz Zentrum München, German Research Center for Health and Environment, 85764 Neuherberg, Germany
| | - Summer A. Helmi
- Department of Biochemistry and Molecular Biology, University of Calgary, 3330 Hospital Dr. NW, Calgary, AB T2N 1N4, Canada; (P.C.); (S.A.H.); (C.H.)
- Department of Oral Biology, Faculty of Dentistry, Mansoura University, Mansoura 35516, Egypt
| | - Charlie Hsu
- Department of Biochemistry and Molecular Biology, University of Calgary, 3330 Hospital Dr. NW, Calgary, AB T2N 1N4, Canada; (P.C.); (S.A.H.); (C.H.)
- Faculty of Medicine University of Queensland. 20 Weightman St, Herston 4006, QLD, Australia
| | - Derrick E. Rancourt
- Department of Biochemistry and Molecular Biology, University of Calgary, 3330 Hospital Dr. NW, Calgary, AB T2N 1N4, Canada; (P.C.); (S.A.H.); (C.H.)
- Correspondence: ; Tel.: +1-403-220-2888
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27
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Racanelli AC, Ding BS. Manmade Macrophage Offers a New Therapy for Pulmonary Alveolar Proteinosis. Am J Respir Crit Care Med 2019; 198:297-298. [PMID: 29669215 DOI: 10.1164/rccm.201803-0478ed] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Affiliation(s)
- Alexandra C Racanelli
- 1 Division of Pulmonary and Critical Care Medicine Weill Cornell Medical College New York, New York.,2 New York-Presbyterian Hospital New York, New York and
| | - Bi-Sen Ding
- 3 Ansary Stem Cell Institute Weill Cornell Medicine New York, New York
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28
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Zhavoronkov A, Mamoshina P, Vanhaelen Q, Scheibye-Knudsen M, Moskalev A, Aliper A. Artificial intelligence for aging and longevity research: Recent advances and perspectives. Ageing Res Rev 2019; 49:49-66. [PMID: 30472217 DOI: 10.1016/j.arr.2018.11.003] [Citation(s) in RCA: 98] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2018] [Revised: 11/07/2018] [Accepted: 11/21/2018] [Indexed: 12/14/2022]
Abstract
The applications of modern artificial intelligence (AI) algorithms within the field of aging research offer tremendous opportunities. Aging is an almost universal unifying feature possessed by all living organisms, tissues, and cells. Modern deep learning techniques used to develop age predictors offer new possibilities for formerly incompatible dynamic and static data types. AI biomarkers of aging enable a holistic view of biological processes and allow for novel methods for building causal models-extracting the most important features and identifying biological targets and mechanisms. Recent developments in generative adversarial networks (GANs) and reinforcement learning (RL) permit the generation of diverse synthetic molecular and patient data, identification of novel biological targets, and generation of novel molecular compounds with desired properties and geroprotectors. These novel techniques can be combined into a unified, seamless end-to-end biomarker development, target identification, drug discovery and real world evidence pipeline that may help accelerate and improve pharmaceutical research and development practices. Modern AI is therefore expected to contribute to the credibility and prominence of longevity biotechnology in the healthcare and pharmaceutical industry, and to the convergence of countless areas of research.
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29
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Guo ZH, Zhang W, Jia YYS, Liu QX, Li ZF, Lin JS. An Insight into the Difficulties in the Discovery of Specific Biomarkers of Limbal Stem Cells. Int J Mol Sci 2018; 19:ijms19071982. [PMID: 29986467 PMCID: PMC6073450 DOI: 10.3390/ijms19071982] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2018] [Revised: 06/25/2018] [Accepted: 06/29/2018] [Indexed: 12/13/2022] Open
Abstract
Keeping the integrity and transparency of the cornea is the most important issue to ensure normal vision. There are more than 10 million patients going blind due to the cornea diseases worldwide. One of the effective ways to cure corneal diseases is corneal transplantation. Currently, donations are the main source of corneas for transplantation, but immune rejection and a shortage of donor corneas are still serious problems. Graft rejection could cause transplanted cornea opacity to fail. Therefore, bioengineer-based corneas become a new source for corneal transplantation. Limbal stem cells (LSCs) are located at the basal layer in the epithelial palisades of Vogt, which serve a homeostatic function for the cornea epithelium and repair the damaged cornea. LSC-based transplantation is one of the hot topics currently. Clinical data showed that the ratio of LSCs to total candidate cells for a transplantation has a significant impact on the effectiveness of the transplantation. It indicates that it is very important to accurately identify the LSCs. To date, several putative biomarkers of LSCs have been widely reported, whereas their specificity is controversial. As reported, the identification of LSCs is based on the characteristics of stem cells, such as a nuclear-to-cytoplasm ratio (N/C) ≥ 0.7, label-retaining, and side population (SP) phenotype. Here, we review recently published data to provide an insight into the circumstances in the study of LSC biomarkers. The particularities of limbus anatomy and histochemistry, the limits of the current technology level for LSC isolation, the heterogeneity of LSCs and the influence of enzyme digestion are discussed. Practical approaches are proposed in order to overcome the difficulties in basic and applied research for LSC-specific biomarkers.
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Affiliation(s)
- Zhi Hou Guo
- School of Medicine, Huaqiao University, Quanzhou 362021, China.
| | - Wei Zhang
- School of Medicine, Huaqiao University, Quanzhou 362021, China.
| | | | - Qing Xiu Liu
- School of Medicine, Huaqiao University, Quanzhou 362021, China.
| | - Zhao Fa Li
- School of Medicine, Huaqiao University, Quanzhou 362021, China.
| | - Jun Sheng Lin
- School of Medicine, Huaqiao University, Quanzhou 362021, China.
