|
1
|
Chen KY, Chan HC, Chan CM. Can Stem Cell Therapy Revolutionize Ocular Disease Treatment? A Critical Review of Preclinical and Clinical Advances. Stem Cell Rev Rep 2025:10.1007/s12015-025-10884-x. [PMID: 40266467 DOI: 10.1007/s12015-025-10884-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/08/2025] [Indexed: 04/24/2025]
Abstract
Stem cell therapy in regenerative medicine has a scope for treating ocular diseases. Stem cell therapy aims to repair damaged tissue and restore vision. The present review focuses on the advancements in stem cell therapies for ocular disorders, their mechanism of action, and clinical applications while addressing some outstanding challenges. Stem cells that include embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), mesenchymal stem cells (MSCs), and retinal progenitor cells have regenerative potential for ocular repair. They differentiate into specialized ocular cell types, conduct neuroprotection, and modulate immune responses. It is emphasized in preclinical and clinical studies that stem cell therapy can treat corneal disorders such as limbal stem cell deficiency, retinal diseases like dry age macular degeneration and retinitis pigmentosa, and diabetic retinopathy. Various studies suggested that stem cells have considerable scope in glaucoma treatment by supporting retinal ganglion cell survival and optic nerve regeneration. Advanced approaches such as gene editing, organoid generation, and artificial intelligence enhance these therapies. Effective delivery to target areas, engraftment, orientation, and long-term survival of transplanted cells need optimization. Issues such as immune rejection and tumorigenicity must be addressed. This approach is further hindered by regulatory issues and overly complicated approval processes and trials. Ethical issues related to sourcing embryonic stem cells and patient consent complicate the issue. The cost of manufacturing stem cells and their accessibility are other factors posing potential barriers to widespread application. These regulatory, ethical, and economic issues must be tackled if stem cell treatments are to be made safe, accessible, and effective. Future studies will include refining therapeutic protocols, scaling manufacturing processes, and overcoming socio-economic barriers, eventually improving clinical outcomes.
Collapse
Affiliation(s)
- Kai-Yang Chen
- School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Hoi-Chun Chan
- School of Pharmacy, China Medical University, Taichung, Taiwan
| | - Chi-Ming Chan
- Department of Ophthalmology, Cardinal Tien Hospital, New Taipei City, Taiwan.
- School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan.
| |
Collapse
|
|
2
|
Deshpande P, Dornbrand-Lo M, Phondge V, Kelly P, Wong AK. Tissue engineering approaches for lymphedema: biomaterial innovations and clinical potential. Front Cell Dev Biol 2025; 13:1537050. [PMID: 40302939 PMCID: PMC12037638 DOI: 10.3389/fcell.2025.1537050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2024] [Accepted: 03/25/2025] [Indexed: 05/02/2025] Open
Abstract
The lymphatic system plays a critical role in maintaining fluid balance and immune regulation. Lymphedema, and other lymphatic disorders, highlight the need for advanced therapeutic approaches, including tissue engineering. This review examines the latest developments in artificial lymphatic tissue engineering, focusing on scaffold materials, lymphangiogenic factors, and regenerative strategies to replicate the intricacy of lymphatic vessels and nodes. We conducted a thorough literature review of current practices and applications in lymphatic tissue engineering. Findings show that biomaterials such as hydrogels, decellularized matrices, and synthetic polymers provide effective scaffolds for lymphatic endothelial cell proliferation and lymphangiogenesis. Advances in growth factor delivery and stem-cell based therapies have further enhanced the viability of engineered lymphatic tissues. Despite promising progress, challenges in achieving functional replication of lymphatic structures and clinical translation of research remain. Ongoing research must address scaffold biocompatibility, optimized growth factor targeting, and scalable production to advance therapeutic options for lymphatic disorders. This review underscores the potential for transformative patient outcomes through innovative bioengineering solutions.
Collapse
Affiliation(s)
| | | | | | | | - Alex K. Wong
- Rutgers New Jersey Medical School, Division of Plastic and Reconstructive Surgery, Newark, NJ, United States
| |
Collapse
|
|
3
|
Sorrentino FS, Di Terlizzi P, De Rosa F, Salati C, Spadea L, Gagliano C, Musa M, Zeppieri M. New frontiers in retinal transplantation. World J Transplant 2024; 14:97690. [PMID: 39697450 PMCID: PMC11438945 DOI: 10.5500/wjt.v14.i4.97690] [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: 06/05/2024] [Revised: 07/22/2024] [Accepted: 07/24/2024] [Indexed: 09/20/2024] Open
Abstract
New frontiers about retinal cell transplantation for retinal degenerative diseases start from the idea that acting on stem cells can help regenerate retinal layers and establish new synapses among retinal cells. Deficiency or alterations of synaptic input and neurotrophic factors result in trans-neuronal degeneration of the inner retinal cells. Thus, the disruption of photoreceptors takes place. However, even in advanced forms of retinal degeneration, a good percentage of the ganglion cells and the inner nuclear layer neurons remain intact. This phenomenon provides evidence for obtaining retinal circuitry through the transplantation of photoreceptors into the subretinal region. The eye is regarded as an optimal organ for cell transplantation because of its immunological privilege and the relatively small number of cells collaborating to carry out visual activities. The eyeball's immunological privilege, characterized by the suppression of delayed-type hypersensitivity responses in ocular tissues, is responsible for the low rate of graft rejection in transplant patients. The main discoveries highlight the capacity of embryonic stem cells (ESCs) and induced pluripotent stem cells to regenerate damaged retinal regions. Recent progress has shown significant enhancements in transplant procedures and results. The research also explores the ethical ramifications linked to the utilization of stem cells, emphasizing the ongoing issue surrounding ESCs. The analysis centers on recent breakthroughs, including the fabrication of three-dimensional retinal organoids and the innovation of scaffolding for cell transportation. Moreover, researchers are currently assessing the possibility of CRISPR and other advanced gene editing technologies to enhance the outcomes of retinal transplantation. The widespread use of universally recognized safe surgical and imaging methods enables retinal transplantation and monitoring of transplanted cell growth toward the correct location. Currently, most therapy approaches are in the first phases of development and necessitate further research, including both pre-clinical and clinical trials, to attain favorable visual results for individuals suffering from retinal degenerative illnesses.
Collapse
Affiliation(s)
| | - Patrick Di Terlizzi
- Department of Surgical Sciences, Unit of Ophthalmology, Ospedale Maggiore, Bologna 40100, Italy
| | - Francesco De Rosa
- Department of Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori “Dino Amadori”, Meldola 47014, Italy
| | - Carlo Salati
- Department of Ophthalmology, University Hospital of Udine, Udine 33100, Italy
| | - Leopoldo Spadea
- Eye Clinic, Policlinico Umberto I, "Sapienza" University of Rome, Rome 00142, Italy
| | - Caterina Gagliano
- Department of Medicine and Surgery, University of Enna "Kore", Enna 94100, Italy
- Eye Clinic, Catania University San Marco Hospital, Catania 95121, Italy
| | - Mutali Musa
- Department of Optometry, University of Benin, Benin 300283, Nigeria
- Department of Ophthalmology, Centre for Sight Africa, Nkpor, Onitsha 434112, Nigeria
| | - Marco Zeppieri
- Department of Ophthalmology, University Hospital of Udine, Udine 33100, Italy
| |
Collapse
|
|
4
|
Ore A, Angelastro JM, Giulivi C. Integrating Mitochondrial Biology into Innovative Cell Therapies for Neurodegenerative Diseases. Brain Sci 2024; 14:899. [PMID: 39335395 PMCID: PMC11429837 DOI: 10.3390/brainsci14090899] [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: 08/08/2024] [Revised: 08/31/2024] [Accepted: 09/03/2024] [Indexed: 09/30/2024] Open
Abstract
The role of mitochondria in neurodegenerative diseases is crucial, and recent developments have highlighted its significance in cell therapy. Mitochondrial dysfunction has been implicated in various neurodegenerative disorders, including Alzheimer's, Parkinson's, amyotrophic lateral sclerosis, and Huntington's diseases. Understanding the impact of mitochondrial biology on these conditions can provide valuable insights for developing targeted cell therapies. This mini-review refocuses on mitochondria and emphasizes the potential of therapies leveraging mesenchymal stem cells, embryonic stem cells, induced pluripotent stem cells, stem cell-derived secretions, and extracellular vesicles. Mesenchymal stem cell-mediated mitochondria transfer is highlighted for restoring mitochondrial health in cells with dysfunctional mitochondria. Additionally, attention is paid to gene-editing techniques such as mito-CRISPR, mitoTALENs, mito-ZNFs, and DdCBEs to ensure the safety and efficacy of stem cell treatments. Challenges and future directions are also discussed, including the possible tumorigenic effects of stem cells, off-target effects, disease targeting, immune rejection, and ethical issues.
Collapse
Affiliation(s)
- Adaleiz Ore
- Department of Molecular Biosciences, School of Veterinary Medicine, University of California Davis, Davis, CA 95616, USA; (A.O.); (J.M.A.)
- Department of Chemical Engineering, School of Engineering, Case Western Reserve University, Cleveland, OH 44106, USA
| | - James M. Angelastro
- Department of Molecular Biosciences, School of Veterinary Medicine, University of California Davis, Davis, CA 95616, USA; (A.O.); (J.M.A.)
| | - Cecilia Giulivi
- Department of Molecular Biosciences, School of Veterinary Medicine, University of California Davis, Davis, CA 95616, USA; (A.O.); (J.M.A.)
- University of California Medical Investigations of Neurodevelopmental Disorders Institute (MIND Institute), University of California Health, Sacramento, CA 95817, USA
| |
Collapse
|
|
5
|
Zhong Y, Zhu Y, Hu X, Zhang L, Xu J, Wang Q, Liu J. Human embryonic stem cell-derived mesenchymal stromal cells suppress inflammation in mouse models of rheumatoid arthritis and lung fibrosis by regulating T-cell function. Cytotherapy 2024; 26:930-938. [PMID: 38520411 DOI: 10.1016/j.jcyt.2024.03.008] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Revised: 03/10/2024] [Accepted: 03/11/2024] [Indexed: 03/25/2024]
Abstract
BACKGROUND AIMS Rheumatoid arthritis (RA) is characterized by an overactive immune system, with limited treatment options beyond immunosuppressive drugs or biological response modifiers. Human embryonic stem cell-derived mesenchymal stromal cells (hESC-MSCs) represent a novel alternative, possessing diverse immunomodulatory effects. In this study, we aimed to elucidate the therapeutic effects and underlying mechanisms of hESC-MSCs in treating RA. METHODS MSC-like cells were differentiated from hESC (hESC-MSCs) and cultured in vitro. Cell proliferation was assessed using Cell Counting Kit-8 assay and Ki-67 staining. Flow cytometry was used to analyze cell surface markers, T-cell proliferation and immune cell infiltration. The collagen-induced arthritis (CIA) mouse model and bleomycin-induced model of lung fibrosis (BLE) were established and treated with hESC-MSCs intravenously for in vivo assessment. Pathological analyses, reverse transcription-quantitative polymerase chain reaction and Western blotting were conducted to evaluate the efficacy of hESC-MSCs treatment. RESULTS Intravenous transplantation of hESC-MSCs effectively reduced inflammation in CIA mice in this study. Furthermore, hESC-MSC administration enhanced regulatory T cell infiltration and activation. Additional findings suggest that hESC-MSCs may reduce lung fibrosis in BLE mouse models, indicating their potential to mitigate complications associated with RA progression. In vitro experiments revealed a significant inhibition of T-cell activation and proliferation during co-culture with hESC-MSCs. In addition, hESC-MSCs demonstrated enhanced proliferative capacity compared with traditional primary MSCs. CONCLUSIONS Transplantation of hESC-MSCs represents a promising therapeutic strategy for RA, potentially regulating T-cell proliferation and differentiation.
Collapse
Affiliation(s)
- Yan Zhong
- Department of Pathology, Shenzhen Hospital, Southern Medical University, Shenzhen, China
| | - Yisheng Zhu
- Department of Rheumatism and Immunology, Peking University Shenzhen Hospital, Shenzhen, China
| | - Xiaohao Hu
- The Fifth Clinical Medical College of Anhui Medical University, Hefei, Anhui, China
| | - Lin Zhang
- Department of Rheumatism and Immunology, Peking University Shenzhen Hospital, Shenzhen, China
| | - Jiahuan Xu
- The Fifth Clinical Medical College of Anhui Medical University, Hefei, Anhui, China
| | - Qingwen Wang
- The Fifth Clinical Medical College of Anhui Medical University, Hefei, Anhui, China; Shenzhen Key Laboratory of Immunity and Inflammatory Diseases, Peking University Shenzhen Hospital, Shenzhen, China.
| | - Jingfeng Liu
- Department of Rheumatism and Immunology, Peking University Shenzhen Hospital, Shenzhen, China; Shenzhen Key Laboratory of Immunity and Inflammatory Diseases, Peking University Shenzhen Hospital, Shenzhen, China; Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Science, Shenzhen, China.
| |
Collapse
|
|
6
|
Bellon A. Comparing stem cells, transdifferentiation and brain organoids as tools for psychiatric research. Transl Psychiatry 2024; 14:127. [PMID: 38418498 PMCID: PMC10901833 DOI: 10.1038/s41398-024-02780-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 01/08/2024] [Accepted: 01/12/2024] [Indexed: 03/01/2024] Open
Abstract
The inaccessibility of neurons coming directly from patients has hindered our understanding of mental illnesses at the cellular level. To overcome this obstacle, six different cellular approaches that carry the genetic vulnerability to psychiatric disorders are currently available: Olfactory Neuroepithelial Cells, Mesenchymal Stem Cells, Pluripotent Monocytes, Induced Pluripotent Stem Cells, Induced Neuronal cells and more recently Brain Organoids. Here we contrast advantages and disadvantages of each of these six cell-based methodologies. Neuronal-like cells derived from pluripotent monocytes are presented in more detail as this technique was recently used in psychiatry for the first time. Among the parameters used for comparison are; accessibility, need for reprograming, time to deliver differentiated cells, differentiation efficiency, reproducibility of results and cost. We provide a timeline on the discovery of these cell-based methodologies, but, our main goal is to assist researchers selecting which cellular approach is best suited for any given project. This manuscript also aims to help readers better interpret results from the published literature. With this goal in mind, we end our work with a discussion about the differences and similarities between cell-based techniques and postmortem research, the only currently available tools that allow the study of mental illness in neurons or neuronal-like cells coming directly from patients.
Collapse
Affiliation(s)
- Alfredo Bellon
- Penn State Hershey Medical Center, Department of Psychiatry and Behavioral Health, Hershey, PA, USA.
- Penn State Hershey Medical Center, Department of Pharmacology, Hershey, PA, USA.
| |
Collapse
|
|
7
|
Zhu W, Li M, Zou J, Zhang D, Fang M, Sun Y, Li C, Tang M, Wang Y, Zhou Q, Zhao T, Li W, Hu Z, Hu B. Induction of local immunosuppression in allogeneic cell transplantation by cell-type-specific expression of PD-L1 and CTLA4Ig. Stem Cell Reports 2023; 18:2344-2355. [PMID: 37995700 PMCID: PMC10724073 DOI: 10.1016/j.stemcr.2023.10.016] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Revised: 10/24/2023] [Accepted: 10/26/2023] [Indexed: 11/25/2023] Open
Abstract
Immune rejection has long hindered allogeneic cell transplantation therapy. Current genetic modification approaches, including direct targeting of major histocompatibility complex or constitutive expression of immune inhibitory molecules, exhibit drawbacks such as severe adverse effects or elevated tumorigenesis risks. To overcome these limitations, we introduce an innovative approach to induce cell-type-specific immune tolerance in differentiated cells. By engineering human embryonic stem cells, we ensure the exclusive production of the immune inhibitory molecules PD-L1/CTLA4Ig in differentiated cells. Using this strategy, we generated hepatocyte-like cells expressing PD-L1 and CTLA4Ig, which effectively induced local immunotolerance. This approach was evaluated in a humanized mouse model that mimics the human immune system dynamics. We thus demonstrate a robust and selective induction of immunotolerance specific to hepatocytes, improving graft survival without observed tumorigenesis. This precise immune tolerance strategy holds great promise for advancing the development of stem cell-based therapeutics in regenerative medicine.
Collapse
Affiliation(s)
- Wenliang Zhu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Savaid Medical School, University of Chinese Academy of Sciences, Beijing 100049, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China
| | - Mengqi Li
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China
| | - Jun Zou
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, The First Hospital of Jilin University, Jilin, China; National-Local Joint Engineering Laboratory of Animal Models for Human Diseases, Jilin 130061, China
| | - Da Zhang
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China
| | - Minghui Fang
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, The First Hospital of Jilin University, Jilin, China; National-Local Joint Engineering Laboratory of Animal Models for Human Diseases, Jilin 130061, China
| | - Yun Sun
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Savaid Medical School, University of Chinese Academy of Sciences, Beijing 100049, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
| | - Can Li
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Savaid Medical School, University of Chinese Academy of Sciences, Beijing 100049, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
| | - Mingming Tang
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
| | - Yukai Wang
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
| | - Qi Zhou
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
| | - Tongbiao Zhao
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Savaid Medical School, University of Chinese Academy of Sciences, Beijing 100049, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China.
| | - Wei Li
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Savaid Medical School, University of Chinese Academy of Sciences, Beijing 100049, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China.
| | - Zheng Hu
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, The First Hospital of Jilin University, Jilin, China; National-Local Joint Engineering Laboratory of Animal Models for Human Diseases, Jilin 130061, China.
| | - Baoyang Hu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Savaid Medical School, University of Chinese Academy of Sciences, Beijing 100049, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China.
| |
Collapse
|
|
8
|
Abubakar M, Masood MF, Javed I, Adil H, Faraz MA, Bhat RR, Fatima M, Abdelkhalek AM, Buccilli B, Raza S, Hajjaj M. Unlocking the Mysteries, Bridging the Gap, and Unveiling the Multifaceted Potential of Stem Cell Therapy for Cardiac Tissue Regeneration: A Narrative Review of Current Literature, Ethical Challenges, and Future Perspectives. Cureus 2023; 15:e41533. [PMID: 37551212 PMCID: PMC10404462 DOI: 10.7759/cureus.41533] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/06/2023] [Indexed: 08/09/2023] Open
Abstract
Revolutionary advancements in regenerative medicine have brought stem cell therapy to the forefront, offering promising prospects for the regeneration of ischemic cardiac tissue. Yet, its full efficacy, safety, and role in treating ischemic heart disease (IHD) remain limited. This literature review explores the intricate mechanisms underlying stem cell therapy. Furthermore, we unravel the innovative approaches employed to bolster stem cell survival, enhance differentiation, and seamlessly integrate them within the ischemic cardiac tissue microenvironment. Our comprehensive analysis uncovers how stem cells enhance cell survival, promote angiogenesis, and modulate the immune response. Stem cell therapy harnesses a multifaceted mode of action, encompassing paracrine effects and direct cell replacement. As our review progresses, we underscore the imperative for standardized protocols, comprehensive preclinical and clinical studies, and careful regulatory considerations. Lastly, we explore the integration of tissue engineering and genetic modifications, envisioning a future where stem cell therapy reigns supreme in regenerative medicine.
Collapse
Affiliation(s)
- Muhammad Abubakar
- Department of Internal Medicine, Ameer-Ud-Din Medical College, Lahore General Hospital, Lahore, PAK
- Department of Internal Medicine, Siddique Sadiq Memorial Trust Hospital, Gujranwala, PAK
| | | | - Izzah Javed
- Department of Internal Medicine, Ameer-Ud-Din Medical College, Lahore General Hospital, Lahore, PAK
| | - Hira Adil
- Department of Community Medicine, Khyber Girls Medical College, Hayatabad, PAK
| | - Muhammad Ahmad Faraz
- Department of Forensic Medicine, Post Graduate Medical Institute, Lahore General Hospital, Lahore, PAK
| | - Rakshita Ramesh Bhat
- Department of Medical Oncology, Mangalore Institute of Oncology, Mangalore, IND
- Department of Internal Medicine, Bangalore Medical College and Research Institute, Bangalore, IND
| | - Mahek Fatima
- Department of Internal Medicine, Osmania Medical College, Hyderabad, IND
| | | | - Barbara Buccilli
- Department of Human Neuroscience, Sapienza University of Rome, Rome, ITA
| | - Saud Raza
- Department of Internal Medicine, Ameer-Ud-Din Medical College, Lahore General Hospital, Lahore, PAK
| | - Mohsin Hajjaj
- Department of Internal Medicine, Jinnah Hospital Lahore, Lahore, PAK
| |
Collapse
|
|
9
|
German OL, Vallese-Maurizi H, Soto TB, Rotstein NP, Politi LE. Retina stem cells, hopes and obstacles. World J Stem Cells 2021; 13:1446-1479. [PMID: 34786153 PMCID: PMC8567457 DOI: 10.4252/wjsc.v13.i10.1446] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 07/14/2021] [Accepted: 09/17/2021] [Indexed: 02/07/2023] Open
Abstract
Retinal degeneration is a major contributor to visual dysfunction worldwide. Although it comprises several eye diseases, loss of retinal pigment epithelial (RPE) and photoreceptor cells are the major contributors to their pathogenesis. Early therapies included diverse treatments, such as provision of anti-vascular endothelial growth factor and many survival and trophic factors that, in some cases, slow down the progression of the degeneration, but do not effectively prevent it. The finding of stem cells (SC) in the eye has led to the proposal of cell replacement strategies for retina degeneration. Therapies using different types of SC, such as retinal progenitor cells (RPCs), embryonic SC, pluripotent SCs (PSCs), induced PSCs (iPSCs), and mesenchymal stromal cells, capable of self-renewal and of differentiating into multiple cell types, have gained ample support. Numerous preclinical studies have assessed transplantation of SC in animal models, with encouraging results. The aim of this work is to revise the different preclinical and clinical approaches, analyzing the SC type used, their efficacy, safety, cell attachment and integration, absence of tumor formation and immunorejection, in order to establish which were the most relevant and successful. In addition, we examine the questions and concerns still open in the field. The data demonstrate the existence of two main approaches, aimed at replacing either RPE cells or photoreceptors. Emerging evidence suggests that RPCs and iPSC are the best candidates, presenting no ethical concerns and a low risk of immunorejection. Clinical trials have already supported the safety and efficacy of SC treatments. Serious concerns are pending, such as the risk of tumor formation, lack of attachment or integration of transplanted cells into host retinas, immunorejection, cell death, and also ethical. However, the amazing progress in the field in the last few years makes it possible to envisage safe and effective treatments to restore vision loss in a near future.