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30
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Ovadia EM, Colby DW, Kloxin AM. Designing well-defined photopolymerized synthetic matrices for three-dimensional culture and differentiation of induced pluripotent stem cells. Biomater Sci 2018; 6:1358-1370. [PMID: 29675520 PMCID: PMC6126667 DOI: 10.1039/c8bm00099a] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Induced pluripotent stem cells (iPSCs) are of interest for the study of disease, where these cells can be derived from patients and have the potential to be differentiated into any cell type; however, three-dimensional (3D) culture and differentiation of iPSCs within well-defined synthetic matrices for these applications remains limited. Here, we aimed to establish synthetic cell-degradable hydrogels that allow precise presentation of specific biochemical cues for 3D culture of iPSCs with relevance for hypothesis testing and lineage-specific differentiation. We synthesized poly(ethylene glycol)-(PEG)-peptide-based hydrogels by photoinitiated step growth polymerization and used them to test the hypothesis that the viability of iPSCs within these matrices could be rescued with appropriate biochemical cues inspired by proteins and integrins important for iPSC culture on Matrigel. Specifically, we selected a range of motifs inspired by iPSC binding to Matrigel, including laminin-derived IKVAV and YIGSR, α5β1-binding PHSRNG10RGDS, αvβ5-binding KKQRFRHRNRKG, and RGDS that is known to bind a variety of integrins for generally promoting cell adhesion. YIGSR and PHSRNG10RGDS resulted in the highest iPSC viability, where binding of β1 integrin was key, and these permissive compositions also allowed iPSC differentiation into neural progenitor cells (NPCs) (decreased oct4 expression and increased pax6 expression) in response to soluble factors. The resulting NPCs formed clusters of different sizes in response to each peptide, suggesting that matrix biochemical cues affect iPSC proliferation and clustering in 3D culture. In summary, we have established photopolymerizable synthetic matrices for the encapsulation, culture, and differentiation of iPSCs for studies of cell-matrix interactions and deployment in disease models.
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Affiliation(s)
- Elisa M Ovadia
- Department of Chemical and Biomolecular Engineering, University of Delaware, Newark, DE 19716, USA.
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31
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Jakovljevic J, Harrell CR, Fellabaum C, Arsenijevic A, Jovicic N, Volarevic V. Modulation of autophagy as new approach in mesenchymal stem cell-based therapy. Biomed Pharmacother 2018; 104:404-410. [PMID: 29787987 DOI: 10.1016/j.biopha.2018.05.061] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2018] [Revised: 05/08/2018] [Accepted: 05/14/2018] [Indexed: 02/07/2023] Open
Abstract
Due to their trophic and immunoregulatory characteristics mesenchymal stem cells (MSCs) have tremendous potential for use in a variety of clinical applications. Challenges in MSCs' clinical applications include low survival of transplanted cells and low grafting efficiency requiring use of a high number of MSCs to achieve therapeutic benefits. Accordingly, new approaches are urgently needed in order to overcome these limitations. Recent evidence indicates that modulation of autophagy in MSCs prior to their transplantation enhances survival and viability of engrafted MSCs and promotes their pro-angiogenic and immunomodulatory characteristics. Here, we review the current literature describing mechanisms by which modulation of autophagy strengthens pro-angiogenic and immunosuppressive characteristics of MSCs in animal models of multiple sclerosis, osteoporosis, diabetic limb ischemia, myocardial infarction, acute graft-versus-host disease, kidney and liver diseases. Obtained results suggest that modulation of autophagy in MSCs may represent a new therapeutic approach that could enhance efficacy of MSCs in the treatment of ischemic and autoimmune diseases.
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Affiliation(s)
- Jelena Jakovljevic
- University of Kragujevac Serbia, Faculty of Medical Sciences, Department of Microbiology and immunology, Center for Molecular Medicine and Stem Cell Research, 69 Svetozar Markovic Street, 34000, Kragujevac, Serbia
| | - C Randall Harrell
- Regenerative Processing Plant, LLC, 34176 US Highway 19 N Palm Harbor, Palm Harbor, Florida, United States
| | - Crissy Fellabaum
- Regenerative Processing Plant, LLC, 34176 US Highway 19 N Palm Harbor, Palm Harbor, Florida, United States
| | - Aleksandar Arsenijevic
- University of Kragujevac Serbia, Faculty of Medical Sciences, Department of Microbiology and immunology, Center for Molecular Medicine and Stem Cell Research, 69 Svetozar Markovic Street, 34000, Kragujevac, Serbia
| | - Nemanja Jovicic
- University of Kragujevac Serbia, Faculty of Medical Sciences, Department of Microbiology and immunology, Center for Molecular Medicine and Stem Cell Research, 69 Svetozar Markovic Street, 34000, Kragujevac, Serbia
| | - Vladislav Volarevic
- University of Kragujevac Serbia, Faculty of Medical Sciences, Department of Microbiology and immunology, Center for Molecular Medicine and Stem Cell Research, 69 Svetozar Markovic Street, 34000, Kragujevac, Serbia.
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Centeno EGZ, Cimarosti H, Bithell A. 2D versus 3D human induced pluripotent stem cell-derived cultures for neurodegenerative disease modelling. Mol Neurodegener 2018; 13:27. [PMID: 29788997 PMCID: PMC5964712 DOI: 10.1186/s13024-018-0258-4] [Citation(s) in RCA: 160] [Impact Index Per Article: 22.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2017] [Accepted: 05/08/2018] [Indexed: 12/11/2022] Open
Abstract
Neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS), affect millions of people every year and so far, there are no therapeutic cures available. Even though animal and histological models have been of great aid in understanding disease mechanisms and identifying possible therapeutic strategies, in order to find disease-modifying solutions there is still a critical need for systems that can provide more predictive and physiologically relevant results. One possible avenue is the development of patient-derived models, e.g. by reprogramming patient somatic cells into human induced pluripotent stem cells (hiPSCs), which can then be differentiated into any cell type for modelling. These systems contain key genetic information from the donors, and therefore have enormous potential as tools in the investigation of pathological mechanisms underlying disease phenotype, and progression, as well as in drug testing platforms. hiPSCs have been widely cultured in 2D systems, but in order to mimic human brain complexity, 3D models have been proposed as a more advanced alternative. This review will focus on the use of patient-derived hiPSCs to model AD, PD, HD and ALS. In brief, we will cover the available stem cells, types of 2D and 3D culture systems, existing models for neurodegenerative diseases, obstacles to model these diseases in vitro, and current perspectives in the field.