Collapse
Affiliation(s)
- Olga L German
- Department of Biology, Biochemistry and Pharmacy, Universidad Nacional del Sur, Bahia blanca 8000, Buenos Aires, Argentina
- Department of Biology, Biochemistry and Pharmacy, Universidad Nacional del Sur, and Neurobiology Department, Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB) Conicet, Bahía Blanca 8000, Buenos Aires, Argentina
| | - Harmonie Vallese-Maurizi
- Department of Biology, Biochemistry and Pharmacy, Universidad Nacional del Sur, Bahia blanca 8000, Buenos Aires, Argentina
- Department of Biology, Biochemistry and Pharmacy, Universidad Nacional del Sur, and Neurobiology Department, Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB) Conicet, Bahía Blanca 8000, Buenos Aires, Argentina
| | - Tamara B Soto
- Department of Biology, Biochemistry and Pharmacy, Universidad Nacional del Sur, and Neurobiology Department, Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB) Conicet, Bahía Blanca 8000, Buenos Aires, Argentina
| | - Nora P Rotstein
- Department of Biology, Biochemistry and Pharmacy, Universidad Nacional del Sur, Bahia blanca 8000, Buenos Aires, Argentina
- Department of Biology, Biochemistry and Pharmacy, Universidad Nacional del Sur, and Neurobiology Department, Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB) Conicet, Bahía Blanca 8000, Buenos Aires, Argentina
| | - Luis Enrique Politi
- Department of Biology, Biochemistry and Pharmacy, Universidad Nacional del Sur, and Neurobiology Department, Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB) Conicet, Bahía Blanca 8000, Buenos Aires, Argentina
| |
Collapse
|
|
10
|
Tezel T, Ruff A. Retinal cell transplantation in retinitis pigmentosa. Taiwan J Ophthalmol 2021; 11:336-347. [PMID: 35070661 PMCID: PMC8757529 DOI: 10.4103/tjo.tjo_48_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 10/10/2021] [Indexed: 11/25/2022] Open
Abstract
Retinitis pigmentosa is the most common hereditary retinal disease. Dietary supplements, neuroprotective agents, cytokines, and lately, prosthetic devices, gene therapy, and optogenetics have been employed to slow down the retinal degeneration or improve light perception. Completing retinal circuitry by transplanting photoreceptors has always been an appealing idea in retinitis pigmentosa. Recent developments in stem cell technology, retinal imaging techniques, tissue engineering, and transplantation techniques have brought us closer to accomplish this goal. The eye is an ideal organ for cell transplantation due to a low number of cells required to restore vision, availability of safe surgical and imaging techniques to transplant and track the cells in vivo, and partial immune privilege provided by the subretinal space. Human embryonic stem cells, induced pluripotential stem cells, and especially retinal organoids provide an adequate number of cells at a desired developmental stage which may maximize integration of the graft to host retina. However, stem cells must be manufactured under strict good manufacturing practice protocols due to known tumorigenicity as well as possible genetic and epigenetic stabilities that may pose a danger to the recipient. Immune compatibility of stem cells still stands as a problem for their widespread use for retinitis pigmentosa. Transplantation of stem cells from different sources revealed that some of the transplanted cells may not integrate the host retina but slow down the retinal degeneration through paracrine mechanisms. Discovery of a similar paracrine mechanism has recently opened a new therapeutic path for reversing the cone dormancy and restoring the sight in retinitis pigmentosa.
Collapse
|
|
11
|
Sekiya T, Holley MC. Cell Transplantation to Restore Lost Auditory Nerve Function is a Realistic Clinical Opportunity. Cell Transplant 2021; 30:9636897211035076. [PMID: 34498511 PMCID: PMC8438274 DOI: 10.1177/09636897211035076] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Hearing is one of our most important means of communication. Disabling hearing loss (DHL) is a long-standing, unmet problem in medicine, and in many elderly people, it leads to social isolation, depression, and even dementia. Traditionally, major efforts to cure DHL have focused on hair cells (HCs). However, the auditory nerve is also important because it transmits electrical signals generated by HCs to the brainstem. Its function is critical for the success of cochlear implants as well as for future therapies for HC regeneration. Over the past two decades, cell transplantation has emerged as a promising therapeutic option for restoring lost auditory nerve function, and two independent studies on animal models show that cell transplantation can lead to functional recovery. In this article, we consider the approaches most likely to achieve success in the clinic. We conclude that the structure and biochemical integrity of the auditory nerve is critical and that it is important to preserve the remaining neural scaffold, and in particular the glial scar, for the functional integration of donor cells. To exploit the natural, autologous cell scaffold and to minimize the deleterious effects of surgery, donor cells can be placed relatively easily on the surface of the nerve endoscopically. In this context, the selection of donor cells is a critical issue. Nevertheless, there is now a very realistic possibility for clinical application of cell transplantation for several different types of hearing loss.
Collapse
Affiliation(s)
- Tetsuji Sekiya
- Department of Otolaryngology, Head and Neck Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
- Department of Neurological Surgery, Hikone Chuo Hospital, Hikone, Japan
- Tetsuji Sekiya, Department of Otolaryngology, Head and Neck Surgery, Kyoto University Graduate School of Medicine, 606-8507 Kyoto, Japan,.
| | - Matthew C. Holley
- Department of Biomedical Science, University of Sheffield, Firth Court, Sheffield, England
| |
Collapse
|
|
12
|
Zenke M. Human ES cell-derived dendritic cells: Meeting the challenge of immune rejection in allogeneic cell therapy. EBioMedicine 2020; 62:103144. [PMID: 33254028 PMCID: PMC7701318 DOI: 10.1016/j.ebiom.2020.103144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Accepted: 11/11/2020] [Indexed: 11/26/2022] Open
Affiliation(s)
- Martin Zenke
- Department of Cell Biology, Institute for Biomedical Engineering, RWTH Aachen University Medical School, Pauwelsstrasse 30, Aachen, Germany; Helmholtz Institute for Biomedical Engineering, RWTH Aachen University, Pauwelsstrasse 20, Aachen, Germany.
| |
Collapse
|
|
13
|
Todorova D, Zhang Y, Chen Q, Liu J, He J, Fu X, Xu Y. hESC-derived immune suppressive dendritic cells induce immune tolerance of parental hESC-derived allografts. EBioMedicine 2020; 62:103120. [PMID: 33242828 PMCID: PMC7695963 DOI: 10.1016/j.ebiom.2020.103120] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2020] [Revised: 09/28/2020] [Accepted: 10/26/2020] [Indexed: 12/21/2022] Open
Abstract
Background With their inherent capability of unlimited self-renewal and unique potential to differentiate into functional cells of the three germ layers, human embryonic stem cells (hESCs) hold great potential in regenerative medicine. A major challenge in the application of hESC-based cell therapy is the allogeneic immune rejection of hESC-derived allografts. Methods We derived dendritic cell-like cells (DCLs) from wild type and CTLA4-Ig/PD-L1 knock-in hESCs, denoted WT DCLs and CP DCLs. The expression of DC-related genes and surface molecules was evaluated, as well as their DCL capacity to stimulate allogeneic T cells and induce regulatory T (Treg) cells in vitro. Using an immune system humanized mouse model, we investigated whether the adoptive transfer of CP DCLs can induce long-term immune tolerance of parental hESC-derived smooth muscle and cardiomyocyte allografts. Findings CP DCLs can maintain immune suppressive properties after robust inflammatory stimulation and induce Treg cells. While CP DCLs survive transiently in vivo, they induce long-term immune tolerance of parental hESC-derived allografts. Interpretation This strategy does not cause systemic immune suppression but induces immune tolerance specific for DCL-specific HLAs, and thus it presents a safe and effective approach to induce immune tolerance of allografts derived from any clinically approved hESC line. Funding NSFC, leading talents of Guangdong Province Program (No. 00201516), Key R&D Program of Guangdong Province (2019B020235003), Science and Technology Innovation Committee of Shenzhen Municipality (JCYJ20180504170301309), National High-tech R&D Program (863 Program No. 2015AA020310), Shenzhen “Sanming” Project of Medicine (SZSM201602102), Development and Reform Commission of Shenzhen Municipality (S2016004730009), CIRM (DISC2–10559).
Collapse
Affiliation(s)
- Dilyana Todorova
- Division of Biological Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
| | - Yue Zhang
- Guangzhou University of Chinese Medicine, Second Clinical Medical College, 232 Waihuan Road E, Guangzhou, Guangdong 510006, China
| | - Qu Chen
- The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong 518033, China
| | - Jingfeng Liu
- Division of Biological Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
| | - Jingjin He
- The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong 518033, China
| | - Xuemei Fu
- The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong 518033, China; Shenzhen Children's Hospital, Shenzhen 518026, China..
| | - Yang Xu
- Division of Biological Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA; Guangzhou University of Chinese Medicine, Second Clinical Medical College, 232 Waihuan Road E, Guangzhou, Guangdong 510006, China; The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong 518033, China.
| |
Collapse
|
|
14
|
Sanjurjo-Rodríguez C, Castro-Viñuelas R, Piñeiro-Ramil M, Rodríguez-Fernández S, Fuentes-Boquete I, Blanco FJ, Díaz-Prado S. Versatility of Induced Pluripotent Stem Cells (iPSCs) for Improving the Knowledge on Musculoskeletal Diseases. Int J Mol Sci 2020; 21:ijms21176124. [PMID: 32854405 PMCID: PMC7504376 DOI: 10.3390/ijms21176124] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 08/06/2020] [Accepted: 08/20/2020] [Indexed: 12/13/2022] Open
Abstract
Induced pluripotent stem cells (iPSCs) represent an unlimited source of pluripotent cells capable of differentiating into any cell type of the body. Several studies have demonstrated the valuable use of iPSCs as a tool for studying the molecular and cellular mechanisms underlying disorders affecting bone, cartilage and muscle, as well as their potential for tissue repair. Musculoskeletal diseases are one of the major causes of disability worldwide and impose an important socio-economic burden. To date there is neither cure nor proven approach for effectively treating most of these conditions and therefore new strategies involving the use of cells have been increasingly investigated in the recent years. Nevertheless, some limitations related to the safety and differentiation protocols among others remain, which humpers the translational application of these strategies. Nonetheless, the potential is indisputable and iPSCs are likely to be a source of different types of cells useful in the musculoskeletal field, for either disease modeling or regenerative medicine. In this review, we aim to illustrate the great potential of iPSCs by summarizing and discussing the in vitro tissue regeneration preclinical studies that have been carried out in the musculoskeletal field by using iPSCs.
Collapse
Affiliation(s)
- Clara Sanjurjo-Rodríguez
- Cell Therapy and Regenerative Medicine Group, Department of Physiotherapy, Medicine and Biomedical Sciences, Faculty of Health Sciences, University of A Coruña (UDC), 15006 A Coruña, Galicia, Spain; (R.C.-V.); (M.P.-R.); (S.R.-F.); (I.F.-B.)