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Affiliation(s)
- Eduarda G Z Centeno
- Department of Biotechnology, Federal University of Pelotas, Campus Capão do Leão, Pelotas, RS, 96160-000, Brazil.,Department of Pharmacology, Federal University of Santa Catarina, Campus Trindade, Florianópolis, SC, 88040-900, Brazil
| | - Helena Cimarosti
- Department of Pharmacology, Federal University of Santa Catarina, Campus Trindade, Florianópolis, SC, 88040-900, Brazil.
| | - Angela Bithell
- School of Pharmacy, University of Reading, Whiteknights Campus, Reading, RG6 6UB, UK.
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Katiyar KS, Winter CC, Gordián-Vélez WJ, O'Donnell JC, Song YJ, Hernandez NS, Struzyna LA, Cullen DK. Three-dimensional Tissue Engineered Aligned Astrocyte Networks to Recapitulate Developmental Mechanisms and Facilitate Nervous System Regeneration. J Vis Exp 2018. [PMID: 29364269 DOI: 10.3791/55848] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
Abstract
Neurotrauma and neurodegenerative disease often result in lasting neurological deficits due to the limited capacity of the central nervous system (CNS) to replace lost neurons and regenerate axonal pathways. However, during nervous system development, neuronal migration and axonal extension often occur along pathways formed by other cells, referred to as "living scaffolds". Seeking to emulate these mechanisms and to design a strategy that circumvents the inhibitory environment of the CNS, this manuscript presents a protocol to fabricate tissue engineered astrocyte-based "living scaffolds". To create these constructs, we employed a novel biomaterial encasement scheme to induce astrocytes to self-assemble into dense three-dimensional bundles of bipolar longitudinally-aligned somata and processes. First, hollow hydrogel micro-columns were assembled, and the inner lumen was coated with collagen extracellular-matrix. Dissociated cerebral cortical astrocytes were then delivered into the lumen of the cylindrical micro-column and, at a critical inner diameter of <350 µm, spontaneously self-aligned and contracted to produce long fiber-like cables consisting of dense bundles of astrocyte processes and collagen fibrils measuring <150 µm in diameter yet extending several cm in length. These engineered living scaffolds exhibited >97% cell viability and were virtually exclusively comprised of astrocytes expressing a combination of the intermediate filament proteins glial-fibrillary acidic protein (GFAP), vimentin, and nestin. These aligned astrocyte networks were found to provide a permissive substrate for neuronal attachment and aligned neurite extension. Moreover, these constructs maintain integrity and alignment when extracted from the hydrogel encasement, making them suitable for CNS implantation. These preformed constructs structurally emulate key cytoarchitectural elements of naturally occurring glial-based "living scaffolds" in vivo. As such, these engineered living scaffolds may serve as test-beds to study neurodevelopmental mechanisms in vitro or facilitate neuroregeneration by directing neuronal migration and/or axonal pathfinding following CNS degeneration in vivo.
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Affiliation(s)
- Kritika S Katiyar
- Center for Brain Injury & Repair, Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania; Center for Neurotrauma, Neurodegeneration & Restoration, Michael J. Crescenz Veterans Affairs Medical Center; School of Biomedical Engineering, Drexel University
| | - Carla C Winter
- Center for Brain Injury & Repair, Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania; Center for Neurotrauma, Neurodegeneration & Restoration, Michael J. Crescenz Veterans Affairs Medical Center; Department of Bioengineering, School of Engineering and Applied Sciences, University of Pennsylvania
| | - Wisberty J Gordián-Vélez
- Center for Brain Injury & Repair, Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania; Center for Neurotrauma, Neurodegeneration & Restoration, Michael J. Crescenz Veterans Affairs Medical Center; Department of Bioengineering, School of Engineering and Applied Sciences, University of Pennsylvania
| | - John C O'Donnell
- Center for Brain Injury & Repair, Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania; Center for Neurotrauma, Neurodegeneration & Restoration, Michael J. Crescenz Veterans Affairs Medical Center
| | - Yeri J Song
- Center for Brain Injury & Repair, Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania; Neuroscience Graduate Group, Perelman School of Medicine, University of Pennsylvania
| | - Nicole S Hernandez
- Center for Brain Injury & Repair, Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania; Neuroscience Graduate Group, Perelman School of Medicine, University of Pennsylvania
| | - Laura A Struzyna
- Center for Brain Injury & Repair, Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania; Center for Neurotrauma, Neurodegeneration & Restoration, Michael J. Crescenz Veterans Affairs Medical Center; Department of Bioengineering, School of Engineering and Applied Sciences, University of Pennsylvania
| | - D Kacy Cullen
- Center for Brain Injury & Repair, Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania; Center for Neurotrauma, Neurodegeneration & Restoration, Michael J. Crescenz Veterans Affairs Medical Center; Neuroscience Graduate Group, Perelman School of Medicine, University of Pennsylvania;
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Gazdhar A, Ravikumar P, Pastor J, Heller M, Ye J, Zhang J, Moe OW, Geiser T, Hsia CCW. Alpha-Klotho Enrichment in Induced Pluripotent Stem Cell Secretome Contributes to Antioxidative Protection in Acute Lung Injury. Stem Cells 2017; 36:616-625. [PMID: 29226550 DOI: 10.1002/stem.2752] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2017] [Revised: 11/07/2017] [Accepted: 11/21/2017] [Indexed: 02/06/2023]
Abstract
Induced pluripotent stem cells (iPSCs) have been reported to alleviate organ injury, although the mechanisms of action remain unclear and administration of intact cells faces many limitations. We hypothesized that cell-free conditioned media (CM) containing the secretome of iPSCs possess antioxidative constituents that can alleviate pulmonary oxidant stress damage. We derived iPSCs from human dermal fibroblasts and harvested the CM. Addition of iPSC CM to cultured human alveolar type-1 epithelial cells mitigated hyperoxia-induced depletion of endogenous total antioxidant capacity while tracheal instillation of iPSC CM into adult rat lungs enhanced hyperoxia-induced increase in TAC. In both the in vitro and in vivo models, iPSC CM ameliorated oxidative damage to DNA, lipid, and protein, and activated the nuclear factor (erythroid 2)-related factor 2 (Nrf2) network of endogenous antioxidant proteins. Compared with control fibroblast-conditioned or cell-free media, iPSC CM is highly enriched with αKlotho at a concentration up to more than 10-fold of that in normal serum. αKlotho is an essential antioxidative cell maintenance and protective factor and an activator of the Nrf2 network. Immunodepletion of αKlotho reduced iPSC CM-mediated cytoprotection by ∼50%. Thus, the abundant αKlotho content significantly contributes to iPSC-mediated antioxidation and cytoprotection. Results uncover a major mechanism of iPSC action, suggest a fundamental role of αKlotho in iPSC maintenance, and support the translational potential of airway delivery of cell-free iPSC secretome for protection against lung injury. The targeted cell-free secretome-based approach may also be applicable to the amelioration of injury in other organs. Stem Cells 2018;36:616-625.