- Institute of Biomedical Research of A Coruña (INIBIC), University Hospital Complex A Coruña (CHUAC), Galician Health Service (SERGAS), 15006 A Coruña, Galicia, Spain;
- Centro de Investigación Biomédica en Red (CIBER) de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), 28029 Madrid, Spain
- Centro de Investigaciones Científicas Avanzadas (CICA), Agrupación estratégica CICA-INIBIC, University of A Coruña, 15008 A Coruña, Galicia, Spain
- Correspondence: (C.S.-R.); (S.D.-P.)
| | - Rocío Castro-Viñuelas
- Cell Therapy and Regenerative Medicine Group, Department of Physiotherapy, Medicine and Biomedical Sciences, Faculty of Health Sciences, University of A Coruña (UDC), 15006 A Coruña, Galicia, Spain; (R.C.-V.); (M.P.-R.); (S.R.-F.); (I.F.-B.)
- Institute of Biomedical Research of A Coruña (INIBIC), University Hospital Complex A Coruña (CHUAC), Galician Health Service (SERGAS), 15006 A Coruña, Galicia, Spain;
- Centro de Investigaciones Científicas Avanzadas (CICA), Agrupación estratégica CICA-INIBIC, University of A Coruña, 15008 A Coruña, Galicia, Spain
| | - María Piñeiro-Ramil
- Cell Therapy and Regenerative Medicine Group, Department of Physiotherapy, Medicine and Biomedical Sciences, Faculty of Health Sciences, University of A Coruña (UDC), 15006 A Coruña, Galicia, Spain; (R.C.-V.); (M.P.-R.); (S.R.-F.); (I.F.-B.)
- Institute of Biomedical Research of A Coruña (INIBIC), University Hospital Complex A Coruña (CHUAC), Galician Health Service (SERGAS), 15006 A Coruña, Galicia, Spain;
- Centro de Investigaciones Científicas Avanzadas (CICA), Agrupación estratégica CICA-INIBIC, University of A Coruña, 15008 A Coruña, Galicia, Spain
| | - Silvia Rodríguez-Fernández
- Cell Therapy and Regenerative Medicine Group, Department of Physiotherapy, Medicine and Biomedical Sciences, Faculty of Health Sciences, University of A Coruña (UDC), 15006 A Coruña, Galicia, Spain; (R.C.-V.); (M.P.-R.); (S.R.-F.); (I.F.-B.)
- Institute of Biomedical Research of A Coruña (INIBIC), University Hospital Complex A Coruña (CHUAC), Galician Health Service (SERGAS), 15006 A Coruña, Galicia, Spain;
- Centro de Investigaciones Científicas Avanzadas (CICA), Agrupación estratégica CICA-INIBIC, University of A Coruña, 15008 A Coruña, Galicia, Spain
| | - Isaac Fuentes-Boquete
- Cell Therapy and Regenerative Medicine Group, Department of Physiotherapy, Medicine and Biomedical Sciences, Faculty of Health Sciences, University of A Coruña (UDC), 15006 A Coruña, Galicia, Spain; (R.C.-V.); (M.P.-R.); (S.R.-F.); (I.F.-B.)
- Institute of Biomedical Research of A Coruña (INIBIC), University Hospital Complex A Coruña (CHUAC), Galician Health Service (SERGAS), 15006 A Coruña, Galicia, Spain;
- Centro de Investigaciones Científicas Avanzadas (CICA), Agrupación estratégica CICA-INIBIC, University of A Coruña, 15008 A Coruña, Galicia, Spain
| | - Francisco J. Blanco
- Institute of Biomedical Research of A Coruña (INIBIC), University Hospital Complex A Coruña (CHUAC), Galician Health Service (SERGAS), 15006 A Coruña, Galicia, Spain;
- Centro de Investigación Biomédica en Red (CIBER) de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), 28029 Madrid, Spain
- Centro de Investigaciones Científicas Avanzadas (CICA), Agrupación estratégica CICA-INIBIC, University of A Coruña, 15008 A Coruña, Galicia, Spain
- Tissular Bioengineering and Cell Therapy Unit (GBTTC-CHUAC), Rheumatology Group, 15006 A Coruña, Galicia, Spain
| | - Silvia Díaz-Prado
- Cell Therapy and Regenerative Medicine Group, Department of Physiotherapy, Medicine and Biomedical Sciences, Faculty of Health Sciences, University of A Coruña (UDC), 15006 A Coruña, Galicia, Spain; (R.C.-V.); (M.P.-R.); (S.R.-F.); (I.F.-B.)
- Institute of Biomedical Research of A Coruña (INIBIC), University Hospital Complex A Coruña (CHUAC), Galician Health Service (SERGAS), 15006 A Coruña, Galicia, Spain;
- Centro de Investigación Biomédica en Red (CIBER) de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), 28029 Madrid, Spain
- Centro de Investigaciones Científicas Avanzadas (CICA), Agrupación estratégica CICA-INIBIC, University of A Coruña, 15008 A Coruña, Galicia, Spain
- Correspondence: (C.S.-R.); (S.D.-P.)
| |
Collapse
|
|
15
|
Zammit M, Tao Y, Olsen ME, Metzger J, Vermilyea SC, Bjornson K, Slesarev M, Block WF, Fuchs K, Phillips S, Bondarenko V, Zhang SC, Emborg ME, Christian BT. [ 18F]FEPPA PET imaging for monitoring CD68-positive microglia/macrophage neuroinflammation in nonhuman primates. EJNMMI Res 2020; 10:93. [PMID: 32761399 PMCID: PMC7410886 DOI: 10.1186/s13550-020-00683-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Accepted: 07/29/2020] [Indexed: 12/13/2022] Open
Abstract
PURPOSE The aim of this study was to examine whether the translocator protein 18-kDa (TSPO) PET ligand [18F]FEPPA has the sensitivity for detecting changes in CD68-positive microglial/macrophage activation in hemiparkinsonian rhesus macaques treated with allogeneic grafts of induced pluripotent stem cell-derived midbrain dopaminergic neurons (iPSC-mDA). METHODS In vivo positron emission tomography (PET) imaging with [18F]FEPPA was used in conjunction with postmortem CD68 immunostaining to evaluate neuroinflammation in the brains of hemiparkinsonian rhesus macaques (n = 6) that received allogeneic iPSC-mDA grafts in the putamen ipsilateral to MPTP administration. RESULTS Based on assessment of radiotracer uptake and confirmed by visual inspection of the imaging data, nonhuman primates with allogeneic grafts showed increased [18F]FEPPA binding at the graft sites relative to the contralateral putamen. From PET asymmetry analysis of the images, the mean asymmetry index of the monkeys was AI = - 0.085 ± 0.018. Evaluation and scoring of CD68 immunoreactivity by an investigator blind to the treatment identified significantly more neuroinflammation in the grafted areas of the putamen compared to the contralateral putamen (p = 0.0004). [18F]FEPPA PET AI showed a positive correlation with CD68 immunoreactivity AI ratings in the monkeys (Spearman's ρ = 0.94; p = 0.005). CONCLUSION These findings reveal that [18F]FEPPA PET is an effective marker for detecting increased CD68-positive microglial/macrophage activation and demonstrates sufficient sensitivity to detect changes in neuroinflammation in vivo following allogeneic cell engraftment.
Collapse
Affiliation(s)
- Matthew Zammit
- Department of Medical Physics, University of Wisconsin-Madison, Madison, WI, USA
- Waisman Center, University of Wisconsin-Madison, Madison, WI, USA
| | - Yunlong Tao
- Waisman Center, University of Wisconsin-Madison, Madison, WI, USA
| | - Miles E Olsen
- Department of Medical Physics, University of Wisconsin-Madison, Madison, WI, USA
| | - Jeanette Metzger
- Preclinical Parkinson's Research Program, Wisconsin National Primate Research Center, University of Wisconsin-Madison, 1220 Capitol Court, Madison, WI, 53715, USA
- Cellular and Molecular Pathology Training Program, University of Wisconsin-Madison, Madison, WI, USA
| | - Scott C Vermilyea
- Preclinical Parkinson's Research Program, Wisconsin National Primate Research Center, University of Wisconsin-Madison, 1220 Capitol Court, Madison, WI, 53715, USA
- Neuroscience Training Program, University of Wisconsin-Madison, Madison, WI, USA
- Department of Neuroscience, University of Minnesota-Twin Cities, Minneapolis, MN, USA
| | - Kathryn Bjornson
- Preclinical Parkinson's Research Program, Wisconsin National Primate Research Center, University of Wisconsin-Madison, 1220 Capitol Court, Madison, WI, 53715, USA
- Neuroscience Training Program, University of Wisconsin-Madison, Madison, WI, USA
| | - Maxim Slesarev
- Waisman Center, University of Wisconsin-Madison, Madison, WI, USA
| | - Walter F Block
- Department of Medical Physics, University of Wisconsin-Madison, Madison, WI, USA
| | - Kerri Fuchs
- Preclinical Parkinson's Research Program, Wisconsin National Primate Research Center, University of Wisconsin-Madison, 1220 Capitol Court, Madison, WI, 53715, USA
| | - Sean Phillips
- Preclinical Parkinson's Research Program, Wisconsin National Primate Research Center, University of Wisconsin-Madison, 1220 Capitol Court, Madison, WI, 53715, USA
| | - Viktorya Bondarenko
- Preclinical Parkinson's Research Program, Wisconsin National Primate Research Center, University of Wisconsin-Madison, 1220 Capitol Court, Madison, WI, 53715, USA
| | - Su-Chun Zhang
- Waisman Center, University of Wisconsin-Madison, Madison, WI, USA
- Department of Neuroscience, University of Wisconsin-Madison, Madison, WI, USA
| | - Marina E Emborg
- Department of Medical Physics, University of Wisconsin-Madison, Madison, WI, USA.
- Preclinical Parkinson's Research Program, Wisconsin National Primate Research Center, University of Wisconsin-Madison, 1220 Capitol Court, Madison, WI, 53715, USA.
- Cellular and Molecular Pathology Training Program, University of Wisconsin-Madison, Madison, WI, USA.
- Neuroscience Training Program, University of Wisconsin-Madison, Madison, WI, USA.
| | - Bradley T Christian
- Department of Medical Physics, University of Wisconsin-Madison, Madison, WI, USA
- Waisman Center, University of Wisconsin-Madison, Madison, WI, USA
| |
Collapse
|
|
16
|
Yu H, Hu W, Song X, Zhao Y. Generation of Multipotent Stem Cells from Adult Human Peripheral Blood Following the Treatment with Platelet-Derived Mitochondria. Cells 2020; 9:cells9061350. [PMID: 32485922 PMCID: PMC7349571 DOI: 10.3390/cells9061350] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Revised: 05/26/2020] [Accepted: 05/28/2020] [Indexed: 12/19/2022] Open
Abstract
Autologous stem cells are highly preferred for cellular therapy to treat human diseases. Mitochondria are organelles normally located in cytoplasm. Our recent studies demonstrated the differentiation of adult peripheral blood-derived insulin-producing cells (designated PB-IPC) into hematopoietic-like cells after the treatment with platelet-derived mitochondria. To further explore the molecular mechanism and their therapeutic potentials, through confocal and electron microscopy, we found that mitochondria enter cells and directly penetrate the nucleus of PB-IPC after the treatment with platelet-derived mitochondria, where they can produce profound epigenetic changes as demonstrated by RNA-seq and PCR array. Ex vivo functional studies established that mitochondrion-induced PB-IPC (miPB-IPC) can give rise to retinal pigment epithelium (RPE) cells and neuronal cells in the presence of different inducers. Further colony analysis highlighted the multipotent capability of the differentiation of PB-IPC into three-germ layer-derived cells. Therefore, these data indicate a novel function of mitochondria in cellular reprogramming, leading to the generation of autologous multipotent stem cells for clinical applications.