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Affiliation(s)
- Amiq Gazdhar
- Department of Pulmonary Medicine, University Hospital, Bern, Switzerland.,Department of Clinical Research, University Hospital, Bern, Switzerland
| | - Priya Ravikumar
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.,Charles and Jane Pak Center of Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Johanne Pastor
- Charles and Jane Pak Center of Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Manfred Heller
- Department of Clinical Research, University Hospital, Bern, Switzerland
| | - Jianfeng Ye
- Charles and Jane Pak Center of Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Jianning Zhang
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.,Charles and Jane Pak Center of Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Orson W Moe
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.,Charles and Jane Pak Center of Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, Texas, USA.,Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Thomas Geiser
- Department of Pulmonary Medicine, University Hospital, Bern, Switzerland.,Department of Clinical Research, University Hospital, Bern, Switzerland
| | - Connie C W Hsia
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
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35
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Berezin AE. New Trends in Stem Cell Transplantation in Diabetes Mellitus Type I and Type II. ACTA ACUST UNITED AC 2017. [DOI: 10.1007/978-3-319-55687-1_3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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36
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Kuo YC, Rajesh R. Nerve growth factor-loaded heparinized cationic solid lipid nanoparticles for regulating membrane charge of induced pluripotent stem cells during differentiation. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2017; 77:680-689. [PMID: 28532079 DOI: 10.1016/j.msec.2017.03.303] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/19/2017] [Revised: 03/27/2017] [Accepted: 03/31/2017] [Indexed: 01/12/2023]
Abstract
Nerve growth factor (NGF)-loaded heparinized cationic solid lipid nanoparticles (NGF-loaded HCSLNs) were developed using heparin-stearic acid conjugate, cacao butter, cholesterol, stearylamine (SA), and esterquat 1 (EQ 1). The effect of cationic lipids and lipid matrix composition on the particle size, particle structure, surface molecular composition, chemical structure, electrophoretic mobility, and zeta potential of HCSLNs was investigated. The effect of HCSLNs on the membrane charge of induced pluripotent stem cells (iPSCs) was also studied. The results indicated that the average diameter of HCSLNs was 90-240nm and the particle size of HCSLNs with EQ 1 was smaller than that with SA. The zeta potential and electrophoresis analysis showed that HCSLNs with SA had a positively charged potential and HCSLNs with EQ 1 had a negatively charged potential at pH7.4. The high-resolution transmission electron microscope confirmed the loading of NGF on the surface of HCSLNs. Differentiation of iPSCs using NGF-loaded HCSLNs with EQ 1 exhibited higher absolute values of the electrophoretic mobility and zeta potential than differentiation using NGF-loaded HCSLNs with SA. The immunochemical staining of neuronal nuclei revealed that NGF-loaded HCSLNs can be used for differentiation of iPSCs into neurons. NGF-loaded HCSLNs with EQ 1 had higher viability of iPSCs than NGF-loaded HCSLNs with SA. NGF-loaded HCSLNs with EQ 1 may be promising formulation to regulate the membrane charge of iPSCs during neuronal differentiation.
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Affiliation(s)
- Yung-Chih Kuo
- Department of Chemical Engineering, National Chung Cheng University, Chia-Yi, Taiwan 62102, Republic of China.
| | - Rajendiran Rajesh
- Department of Chemical Engineering, National Chung Cheng University, Chia-Yi, Taiwan 62102, Republic of China
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37
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Hu ZQ. CMI: Highlights in last three years. Cell Mol Immunol 2016; 13:709-10. [PMID: 27569561 DOI: 10.1038/cmi.2016.44] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2016] [Accepted: 06/30/2016] [Indexed: 11/09/2022] Open
Affiliation(s)
- Zhi-Qing Hu
- Microbiology and Immunology, Showa University School of Medicine, Tokyo 142-8555, Japan
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38
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Mahla RS. Stem Cells Applications in Regenerative Medicine and Disease Therapeutics. Int J Cell Biol 2016; 2016:6940283. [PMID: 27516776 PMCID: PMC4969512 DOI: 10.1155/2016/6940283] [Citation(s) in RCA: 332] [Impact Index Per Article: 36.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2016] [Accepted: 06/05/2016] [Indexed: 12/18/2022] Open
Abstract
Regenerative medicine, the most recent and emerging branch of medical science, deals with functional restoration of tissues or organs for the patient suffering from severe injuries or chronic disease. The spectacular progress in the field of stem cell research has laid the foundation for cell based therapies of disease which cannot be cured by conventional medicines. The indefinite self-renewal and potential to differentiate into other types of cells represent stem cells as frontiers of regenerative medicine. The transdifferentiating potential of stem cells varies with source and according to that regenerative applications also change. Advancements in gene editing and tissue engineering technology have endorsed the ex vivo remodelling of stem cells grown into 3D organoids and tissue structures for personalized applications. This review outlines the most recent advancement in transplantation and tissue engineering technologies of ESCs, TSPSCs, MSCs, UCSCs, BMSCs, and iPSCs in regenerative medicine. Additionally, this review also discusses stem cells regenerative application in wildlife conservation.
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Affiliation(s)
- Ranjeet Singh Mahla
- Department of Biological Sciences, Indian Institute of Science Education and Research (IISER), Bhopal, Madhya Pradesh 462066, India
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Tang D, Chen Y, He H, Huang J, Chen W, Peng W, Lu Q, Dai Y. Integrated analysis of mRNA, microRNA and protein in systemic lupus erythematosus-specific induced pluripotent stem cells from urine. BMC Genomics 2016; 17:488. [PMID: 27402083 PMCID: PMC4940874 DOI: 10.1186/s12864-016-2809-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2015] [Accepted: 05/28/2016] [Indexed: 12/16/2022] Open
Abstract
Background In clinical practice, it is difficult to monitor the repeating relapse in patients who have been suffering from systemic lupus erythematosus (SLE). The underlying etiology remains largely unknown. Methods Aiming to understand the pathogenesis of SLE, a detailed study was conducted. Renal tubular cells–derived iPSCs were successfully obtained from the urine of SLE patients and healthy controls. With the purpose to identify simultaneous expression profiling of microRNA, mRNA and protein, Illumina HiSeq™ 2000 System and iTRAQ-coupled 2D LC-MS/MS analysis were utilized in systemic lupus erythematosus-specific induced pluripotent stem cells (SLE-iPSCs) and normal control-iPSCs (NC-iPSCs). The integration of multiple profiling datasets was realized since it could facilitate the identification of non-seed miRNA targets, as well as differentially expressed mRNAs and proteins. Results For this study, profiling datasets of 1099 differentially expressed mRNAs, 223 differentially expressed microRNAs and 94 differentially expressed proteins were integrated. In order to investigate the influence of miRNA on the processes of regulating mRNAs and proteins’ levels, potential targets of differentially expressed mRNAs and proteins were predicted using miRanda, TargetScan and Pictar. Multiple profiling datasets were integrated to facilitate the identification of miRNA targets, as well as differentially expressed mRNAs and proteins. Through gene ontology (GO) analysis of differentially expressed mRNAs and proteins, biological processes that drive proliferation were identified, such as mRNA processing and translation. Western blot and Q-PCR confirmed AK4 protein and mRNA up-regulation. The findings also showed that TAGLN’s protein and mRNA level were down-regulated in SLE-iPSCs, both miR-371a-5p and let-7a-5p in SLE-iPSC were down-regulated and verified using Q-PCR. The up-regulation of AK4 involved in nucleotide biosynthesis suggested a general acceleration of anabolic metabolism induced by down-regulated miR-371a-5p, which might contribute to SLE. Conclusion Based on high throughput analysis, integrated miRNA, mRNA, and protein expression data were generated. Differentially expressed dates were also adopted in conjunction with in-silico tools to identify potential candidates for SLE-iPSCs. Representative miRNA, mRNA and proteins were verified. It was also expected that the knowledge gained from this study can be applied to assess the usefulness of pathogenesis and novel biomarker candidates of SLE, which may develop a new way for SLE diagnosis. Electronic supplementary material The online version of this article (doi:10.1186/s12864-016-2809-9) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Donge Tang
- Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou, 510632, People's Republic of China
| | - Yuyu Chen
- Clinical Medical Research Center, The Second Clinical Medical College of Jinan University (Shenzhen People's Hospital), Shenzhen, Guangdong, 518020, People's Republic of China
| | - Huiyan He
- Clinical Medical Research Center, The Second Clinical Medical College of Jinan University (Shenzhen People's Hospital), Shenzhen, Guangdong, 518020, People's Republic of China
| | - Jianrong Huang
- Clinical Medical Research Center, The Second Clinical Medical College of Jinan University (Shenzhen People's Hospital), Shenzhen, Guangdong, 518020, People's Republic of China
| | - Wenbiao Chen
- Clinical Medical Research Center, The Second Clinical Medical College of Jinan University (Shenzhen People's Hospital), Shenzhen, Guangdong, 518020, People's Republic of China
| | - Wujian Peng
- Clinical Medical Research Center, The Second Clinical Medical College of Jinan University (Shenzhen People's Hospital), Shenzhen, Guangdong, 518020, People's Republic of China
| | - Qianjin Lu
- Department of Dermatology, Second Xiangya Hospital, Central South University, Hunan Key Laboratory of Medical Epigenomics, Changsha, Hunan, 410011, People's Republic of China
| | - Yong Dai
- Clinical Medical Research Center, The Second Clinical Medical College of Jinan University (Shenzhen People's Hospital), Shenzhen, Guangdong, 518020, People's Republic of China.