Collapse
Affiliation(s)
| | | | | | - Yong Zhao
- Correspondence: ; Tel.: +201-880-3460
| |
Collapse
|
|
17
|
Nejadnik H, Tseng J, Daldrup-Link H. Magnetic resonance imaging of stem cell-macrophage interactions with ferumoxytol and ferumoxytol-derived nanoparticles. WILEY INTERDISCIPLINARY REVIEWS. NANOMEDICINE AND NANOBIOTECHNOLOGY 2019; 11:e1552. [PMID: 30734542 PMCID: PMC6579657 DOI: 10.1002/wnan.1552] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/24/2018] [Revised: 12/13/2018] [Accepted: 12/19/2018] [Indexed: 01/07/2023]
Abstract
"Off the shelf" allogeneic stem cell transplants and stem cell nano-composites are being used for the treatment of degenerative bone diseases. However, major and minor histocompatibility antigens of therapeutic cell transplants can be recognized as foreign and lead to their rejection by the host immune system. If a host immune response is identified within the first week post-transplant, immune modulating therapies could be applied to prevent graft failure and support engraftment. Ferumoxytol (Feraheme™) is an FDA approved iron oxide nanoparticle preparation for the treatment of anemia in patients. Ferumoxytol can be used "off label" as an magnetic resonance (MR) contrast agent, as these nanoparticles provide measurable signal changes on magnetic resonance imaging (MRI). In this focused review article, we will discuss three methods to localize and identify innate immune responses to stem cell transplants using ferumoxytol-enhanced MRI, which are based on tracking stem cells, tracking macrophages or detecting mediators of cell death: (a) monitor MRI signal changes of ferumoxytol-labeled stem cells in the presence or absence of innate immune responses, (b) monitor influx of ferumoxytol-labeled macrophages into stem cell implants, and (c) monitor apoptosis of stem cell implants with caspase-3 activatable nanoparticles. These techniques can detect transplant failure at an early stage, when immune-modulating interventions can potentially preserve the viability of the cell transplants and thereby improve bone and cartilage repair outcomes. Approaches 1 and 2 are immediately translatable to clinical practice. This article is categorized under: Diagnostic Tools > in vivo Nanodiagnostics and Imaging Nanotechnology Approaches to Biology > Cells at the Nanoscale Diagnostic Tools > Biosensing.
Collapse
Affiliation(s)
- Hossein Nejadnik
- Department of Radiology, Molecular Imaging Program at Stanford (MIPS), Stanford University, Stanford, California
| | - Jessica Tseng
- Department of Radiology, Molecular Imaging Program at Stanford (MIPS), Stanford University, Stanford, California
| | - Heike Daldrup-Link
- Department of Radiology, Molecular Imaging Program at Stanford (MIPS), Stanford University, Stanford, California
| |
Collapse
|
|
18
|
Stem Cell Extracellular Vesicles in Skin Repair. Bioengineering (Basel) 2018; 6:bioengineering6010004. [PMID: 30598033 PMCID: PMC6466099 DOI: 10.3390/bioengineering6010004] [Citation(s) in RCA: 63] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Revised: 12/19/2018] [Accepted: 12/25/2018] [Indexed: 12/13/2022] Open
Abstract
Stem cell extracellular vesicles (EVs) have been widely studied because of their excellent therapeutic potential. EVs from different types of stem cell can improve vascularization as well as aid in the treatment of cancer and neurodegenerative diseases. The skin is a complex organ that is susceptible to various types of injury. Strategies designed to restore epithelial tissues’ integrity with stem cell EVs have shown promising results. Different populations of stem cell EVs are able to control inflammation, accelerate skin cell migration and proliferation, control wound scarring, improve angiogenesis, and even ameliorate signs of skin aging. However, large-scale production of such stem cell EVs for human therapy is still a challenge. This review focuses on recent studies that explore the potential of stem cell EVs in skin wound healing and skin rejuvenation, as well as challenges of their use in therapy.
Collapse
|
|
19
|
Kwon SG, Kwon YW, Lee TW, Park GT, Kim JH. Recent advances in stem cell therapeutics and tissue engineering strategies. Biomater Res 2018; 22:36. [PMID: 30598836 PMCID: PMC6299977 DOI: 10.1186/s40824-018-0148-4] [Citation(s) in RCA: 126] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Accepted: 12/07/2018] [Indexed: 12/19/2022] Open
Abstract
Background Tissue regeneration includes delivering specific types of cells or cell products to injured tissues or organs for restoration of tissue and organ function. Stem cell therapy has drawn considerable attention since transplantation of stem cells can overcome the limitations of autologous transplantation of patient’s tissues; however, it is not perfect for treating diseases. To overcome the hurdles associated with stem cell therapy, tissue engineering techniques have been developed. Development of stem cell technology in combination with tissue engineering has opened new ways of producing engineered tissue substitutes. Several studies have shown that this combination of tissue engineering and stem cell technologies enhances cell viability, differentiation, and therapeutic efficacy of transplanted stem cells. Main body Stem cells that can be used for tissue regeneration include mesenchymal stem cells, embryonic stem cells, and induced pluripotent stem cells. Transplantation of stem cells alone into injured tissues exhibited low therapeutic efficacy due to poor viability and diminished regenerative activity of transplanted cells. In this review, we will discuss the progress of biomedical engineering, including scaffolds, biomaterials, and tissue engineering techniques to overcome the low therapeutic efficacy of stem cells and to treat human diseases. Conclusion The combination of stem cell and tissue engineering techniques overcomes the limitations of stem cells in therapy of human diseases, and presents a new path toward regeneration of injured tissues.
Collapse
Affiliation(s)
- Seong Gyu Kwon
- 1Department of Physiology, Pusan National University School of Medicine, Yangsan, 50612 Gyeongsangnam-do Republic of Korea
| | - Yang Woo Kwon
- 1Department of Physiology, Pusan National University School of Medicine, Yangsan, 50612 Gyeongsangnam-do Republic of Korea
| | - Tae Wook Lee
- 1Department of Physiology, Pusan National University School of Medicine, Yangsan, 50612 Gyeongsangnam-do Republic of Korea
| | - Gyu Tae Park
- 1Department of Physiology, Pusan National University School of Medicine, Yangsan, 50612 Gyeongsangnam-do Republic of Korea
| | - Jae Ho Kim
- 1Department of Physiology, Pusan National University School of Medicine, Yangsan, 50612 Gyeongsangnam-do Republic of Korea.,2Research Institute of Convergence Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan, 50612 Republic of Korea
| |
Collapse
|
|
20
|
Abstract
The retina is a very fine and layered neural tissue, which vitally depends on the preservation of cells, structure, connectivity and vasculature to maintain vision. There is an urgent need to find technical and biological solutions to major challenges associated with functional replacement of retinal cells. The major unmet challenges include generating sufficient numbers of specific cell types, achieving functional integration of transplanted cells, especially photoreceptors, and surgical delivery of retinal cells or tissue without triggering immune responses, inflammation and/or remodeling. The advances of regenerative medicine enabled generation of three-dimensional tissues (organoids), partially recreating the anatomical structure, biological complexity and physiology of several tissues, which are important targets for stem cell replacement therapies. Derivation of retinal tissue in a dish creates new opportunities for cell replacement therapies of blindness and addresses the need to preserve retinal architecture to restore vision. Retinal cell therapies aimed at preserving and improving vision have achieved many improvements in the past ten years. Retinal organoid technologies provide a number of solutions to technical and biological challenges associated with functional replacement of retinal cells to achieve long-term vision restoration. Our review summarizes the progress in cell therapies of retina, with focus on human pluripotent stem cell-derived retinal tissue, and critically evaluates the potential of retinal organoid approaches to solve a major unmet clinical need—retinal repair and vision restoration in conditions caused by retinal degeneration and traumatic ocular injuries. We also analyze obstacles in commercialization of retinal organoid technology for clinical application.
Collapse
|
|
21
|
Pesaresi M, Sebastian-Perez R, Cosma MP. Dedifferentiation, transdifferentiation and cell fusion: in vivo reprogramming strategies for regenerative medicine. FEBS J 2018; 286:1074-1093. [PMID: 30103260 DOI: 10.1111/febs.14633] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2018] [Revised: 07/01/2018] [Accepted: 08/10/2018] [Indexed: 12/23/2022]
Abstract
Regenerative capacities vary enormously across the animal kingdom. In contrast to most cold-blooded vertebrates, mammals, including humans, have very limited regenerative capacity when it comes to repairing damaged or degenerating tissues. Here, we review the main mechanisms of tissue regeneration, underlying the importance of cell dedifferentiation and reprogramming. We discuss the significance of cell fate and identity changes in the context of regenerative medicine, with a particular focus on strategies aiming at the promotion of the body's self-repairing mechanisms. We also introduce some of the most recent advances that have resulted in complete reprogramming of cell identity in vivo. Lastly, we discuss the main challenges that need to be addressed in the near future to develop in vivo reprogramming approaches with therapeutic potential.
Collapse
Affiliation(s)
- Martina Pesaresi
- Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Spain
| | - Ruben Sebastian-Perez
- Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Spain
| | - Maria Pia Cosma
- Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Spain.,Universitat Pompeu Fabra (UPF), Barcelona, Spain.,Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
| |
Collapse
|
|
22
|
Li K, Chan CT, Nejadnik H, Lenkov OD, Wolterman C, Paulmurugan R, Yang H, Gambhir SS, Daldrup-Link HE. Ferumoxytol-based Dual-modality Imaging Probe for Detection of Stem Cell Transplant Rejection. Nanotheranostics 2018; 2:306-319. [PMID: 29977742 PMCID: PMC6030766 DOI: 10.7150/ntno.26389] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2018] [Accepted: 06/14/2018] [Indexed: 12/24/2022] Open
Abstract
Purpose: Stem cell transplants are an effective approach to repair large bone defects. However, comprehensive techniques to monitor the fate of transplanted stem cells in vivo are lacking. Such strategies would enable corrective interventions at an early stage and greatly benefit the development of more successful tissue regeneration approaches. In this study, we designed and synthesized a dual-modality imaging probe (Feru-AFC) that can simultaneously localize transplanted stem cells and diagnose immune rejection-induced apoptosis at an early stage in vivo. Methods: We used a customized caspase-3 cleavable peptide-dye conjugate to modify the surface of clinically approved ferumoxytol nanoparticles (NPs) to generate the dual-modality imaging probe with fluorescence "light-up" feature. We labeled both mouse mesenchymal stem cells (mMSCs, matched) and pig mesenchymal stem cells (pMSCs, mismatched) with the probe and transplanted the labeled cells with biocompatible scaffold at the calvarial defects in mice. We then employed intravital microscopy (IVM) and magnetic resonance imaging (MRI) to investigate the localization, engraftment, and viability of matched and mismatched stem cells, followed by histological analyses to evaluate the results obtained from in vivo studies. Results: The Feru-AFC NPs showed good cellular uptake efficiency in the presence of lipofectin without cytotoxicity to mMSCs and pMSCs. The fluorescence of Feru-AFC NPs was turned on inside apoptotic cells due to the cleavage of peptide by activated caspase-3 and subsequent release of fluorescence dye molecules. Upon transplantation at the calvarial defects in mice, the intense fluorescence from the cleaved Feru-AFC NPs in apoptotic pMSCs was observed with a concomitant decrease in the overall cell number from days 1 to 6. In contrast, the Feru-AFC NP-treated mMSCs exhibited minimum fluorescence and the cell number also remained similar. Furthermore, in vivo MRI of the Feru-AFC NP-treated mMSC and pMSCs transplants could clearly indicate the localization of matched and mismatched cells, respectively. Conclusions: We successfully developed a dual-modality imaging probe for evaluation of the localization and viability of transplanted stem cells in mouse calvarial defects. Using ferumoxytol NPs as the platform, our Feru-AFC NPs are superparamagnetic and display a fluorescence "light-up" signature upon exposure to activated caspase-3. The results show that the probe is a promising tool for long-term stem cell tracking through MRI and early diagnosis of immune rejection-induced apoptosis through longitudinal fluorescence imaging.