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Zhou H, Martinez H, Sun B, Li A, Zimmer M, Katsanis N, Davis EE, Kurtzberg J, Lipnick S, Noggle S, Rao M, Chang S. Rapid and Efficient Generation of Transgene-Free iPSC from a Small Volume of Cryopreserved Blood. Stem Cell Rev Rep 2016; 11:652-65. [PMID: 25951995 PMCID: PMC4493720 DOI: 10.1007/s12015-015-9586-8] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Human peripheral blood and umbilical cord blood represent attractive sources of cells for reprogramming to induced pluripotent stem cells (iPSCs). However, to date, most of the blood-derived iPSCs were generated using either integrating methods or starting from T-lymphocytes that have genomic rearrangements thus bearing uncertain consequences when using iPSC-derived lineages for disease modeling and cell therapies. Recently, both peripheral blood and cord blood cells have been reprogrammed into transgene-free iPSC using the Sendai viral vector. Here we demonstrate that peripheral blood can be utilized for medium-throughput iPSC production without the need to maintain cell culture prior to reprogramming induction. Cell reprogramming can also be accomplished with as little as 3000 previously cryopreserved cord blood cells under feeder-free and chemically defined Xeno-free conditions that are compliant with standard Good Manufacturing Practice (GMP) regulations. The first iPSC colonies appear 2–3 weeks faster in comparison to previous reports. Notably, these peripheral blood- and cord blood-derived iPSCs are free of detectable immunoglobulin heavy chain (IGH) and T cell receptor (TCR) gene rearrangements, suggesting they did not originate from B- or T- lymphoid cells. The iPSCs are pluripotent as evaluated by the scorecard assay and in vitro multi lineage functional cell differentiation. Our data show that small volumes of cryopreserved peripheral blood or cord blood cells can be reprogrammed efficiently at a convenient, cost effective and scalable way. In summary, our method expands the reprogramming potential of limited or archived samples either stored at blood banks or obtained from pediatric populations that cannot easily provide large quantities of peripheral blood or a skin biopsy.
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Affiliation(s)
- Hongyan Zhou
- The New York Stem Cell Foundation Research Institute, New York, NY, 10032, USA,
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Current Progress in Therapeutic Gene Editing for Monogenic Diseases. Mol Ther 2016; 24:465-74. [PMID: 26765770 DOI: 10.1038/mt.2016.5] [Citation(s) in RCA: 80] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2015] [Accepted: 12/29/2015] [Indexed: 02/06/2023] Open
Abstract
Programmable nucleases allow defined alterations in the genome with ease-of-use, efficiency, and specificity. Their availability has led to accurate and widespread genome engineering, with multiple applications in basic research, biotechnology, and therapy. With regard to human gene therapy, nuclease-based gene editing has facilitated development of a broad range of therapeutic strategies based on both nonhomologous end joining and homology-dependent repair. This review discusses current progress in nuclease-based therapeutic applications for a subset of inherited monogenic diseases including cystic fibrosis, Duchenne muscular dystrophy, diseases of the bone marrow, and hemophilia and highlights associated challenges and future prospects.
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42
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Ebrahimi B. Reprogramming barriers and enhancers: strategies to enhance the efficiency and kinetics of induced pluripotency. CELL REGENERATION (LONDON, ENGLAND) 2015; 4:10. [PMID: 26566431 PMCID: PMC4642739 DOI: 10.1186/s13619-015-0024-9] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/25/2015] [Accepted: 09/19/2015] [Indexed: 12/13/2022]
Abstract
Induced pluripotent stem cells are powerful tools for disease modeling, drug screening, and cell transplantation therapies. These cells can be generated directly from somatic cells by ectopic expression of defined factors through a reprogramming process. However, pluripotent reprogramming is an inefficient process because of various defined and unidentified barriers. Recent studies dissecting the molecular mechanisms of reprogramming have methodically improved the quality, ease, and efficiency of reprogramming. Different strategies have been applied for enhancing reprogramming efficiency, including depletion/inhibition of barriers (p53, p21, p57, p16(Ink4a)/p19(Arf), Mbd3, etc.), overexpression of enhancing genes (e.g., FOXH1, C/EBP alpha, UTF1, and GLIS1), and administration of certain cytokines and small molecules. The current review provides an in-depth overview of the cutting-edge findings regarding distinct barriers of reprogramming to pluripotency and strategies to enhance reprogramming efficiency. By incorporating the mechanistic insights from these recent findings, a combined method of inhibition of roadblocks and application of enhancing factors may yield the most reliable and effective approach in pluripotent reprogramming.
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Affiliation(s)
- Behnam Ebrahimi
- Yazd Cardiovascular Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
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43
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Roch T, Kratz K, Ma N, Lendlein A. Polymeric inserts differing in their chemical composition as substrates for dendritic cell cultivation. Clin Hemorheol Microcirc 2015; 61:347-57. [DOI: 10.3233/ch-152004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Affiliation(s)
- Toralf Roch
- Institute of Biomaterial Science and Berlin-Brandenburg Center for Regenerative Therapies, Helmholtz-Zentrum Geesthacht, Teltow, Germany
- Helmholtz Virtual Institute, “Multifunctional Biomaterials for Medicine”, Teltow, Germany
| | - Karl Kratz
- Institute of Biomaterial Science and Berlin-Brandenburg Center for Regenerative Therapies, Helmholtz-Zentrum Geesthacht, Teltow, Germany
- Helmholtz Virtual Institute, “Multifunctional Biomaterials for Medicine”, Teltow, Germany
| | - Nan Ma
- Institute of Biomaterial Science and Berlin-Brandenburg Center for Regenerative Therapies, Helmholtz-Zentrum Geesthacht, Teltow, Germany
- Institute of Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany
- Helmholtz Virtual Institute, “Multifunctional Biomaterials for Medicine”, Teltow, Germany
| | - Andreas Lendlein
- Institute of Biomaterial Science and Berlin-Brandenburg Center for Regenerative Therapies, Helmholtz-Zentrum Geesthacht, Teltow, Germany
- Institute of Chemistry, University of Potsdam, Potsdam, Germany
- Institute of Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany
- Helmholtz Virtual Institute, “Multifunctional Biomaterials for Medicine”, Teltow, Germany
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Wenker SD, Casalía M, Candedo VC, Casabona JC, Pitossi FJ. Cell reprogramming and neuronal differentiation applied to neurodegenerative diseases: Focus on Parkinson's disease. FEBS Lett 2015; 589:3396-406. [PMID: 26226418 DOI: 10.1016/j.febslet.2015.07.023] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2015] [Revised: 07/20/2015] [Accepted: 07/21/2015] [Indexed: 12/11/2022]
Abstract
Adult cells from patients can be reprogrammed to induced pluripotent stem cells (iPSCs) which successively can be used to obtain specific cells such as neurons. This remarkable breakthrough represents a new way of studying diseases and brought new therapeutic perspectives in the field of regenerative medicine. This is particular true in the neurology field, where few techniques are amenable to study the affected tissue of the patient during illness progression, in addition to the lack of neuroprotective therapies for many diseases. In this review we discuss the advantages and unresolved issues of cell reprogramming and neuronal differentiation. We reviewed evidence using iPSCs-derived neurons from neurological patients. Focusing on data obtained from Parkinson's disease (PD) patients, we show that iPSC-derived neurons possess morphological and functional characteristics of this disease and build a case for the use of this technology to study PD and other neuropathologies while disease is in progress. These data show the enormous impact that this new technology starts to have on different purposes such as the study and design of future therapies of neurological disease, especially PD.