Collapse
Affiliation(s)
- Kai Li
- Department of Radiology and Molecular Imaging Program at Stanford (MIPS), Stanford School of Medicine, Stanford, CA 94305.,Institute of Materials Research and Engineering, ASTAR, Singapore, 138634
| | - Carmel T Chan
- Department of Radiology and Molecular Imaging Program at Stanford (MIPS), Stanford School of Medicine, Stanford, CA 94305
| | - Hossein Nejadnik
- Department of Radiology and Molecular Imaging Program at Stanford (MIPS), Stanford School of Medicine, Stanford, CA 94305
| | - Olga D Lenkov
- Department of Radiology and Molecular Imaging Program at Stanford (MIPS), Stanford School of Medicine, Stanford, CA 94305
| | - Cody Wolterman
- Department of Radiology and Molecular Imaging Program at Stanford (MIPS), Stanford School of Medicine, Stanford, CA 94305
| | - Ramasamy Paulmurugan
- Department of Radiology and Molecular Imaging Program at Stanford (MIPS), Stanford School of Medicine, Stanford, CA 94305
| | - Huaxiao Yang
- Stanford Cardiovascular Institute, Stanford, CA 94305
| | - Sanjiv Sam Gambhir
- Department of Radiology and Molecular Imaging Program at Stanford (MIPS), Stanford School of Medicine, Stanford, CA 94305
| | - Heike E Daldrup-Link
- Department of Radiology and Molecular Imaging Program at Stanford (MIPS), Stanford School of Medicine, Stanford, CA 94305
| |
Collapse
|
|
23
|
Veron AD, Bienboire-Frosini C, Feron F, Codecasa E, Deveze A, Royer D, Watelet P, Asproni P, Sadelli K, Chabaud C, Stamegna JC, Fagot J, Khrestchatisky M, Cozzi A, Roman FS, Pageat P, Mengoli M, Girard SD. Isolation and characterization of olfactory ecto-mesenchymal stem cells from eight mammalian genera. BMC Vet Res 2018; 14:17. [PMID: 29343270 PMCID: PMC5772688 DOI: 10.1186/s12917-018-1342-2] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2017] [Accepted: 01/11/2018] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND Stem cell-based therapies are an attractive option to promote regeneration and repair defective tissues and organs. Thanks to their multipotency, high proliferation rate and the lack of major ethical limitations, "olfactory ecto-mesenchymal stem cells" (OE-MSCs) have been described as a promising candidate to treat a variety of damaged tissues. Easily accessible in the nasal cavity of most mammals, these cells are highly suitable for autologous cell-based therapies and do not face issues associated with other stem cells. However, their clinical use in humans and animals is limited due to a lack of preclinical studies on autologous transplantation and because no well-established methods currently exist to cultivate these cells. Here we evaluated the feasibility of collecting, purifying and amplifying OE-MSCs from different mammalian genera with the goal of promoting their interest in veterinary regenerative medicine. Biopsies of olfactory mucosa from eight mammalian genera (mouse, rat, rabbit, sheep, dog, horse, gray mouse lemur and macaque) were collected, using techniques derived from those previously used in humans and rats. The possibility of amplifying these cells and their stemness features and differentiation capability were then evaluated. RESULTS Biopsies were successfully performed on olfactory mucosa without requiring the sacrifice of the donor animal, except mice. Cell populations were rapidly generated from olfactory mucosa explants. These cells displayed similar key features of their human counterparts: a fibroblastic morphology, a robust expression of nestin, an ability to form spheres and similar expression of surface markers (CD44, CD73). Moreover, most of them also exhibited high proliferation rates and clonogenicity with genus-specific properties. Finally, OE-MSCs also showed the ability to differentiate into mesodermal lineages. CONCLUSIONS This article describes for the first time how millions of OE-MSCs can be quickly and easily obtained from different mammalian genera through protocols that are well-suited for autologous transplantations. Moreover, their multipotency makes them relevant to evaluate therapeutic application in a wide variety of tissue injury models. This study paves the way for the development of new fundamental and clinical studies based on OE-MSCs transplantation and suggests their interest in veterinary medicine.
Collapse
Affiliation(s)
- Antoine D Veron
- IRSEA, Research Institute in Semiochemistry and Applied Ethology, Quartier Salignan, 84400, Apt, France. .,Aix Marseille Univ, CNRS, NICN, Marseille, France.
| | - Cécile Bienboire-Frosini
- IRSEA, Research Institute in Semiochemistry and Applied Ethology, Quartier Salignan, 84400, Apt, France
| | - François Feron
- Aix Marseille Univ, CNRS, NICN, Marseille, France.,Inserm CBT 1409, Centre d'Investigations Cliniques en Biothérapie, Marseille, France
| | - Elisa Codecasa
- IRSEA, Research Institute in Semiochemistry and Applied Ethology, Quartier Salignan, 84400, Apt, France
| | - Arnaud Deveze
- Département ORL, Hôpital Universitaire Nord, AP-HM, Marseille, France.,Aix-Marseille Univ, IFSTTAR, LBA, Marseille, France
| | - Dany Royer
- Centre Hospitalier Vétérinaire Pommery, 51100, Reims, France
| | - Paul Watelet
- Société Hippique Le frigouyé, 30650, Saze, France
| | - Pietro Asproni
- IRSEA, Research Institute in Semiochemistry and Applied Ethology, Quartier Salignan, 84400, Apt, France
| | | | - Camille Chabaud
- IRSEA, Research Institute in Semiochemistry and Applied Ethology, Quartier Salignan, 84400, Apt, France
| | | | - Joël Fagot
- Aix-Marseille Univ, CNRS, LPC, Marseille, France
| | | | - Alessandro Cozzi
- IRSEA, Research Institute in Semiochemistry and Applied Ethology, Quartier Salignan, 84400, Apt, France
| | | | - Patrick Pageat
- IRSEA, Research Institute in Semiochemistry and Applied Ethology, Quartier Salignan, 84400, Apt, France
| | - Manuel Mengoli
- IRSEA, Research Institute in Semiochemistry and Applied Ethology, Quartier Salignan, 84400, Apt, France
| | - Stéphane D Girard
- Aix Marseille Univ, CNRS, NICN, Marseille, France.,Present address: Vect-Horus S.A.S., Faculté de Médecine Secteur Nord, CS80011, Boulevard Pierre Dramard, 13344, Marseille, Cedex 15, France
| |
Collapse
|
|
24
|
Steinhoff G, Nesteruk J, Wolfien M, Große J, Ruch U, Vasudevan P, Müller P. Stem cells and heart disease - Brake or accelerator? Adv Drug Deliv Rev 2017; 120:2-24. [PMID: 29054357 DOI: 10.1016/j.addr.2017.10.007] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2017] [Revised: 10/12/2017] [Accepted: 10/13/2017] [Indexed: 12/11/2022]
Abstract
After two decades of intensive research and attempts of clinical translation, stem cell based therapies for cardiac diseases are not getting closer to clinical success. This review tries to unravel the obstacles and focuses on underlying mechanisms as the target for regenerative therapies. At present, the principal outcome in clinical therapy does not reflect experimental evidence. It seems that the scientific obstacle is a lack of integration of knowledge from tissue repair and disease mechanisms. Recent insights from clinical trials delineate mechanisms of stem cell dysfunction and gene defects in repair mechanisms as cause of atherosclerosis and heart disease. These findings require a redirection of current practice of stem cell therapy and a reset using more detailed analysis of stem cell function interfering with disease mechanisms. To accelerate scientific development the authors suggest intensifying unified computational data analysis and shared data knowledge by using open-access data platforms.
Collapse
Affiliation(s)
- Gustav Steinhoff
- University Medicine Rostock, Department of Cardiac Surgery, Reference and Translation Center for Cardiac Stem Cell Therapy, University Medical Center Rostock, Schillingallee 35, 18055 Rostock, Germany.
| | - Julia Nesteruk
- University Medicine Rostock, Department of Cardiac Surgery, Reference and Translation Center for Cardiac Stem Cell Therapy, University Medical Center Rostock, Schillingallee 35, 18055 Rostock, Germany.
| | - Markus Wolfien
- University Rostock, Institute of Computer Science, Department of Systems Biology and Bioinformatics, Ulmenstraße 69, 18057 Rostock, Germany.
| | - Jana Große
- University Medicine Rostock, Department of Cardiac Surgery, Reference and Translation Center for Cardiac Stem Cell Therapy, University Medical Center Rostock, Schillingallee 35, 18055 Rostock, Germany.
| | - Ulrike Ruch
- University Medicine Rostock, Department of Cardiac Surgery, Reference and Translation Center for Cardiac Stem Cell Therapy, University Medical Center Rostock, Schillingallee 35, 18055 Rostock, Germany.
| | - Praveen Vasudevan
- University Medicine Rostock, Department of Cardiac Surgery, Reference and Translation Center for Cardiac Stem Cell Therapy, University Medical Center Rostock, Schillingallee 35, 18055 Rostock, Germany.
| | - Paula Müller
- University Medicine Rostock, Department of Cardiac Surgery, Reference and Translation Center for Cardiac Stem Cell Therapy, University Medical Center Rostock, Schillingallee 35, 18055 Rostock, Germany.
| |
Collapse
|
|
25
|
Wu CE, Yu CW, Chang KW, Chou WH, Lu CY, Ghelfi E, Wu FC, Jan PS, Huang MC, Allard P, Lin SP, Ho HN, Chen HF. Comparative global immune-related gene profiling of somatic cells, human pluripotent stem cells and their derivatives: implication for human lymphocyte proliferation. Exp Mol Med 2017; 49:e376. [PMID: 28912571 PMCID: PMC5628273 DOI: 10.1038/emm.2017.134] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2016] [Revised: 02/19/2017] [Accepted: 03/19/2017] [Indexed: 12/14/2022] Open
Abstract
Human pluripotent stem cells (hPSCs), including embryonic stem cells (ESCs) and induced PSCs (iPSCs), represent potentially unlimited cell sources for clinical applications. Previous studies have suggested that hPSCs may benefit from immune privilege and limited immunogenicity, as reflected by the reduced expression of major histocompatibility complex class-related molecules. Here we investigated the global immune-related gene expression profiles of human ESCs, hiPSCs and somatic cells and identified candidate immune-related genes that may alter their immunogenicity. The expression levels of global immune-related genes were determined by comparing undifferentiated and differentiated stem cells and three types of human somatic cells: dermal papilla cells, ovarian granulosa cells and foreskin fibroblast cells. We identified the differentially expressed genes CD24, GATA3, PROM1, THBS2, LY96, IFIT3, CXCR4, IL1R1, FGFR3, IDO1 and KDR, which overlapped with selected immune-related gene lists. In further analyses, mammalian target of rapamycin complex (mTOR) signaling was investigated in the differentiated stem cells following treatment with rapamycin and lentiviral transduction with specific short-hairpin RNAs. We found that the inhibition of mTOR signal pathways significantly downregulated the immunogenicity of differentiated stem cells. We also tested the immune responses induced in differentiated stem cells by mixed lymphocyte reactions. We found that CD24- and GATA3-deficient differentiated stem cells including neural lineage cells had limited abilities to activate human lymphocytes. By analyzing the transcriptome signature of immune-related genes, we observed a tendency of the hPSCs to differentiate toward an immune cell phenotype. Taken together, these data identify candidate immune-related genes that might constitute valuable targets for clinical applications.