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Duncan HF, Smith AJ, Fleming GJP, Cooper PR. Epigenetic modulation of dental pulp stem cells: implications for regenerative endodontics. Int Endod J 2015; 49:431-46. [PMID: 26011759 DOI: 10.1111/iej.12475] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2014] [Accepted: 05/24/2015] [Indexed: 12/28/2022]
Abstract
Dental pulp stem cells (DPSCs) offer significant potential for use in regenerative endodontics, and therefore, identifying cellular regulators that control stem cell fate is critical to devising novel treatment strategies. Stem cell lineage commitment and differentiation are regulated by an intricate range of host and environmental factors of which epigenetic influence is considered vital. Epigenetic modification of DNA and DNA-associated histone proteins has been demonstrated to control cell phenotype and regulate the renewal and pluripotency of stem cell populations. The activities of the nuclear enzymes, histone deacetylases, are increasingly being recognized as potential targets for pharmacologically inducing stem cell differentiation and dedifferentiation. Depending on cell maturity and niche in vitro, low concentration histone deacetylase inhibitor (HDACi) application can promote dedifferentiation of several post-natal and mouse embryonic stem cell populations and conversely increase differentiation and accelerate mineralization in DPSC populations, whilst animal studies have shown an HDACi-induced increase in stem cell marker expression during organ regeneration. Notably, both HDAC and DNA methyltransferase inhibitors have also been demonstrated to dramatically increase the reprogramming of somatic cells to induced pluripotent stem cells (iPSCs) for use in regenerative therapeutic procedures. As the regulation of cell fate will likely remain the subject of intense future research activity, this review aims to describe the current knowledge relating to stem cell epigenetic modification, focusing on the role of HDACi on alteration of DPSC phenotype, whilst presenting the potential for therapeutic application as part of regenerative endodontic regimens.
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Affiliation(s)
- H F Duncan
- Division of Restorative Dentistry & Periodontology, Dublin Dental University Hospital, Trinity College, Dublin, Ireland
| | - A J Smith
- Oral Biology, School of Dentistry, University of Birmingham, Birmingham, UK
| | - G J P Fleming
- Material Science Unit, Dublin Dental University Hospital, Trinity College, Dublin, Ireland
| | - P R Cooper
- Oral Biology, School of Dentistry, University of Birmingham, Birmingham, UK
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Okeyo KO, Kurosawa O, Yamazaki S, Oana H, Kotera H, Nakauchi H, Washizu M. Cell Adhesion Minimization by a Novel Mesh Culture Method Mechanically Directs Trophoblast Differentiation and Self-Assembly Organization of Human Pluripotent Stem Cells. Tissue Eng Part C Methods 2015; 21:1105-15. [PMID: 25914965 DOI: 10.1089/ten.tec.2015.0038] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Mechanical methods for inducing differentiation and directing lineage specification will be instrumental in the application of pluripotent stem cells. Here, we demonstrate that minimization of cell-substrate adhesion can initiate and direct the differentiation of human pluripotent stem cells (hiPSCs) into cyst-forming trophoblast lineage cells (TLCs) without stimulation with cytokines or small molecules. To precisely control cell-substrate adhesion area, we developed a novel culture method where cells are cultured on microstructured mesh sheets suspended in a culture medium such that cells on mesh are completely out of contact with the culture dish. We used microfabricated mesh sheets that consisted of open meshes (100∼200 μm in pitch) with narrow mesh strands (3-5 μm in width) to provide support for initial cell attachment and growth. We demonstrate that minimization of cell adhesion area achieved by this culture method can trigger a sequence of morphogenetic transformations that begin with individual hiPSCs attached on the mesh strands proliferating to form cell sheets by self-assembly organization and ultimately differentiating after 10-15 days of mesh culture to generate spherical cysts that secreted human chorionic gonadotropin (hCG) hormone and expressed caudal-related homeobox 2 factor (CDX2), a specific marker of trophoblast lineage. Thus, this study demonstrates a simple and direct mechanical approach to induce trophoblast differentiation and generate cysts for application in the study of early human embryogenesis and drug development and screening.