Collapse
Affiliation(s)
- Chia-Eng Wu
- College of Medicine, Graduate Institute of Immunology, National Taiwan University, Taipei, Taiwan
| | - Chen-Wei Yu
- Department of Obstetrics and Gynecology, College of Medicine and the Hospital, National Taiwan University, Taipei, Taiwan.,College of Medicine, Graduate Institute of Medical Genomics and Proteomics, National Taiwan University, Taipei, Taiwan
| | - Kai-Wei Chang
- Genome and Systems Biology Degree Program, National Taiwan University, Taipei, Taiwan
| | - Wen-Hsi Chou
- Department of Obstetrics and Gynecology, College of Medicine and the Hospital, National Taiwan University, Taipei, Taiwan.,College of Medicine, Graduate Institute of Medical Genomics and Proteomics, National Taiwan University, Taipei, Taiwan
| | - Chen-Yu Lu
- College of Medicine, Graduate Institute of Medical Genomics and Proteomics, National Taiwan University, Taipei, Taiwan
| | - Elisa Ghelfi
- Department of Environmental Health, Harvard University - Harvard T.H. Chan School of Public Health, Molecular and Integrative Physiological Sciences, Boston, MA, USA
| | - Fang-Chun Wu
- Department of Obstetrics and Gynecology, College of Medicine and the Hospital, National Taiwan University, Taipei, Taiwan.,College of Medicine, Graduate Institute of Medical Genomics and Proteomics, National Taiwan University, Taipei, Taiwan
| | - Pey-Shynan Jan
- Department of Obstetrics and Gynecology, College of Medicine and the Hospital, National Taiwan University, Taipei, Taiwan.,College of Medicine, Graduate Institute of Medical Genomics and Proteomics, National Taiwan University, Taipei, Taiwan
| | - Mei-Chi Huang
- College of Medicine, Graduate Institute of Medical Genomics and Proteomics, National Taiwan University, Taipei, Taiwan
| | - Patrick Allard
- Department of Environment Health Science, University of California, Los Angeles, Los Angeles, CA, USA
| | - Shau-Ping Lin
- Genome and Systems Biology Degree Program, National Taiwan University, Taipei, Taiwan.,Institute of Biotechnology, National Taiwan University, Taipei, Taiwan.,Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan
| | - Hong-Nerng Ho
- College of Medicine, Graduate Institute of Immunology, National Taiwan University, Taipei, Taiwan.,Department of Obstetrics and Gynecology, College of Medicine and the Hospital, National Taiwan University, Taipei, Taiwan.,College of Medicine, Graduate Institute of Medical Genomics and Proteomics, National Taiwan University, Taipei, Taiwan
| | - Hsin-Fu Chen
- Department of Obstetrics and Gynecology, College of Medicine and the Hospital, National Taiwan University, Taipei, Taiwan.,College of Medicine, Graduate Institute of Medical Genomics and Proteomics, National Taiwan University, Taipei, Taiwan
| |
Collapse
|
|
26
|
Precise immune tolerance for hPSC derivatives in clinical application. Cell Immunol 2017; 326:15-23. [PMID: 28866278 DOI: 10.1016/j.cellimm.2017.08.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2017] [Revised: 08/03/2017] [Accepted: 08/04/2017] [Indexed: 11/22/2022]
Abstract
Human pluripotent stem cells (hPSCs) promise a foreseeing future for regeneration medicine and cell replacement therapy with their abilities to produce almost any types of somatic cells of the body. The complicated immunogenicity of hPSC derivatives and context dependent responses in variable transplantations greatly hurdle the practical application of hPSCs in clinic. Especially for applications of hPSCs, induction of immune tolerance at the same time increases the risks of tumorigenesis. Over the past few years, thanks to the progress in immunology and practices in organ transplantation, endeavors on exploring strategies to induce long term protection of allogeneic transplants have shed light on overcoming this barrier. Novel genetic engineering techniques also allow to precisely cradle the immune response of transplantation. Here we reviewed the current understanding on immunogenicity, and efforts have been attempted on inducing immune tolerance for hPSC derivatives, with extra focus on modifying the graft cells. We also glimpse on employing cutting-edge genome editing technologies for this purpose, which will potentially endow hPSC derivatives with the nature of wide spectrum drugs for therapy.
Collapse
|
|
27
|
Zhao Y, Jiang Z, Delgado E, Li H, Zhou H, Hu W, Perez-Basterrechea M, Janostakova A, Tan Q, Wang J, Mao M, Yin Z, Zhang Y, Li Y, Li Q, Zhou J, Li Y, Martinez Revuelta E, Maria García-Gala J, Wang H, Perez-Lopez S, Alvarez-Viejo M, Menendez E, Moss T, Guindi E, Otero J. Platelet-Derived Mitochondria Display Embryonic Stem Cell Markers and Improve Pancreatic Islet β-cell Function in Humans. Stem Cells Transl Med 2017; 6:1684-1697. [PMID: 28685960 PMCID: PMC5689778 DOI: 10.1002/sctm.17-0078] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2017] [Accepted: 05/24/2017] [Indexed: 01/09/2023] Open
Abstract
Diabetes is a major global health issue and the number of individuals with type 1 diabetes (T1D) and type 2 diabetes (T2D) increases annually across multiple populations. Research to develop a cure must overcome multiple immune dysfunctions and the shortage of pancreatic islet β cells, but these challenges have proven intractable despite intensive research effort more than the past decades. Stem Cell Educator (SCE) therapy-which uses only autologous blood immune cells that are externally exposed to cord blood stem cells adhering to the SCE device, has previously been proven safe and effective in Chinese and Spanish subjects for the improvement of T1D, T2D, and other autoimmune diseases. Here, 4-year follow-up studies demonstrated the long-term safety and clinical efficacy of SCE therapy for the treatment of T1D and T2D. Mechanistic studies found that the nature of platelets was modulated in diabetic subjects after receiving SCE therapy. Platelets and their released mitochondria display immune tolerance-associated markers that can modulate the proliferation and function of immune cells. Notably, platelets also expressed embryonic stem cell- and pancreatic islet β-cell-associated markers that are encoded by mitochondrial DNA. Using freshly-isolated human pancreatic islets, ex vivo studies established that platelet-releasing mitochondria can migrate to pancreatic islets and be taken up by islet β cells, leading to the proliferation and enhancement of islet β-cell functions. These findings reveal new mechanisms underlying SCE therapy and open up new avenues to improve the treatment of diabetes in clinics. Stem Cells Translational Medicine 2017;6:1684-1697.
Collapse
Affiliation(s)
- Yong Zhao
- Department of Research, Hackensack University Medical Center, Hackensack, New Jersey, USA
| | - Zhaoshun Jiang
- Section of Endocrinology, General Hospital of Jinan Military Command, Jinan, Shandong, People's Republic of China
| | - Elias Delgado
- Endocrinology Section, Department of Medicine, University of Oviedo, Oviedo, Spain
| | - Heng Li
- Section of Neurology, Jinan Central Hospital, Jinan, Shandong, People's Republic of China
| | - Huimin Zhou
- Section of Endocrinology, The First Affiliated Hospital of Hebei Medical University, Shijiazhuang, Hebei, People's Republic of China
| | - Wei Hu
- Department of Research, Hackensack University Medical Center, Hackensack, New Jersey, USA
| | - Marcos Perez-Basterrechea
- Unit of Transplants, Cell Therapy and Regenerative Medicine, Hospital Universitario Central de Asturias, Oviedo, Spain
| | - Anna Janostakova
- Department of Research, Hackensack University Medical Center, Hackensack, New Jersey, USA
| | - Qidong Tan
- Section of Endocrinology, General Hospital of Jinan Military Command, Jinan, Shandong, People's Republic of China
| | - Jing Wang
- Section of Endocrinology, General Hospital of Jinan Military Command, Jinan, Shandong, People's Republic of China
| | - Mao Mao
- Department of Research, Hackensack University Medical Center, Hackensack, New Jersey, USA
| | - Zhaohui Yin
- Section of Endocrinology, General Hospital of Jinan Military Command, Jinan, Shandong, People's Republic of China
| | - Ye Zhang
- Tianhe Stem Cell Biotechnologies Inc., Jinan, Shandong, People's Republic of China
| | - Ying Li
- Tianhe Stem Cell Biotechnologies Inc., Jinan, Shandong, People's Republic of China
| | - Quanhai Li
- Cell Therapy Center, The First Affiliated Hospital of Hebei Medical University, Shijiazhuang, Hebei, People's Republic of China
| | - Jing Zhou
- Cell Therapy Center, The First Affiliated Hospital of Hebei Medical University, Shijiazhuang, Hebei, People's Republic of China
| | - Yunxiang Li
- Tianhe Stem Cell Biotechnologies Inc., Jinan, Shandong, People's Republic of China
| | - Eva Martinez Revuelta
- Hematology and Hemotherapy Service, Hospital Universitario Central de Asturias, Oviedo, Spain
| | - Jose Maria García-Gala
- Hematology and Hemotherapy Service, Hospital Universitario Central de Asturias, Oviedo, Spain
| | - Honglan Wang
- Department of Research, Hackensack University Medical Center, Hackensack, New Jersey, USA
| | - Silvia Perez-Lopez
- Unit of Transplants, Cell Therapy and Regenerative Medicine, Hospital Universitario Central de Asturias, Oviedo, Spain
| | - Maria Alvarez-Viejo
- Unit of Transplants, Cell Therapy and Regenerative Medicine, Hospital Universitario Central de Asturias, Oviedo, Spain
| | - Edelmiro Menendez
- Endocrinology Section, Department of Medicine, University of Oviedo, Oviedo, Spain
| | - Thomas Moss
- CORD:USE Cord Blood Bank, Orlando, Florida, USA
| | | | - Jesus Otero
- Unit of Transplants, Cell Therapy and Regenerative Medicine, Hospital Universitario Central de Asturias, Oviedo, Spain
| |
Collapse
|
|
28
|
From Blood to Lesioned Brain: An In Vitro Study on Migration Mechanisms of Human Nasal Olfactory Stem Cells. Stem Cells Int 2017; 2017:1478606. [PMID: 28698717 PMCID: PMC5494110 DOI: 10.1155/2017/1478606] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2017] [Accepted: 03/19/2017] [Indexed: 02/08/2023] Open
Abstract
Stem cell-based therapies critically rely on selective cell migration toward pathological or injured areas. We previously demonstrated that human olfactory ectomesenchymal stem cells (OE-MSCs), derived from an adult olfactory lamina propria, migrate specifically toward an injured mouse hippocampus after transplantation in the cerebrospinal fluid and promote functional recoveries. However, the mechanisms controlling their recruitment and homing remain elusive. Using an in vitro model of blood-brain barrier (BBB) and secretome analysis, we observed that OE-MSCs produce numerous proteins allowing them to cross the endothelial wall. Then, pan-genomic DNA microarrays identified signaling molecules that lesioned mouse hippocampus overexpressed. Among the most upregulated cytokines, both recombinant SPP1/osteopontin and CCL2/MCP-1 stimulate OE-MSC migration whereas only CCL2 exerts a chemotactic effect. Additionally, OE-MSCs express SPP1 receptors but not the CCL2 cognate receptor, suggesting a CCR2-independent pathway through other CCR receptors. These results confirm that OE-MSCs can be attracted by chemotactic cytokines overexpressed in inflamed areas and demonstrate that CCL2 is an important factor that could promote OE-MSC engraftment, suggesting improvement for future clinical trials.