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Affiliation(s)
| | - Osamu Kurosawa
- 2 Department of Bioengineering, School of Engineering, The University of Tokyo , Tokyo, Japan
| | - Satoshi Yamazaki
- 3 Center for Stem Cell Therapy, The Institute of Medical Science, The University of Tokyo , Tokyo, Japan
| | - Hidehiro Oana
- 1 Department of Mechanical Engineering, The University of Tokyo , Tokyo, Japan
| | - Hidetoshi Kotera
- 4 Department of Microengineering, Postgraduate School of Engineering, Kyoto University , Kyoto, Japan
| | - Hiromitsu Nakauchi
- 3 Center for Stem Cell Therapy, The Institute of Medical Science, The University of Tokyo , Tokyo, Japan
| | - Masao Washizu
- 1 Department of Mechanical Engineering, The University of Tokyo , Tokyo, Japan .,2 Department of Bioengineering, School of Engineering, The University of Tokyo , Tokyo, Japan
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Abstract
PURPOSE OF REVIEW Ongoing research is constantly looking for means to modulate the immune system for long-lasting engraftment of pluripotent stem cells (PSC) during stem cell-based therapies. This study reviews data on in-vitro and in-vivo immunogenicity of embryonic and induced-PSC and describes how their immunological properties can be harnessed for tolerance induction in organ transplantation. RECENT FINDINGS Although PSC display immunomodulatory properties in vitro, they are capable of eliciting an immune response that leads to cell rejection when transplanted into immune-competent recipients. Nevertheless, long-term acceptance of PSC-derived cells/tissues in an allogeneic environment can be achieved using minimal host conditioning. Protocols for differentiating PSC towards haematopoietic stem cells, thymic epithelial precursors, dendritic cells, regulatory T cells and myeloid-derived suppressor cells are being developed, suggesting the possibility to use PSC-derived immunomodulatory cells to induce tolerance to a solid organ transplant. SUMMARY PSC and/or their derivatives possess unique immunological properties that allow for acceptance of PSC-derived tissue with minimal host conditioning. Investigators involved either in regenerative or in transplant medicine must join their efforts with the ultimate aim of using PSC as a source of donor-specific cells that would create a protolerogenic environment to achieve tolerance in solid organ transplantation.
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48
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Souza GTD, Maranduba CP, Souza CMD, Amaral DLASD, Guia FCD, Zanette RDSS, Rettore JVP, Rabelo NC, Nascimento LM, Pinto &IFN, Farani JB, Neto AEH, Silva FDS, Maranduba CMDC, Atalla A. Advances in cellular technology in the hematology field: What have we learned so far? World J Stem Cells 2015; 7:106-115. [PMID: 25621110 PMCID: PMC4300920 DOI: 10.4252/wjsc.v7.i1.106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2014] [Revised: 09/12/2014] [Accepted: 09/19/2014] [Indexed: 02/07/2023] Open
Abstract
Despite the advances in the hematology field, blood transfusion-related iatrogenesis is still a major issue to be considered during such procedures due to blood antigenic incompatibility. This places pluripotent stem cells as a possible ally in the production of more suitable blood products. The present review article aims to provide a comprehensive summary of the state-of-the-art concerning the differentiation of both embryonic stem cells and induced pluripotent stem cells to hematopoietic cell lines. Here, we review the most recently published protocols to achieve the production of blood cells for future application in hemotherapy, cancer therapy and basic research.
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49
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Berezin AE. Diabetes mellitus and cellular replacement therapy: Expected clinical potential and perspectives. World J Diabetes 2014; 5:777-786. [PMID: 25512780 PMCID: PMC4265864 DOI: 10.4239/wjd.v5.i6.777] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2014] [Revised: 07/16/2014] [Accepted: 09/23/2014] [Indexed: 02/05/2023] Open
Abstract
Diabetes mellitus (DM) is the most prevailing disease with progressive incidence worldwide. Despite contemporary treatment type one DM and type two DM are frequently associated with long-term major microvascular and macrovascular complications. Currently restoration of failing β-cell function, regulation of metabolic processes with stem cell transplantation is discussed as complements to contemporary DM therapy regimens. The present review is considered paradigm of the regenerative care and the possibly effects of cell therapy in DM. Reprogramming stem cells, bone marrow-derived mononuclear cells; lineage-specified progenitor cells are considered for regenerative strategy in DM. Finally, perspective component of stem cell replacement in DM is discussed.
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50
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Schnabel LV, Abratte CM, Schimenti JC, Felippe MJB, Cassano JM, Southard TL, Cross JA, Fortier LA. Induced pluripotent stem cells have similar immunogenic and more potent immunomodulatory properties compared with bone marrow-derived stromal cells in vitro. Regen Med 2014; 9:621-35. [PMID: 24773530 PMCID: PMC4352342 DOI: 10.2217/rme.14.29] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
AIM To evaluate the in vitro immunogenic and immunomodulatory properties of induced pluripotent stem cells (iPSCs) compared with bone marrow-derived mesenchymal stromal cells (MSCs). MATERIALS & METHODS Mouse embryonic fibroblasts (MEFs) were isolated from C3HeB/FeJ and C57BL/6J mice, and reprogrammed to generate iPSCs. Mixed leukocyte reactions were performed using MHC-matched and -mismatched responder leukocytes and stimulator leukocytes, iPSCs or MSCs. To assess immunogenic potential, iPSCs and MSCs were used as stimulator cells for responder leukocytes. To assess immunomodulatory properties, iPSCs and MSCs were cultured in the presence of stimulator and responder leukocytes. MEFs were used as a control. RESULTS iPSCs had similar immunogenic properties but more potent immunomodulatory effects than MSCs. Co-culture of MHC-mismatched leukocytes with MHC-matched iPSCs resulted in significantly less responder T-cell proliferation than observed for MHC-mismatched leukocytes alone and at more responder leukocyte concentrations than with MSCs. In addition, MHC-mismatched iPSCs significantly reduced responder T-cell proliferation when co-cultured with MHC-mismatched leukocytes, while MHC-mismatched MSCs did not. CONCLUSION These results provide important information when considering the use of iPSCs in place of MSCs in both regenerative and transplantation medicine.
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Affiliation(s)
- Lauren V Schnabel
- Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27607, USA
| | - Christian M Abratte
- Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA
| | - John C Schimenti
- Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA
| | - M Julia Bevilaqua Felippe
- Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA
| | - Jennifer M Cassano
- Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA
| | - Teresa L Southard
- Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA
| | - Jessica A Cross
- Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA
| | - Lisa A Fortier
- Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA
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