Collapse
|
|
29
|
Heggeness MH, Strong N, Wooley PH, Yang SY. Quiescent pluripotent stem cells reside within murine peripheral nerves that can be stimulated to proliferate by recombinant human bone morphogenic protein 2 or by nerve trauma. Spine J 2017; 17:252-259. [PMID: 27664339 DOI: 10.1016/j.spinee.2016.09.016] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2016] [Revised: 08/24/2016] [Accepted: 09/12/2016] [Indexed: 02/03/2023]
Abstract
BACKGROUND The clinical use of recombinant human bone morphogenic protein 2 (rhBMP-2, Infuse) has been associated with nerve-related complications including new-onset sciatica, and retrograde ejaculation. PURPOSE To better understand the interaction of rhBMP-2 and peripheral nerves with the intent of making procedures safer. STUDY DESIGN/SETTING Using a mouse model to examine the direct effect of diluted rhBMP-2 (Infuse) on murine sciatic nerves. METHODS Animal studies were approved by the Institutional Animal Care and Use Committee. Balb/c mouse sciatic nerves were surgically exposed and 60 ng (in 10 µL) of rhBMP-2 was applied to the nerve. In separate experiments, the sciatic nerves were subjected to mechanical compression using forceps (and not exposed to rhBMP-2). The third group of mice received direct injection of the same amount of rhBMP-2, or sterile saline as a control, into the hamstring area of the posterior thigh without surgery. Mouse limbs with intact sciatic nerve were collected at 24, 48, or 72 hours after treatment for histology processing. A separate set of identically treated sciatic nerves were retrieved from mice at the same time points and cells were isolated by collagenase and trypsin digestion. The isolated cells were cultured in a stem cell medium containing 20% knockout serum and human leukemia inhibitory factor. Immunohistochemical or immunofluorescent cell stains against KLF4, Sox2, c-Myc, and Oct4 were performed on the mouse tissue sections and cell culture slides. In addition, real-time polymerase chain reaction (PCR) was performed to quantify the mRNA expression profiles of the stem cell marker genes in cultured cells. RESULTS Profound morphological changes of the mouse sciatic nerves were noted after exposure to rhBMP-2, with a rapid and robust cell proliferation within the nerves followed by migration of these cells into surrounding tissue. Immunohistochemical stain revealed strong nuclear stains of KLF4, Sox2, Oct4, and c-Myc on the overwhelming majority of these proliferating cells in the nerve. Intramuscular injections of rhBMP-2 or willful physical compression of the nerves showed similar cell proliferation effects as the direct application of Infuse to the sciatic nerve. The cells in stem cell culture medium grew steadily without feeder cells and appeared fairly uniform. They were adherent to substrate and were motile. Double fluorescent staining on the cells indicated colocalizationof all pairs of the four stem cell markers in the cell nuclei. Real-time PCR confirmed the strong mRNA expressions of KLF4, Sox2, Oct4, and c-Myc in these isolated cells. CONCLUSION Exposure to BMP-2 causes a marked proliferation of previously quiescent cells within peripheral nerves. These cells simultaneously express KLF4, Sox2, Oct4, and c-Myc, the transcription factors that confer embryonic pluripotency. Work described in the companion paper reveals some of the differentiation capacity of the cells and their likely clinical significance. In addition, the effects of direct exposure of nerves to rhBMP-2 as described here should clearly illuminate the mechanism of BMP-2-related nerve complications. We would suggest that the use of this agent in proximity to known neural structures should only be done with extreme caution.
Collapse
Affiliation(s)
- Michael H Heggeness
- Department of Orthopaedic Surgery, University of Kansas School of Medicine-Wichita, Wichita, Kansas, USA.
| | - Nora Strong
- Department of Orthopaedic Surgery, University of Kansas School of Medicine-Wichita, Wichita, Kansas, USA
| | - Paul H Wooley
- Department of Orthopaedic Surgery, University of Kansas School of Medicine-Wichita, Wichita, Kansas, USA
| | - Shang-You Yang
- Department of Orthopaedic Surgery, University of Kansas School of Medicine-Wichita, Wichita, Kansas, USA; Department of Biological Sciences, Wichita State University, Wichita, KS, USA
| |
Collapse
|
|
30
|
Daldrup-Link HE, Chan C, Lenkov O, Taghavigarmestani S, Nazekati T, Nejadnik H, Chapelin F, Khurana A, Tong X, Yang F, Pisani L, Longaker M, Gambhir SS. Detection of Stem Cell Transplant Rejection with Ferumoxytol MR Imaging: Correlation of MR Imaging Findings with Those at Intravital Microscopy. Radiology 2017; 284:495-507. [PMID: 28128708 DOI: 10.1148/radiol.2017161139] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Purpose To determine whether endogenous labeling of macrophages with clinically applicable nanoparticles enables noninvasive detection of innate immune responses to stem cell transplants with magnetic resonance (MR) imaging. Materials and Methods Work with human stem cells was approved by the institutional review board and the stem cell research oversight committee, and animal experiments were approved by the administrative panel on laboratory animal care. Nine immunocompetent Sprague-Dawley rats received intravenous injection of ferumoxytol, and 18 Jax C57BL/6-Tg (Csf1r-EGFP-NGFR/FKBP1A/TNFRSF6) 2Bck/J mice received rhodamine-conjugated ferumoxytol. Then, 48 hours later, immune-matched or mismatched stem cells were implanted into osteochondral defects of the knee joints of experimental rats and calvarial defects of Jax mice. All animals underwent serial MR imaging and intravital microscopy (IVM) up to 4 weeks after surgery. Macrophages of Jax C57BL/6-Tg (Csf1r-EGFP-NGFR/FKBP1A/TNFRSF6) 2Bck/J mice express enhanced green fluorescent protein (GFP), which enables in vivo correlation of ferumoxytol enhancement at MR imaging with macrophage quantities at IVM. All quantitative data were compared between experimental groups by using a mixed linear model and t tests. Results Immune-mismatched stem cell implants demonstrated stronger ferumoxytol enhancement than did matched stem cell implants. At 4 weeks, T2 values of mismatched implants were significantly lower than those of matched implants in osteochondral defects of female rats (mean, 10.72 msec for human stem cells and 11.55 msec for male rat stem cells vs 15.45 msec for sex-matched rat stem cells; P = .02 and P = .04, respectively) and calvarial defects of recipient mice (mean, 21.7 msec vs 27.1 msec, respectively; P = .0444). This corresponded to increased recruitment of enhanced GFP- and rhodamine-ferumoxytol-positive macrophages into stem cell transplants, as visualized with IVM and histopathologic examination. Conclusion Endogenous labeling of macrophages with ferumoxytol enables noninvasive detection of innate immune responses to stem cell transplants with MR imaging. © RSNA, 2017 Online supplemental material is available for this article.
Collapse
Affiliation(s)
- Heike E Daldrup-Link
- From the Department of Radiology, Molecular Imaging Program at Stanford (MIPS) (H.E.D.L., C.C., O.L., S.T., T.N., H.N., F.C., A.K., F.Y., L.P., M.L., S.S.G.), Department of Pediatrics (H.E.D.L.), Institute for Stem Cell Biology and Regenerative Medicine (H.E.D.L.), Department of Orthopaedic Surgery (X.T., F.Y.), Department of Bioengineering (F.Y., S.S.G.), Department of Surgery, Division of Plastic and Reconstructive Surgery (M.L.), and Department of Materials Science and Engineering (M.L., S.S.G.), Stanford University, 725 Welch Rd, Room 1665, Stanford, CA 94305-5614
| | - Carmel Chan
- From the Department of Radiology, Molecular Imaging Program at Stanford (MIPS) (H.E.D.L., C.C., O.L., S.T., T.N., H.N., F.C., A.K., F.Y., L.P., M.L., S.S.G.), Department of Pediatrics (H.E.D.L.), Institute for Stem Cell Biology and Regenerative Medicine (H.E.D.L.), Department of Orthopaedic Surgery (X.T., F.Y.), Department of Bioengineering (F.Y., S.S.G.), Department of Surgery, Division of Plastic and Reconstructive Surgery (M.L.), and Department of Materials Science and Engineering (M.L., S.S.G.), Stanford University, 725 Welch Rd, Room 1665, Stanford, CA 94305-5614
| | - Olga Lenkov
- From the Department of Radiology, Molecular Imaging Program at Stanford (MIPS) (H.E.D.L., C.C., O.L., S.T., T.N., H.N., F.C., A.K., F.Y., L.P., M.L., S.S.G.), Department of Pediatrics (H.E.D.L.), Institute for Stem Cell Biology and Regenerative Medicine (H.E.D.L.), Department of Orthopaedic Surgery (X.T., F.Y.), Department of Bioengineering (F.Y., S.S.G.), Department of Surgery, Division of Plastic and Reconstructive Surgery (M.L.), and Department of Materials Science and Engineering (M.L., S.S.G.), Stanford University, 725 Welch Rd, Room 1665, Stanford, CA 94305-5614
| | - Seyedmeghdad Taghavigarmestani
- From the Department of Radiology, Molecular Imaging Program at Stanford (MIPS) (H.E.D.L., C.C., O.L., S.T., T.N., H.N., F.C., A.K., F.Y., L.P., M.L., S.S.G.), Department of Pediatrics (H.E.D.L.), Institute for Stem Cell Biology and Regenerative Medicine (H.E.D.L.), Department of Orthopaedic Surgery (X.T., F.Y.), Department of Bioengineering (F.Y., S.S.G.), Department of Surgery, Division of Plastic and Reconstructive Surgery (M.L.), and Department of Materials Science and Engineering (M.L., S.S.G.), Stanford University, 725 Welch Rd, Room 1665, Stanford, CA 94305-5614
| | - Toktam Nazekati
- From the Department of Radiology, Molecular Imaging Program at Stanford (MIPS) (H.E.D.L., C.C., O.L., S.T., T.N., H.N., F.C., A.K., F.Y., L.P., M.L., S.S.G.), Department of Pediatrics (H.E.D.L.), Institute for Stem Cell Biology and Regenerative Medicine (H.E.D.L.), Department of Orthopaedic Surgery (X.T., F.Y.), Department of Bioengineering (F.Y., S.S.G.), Department of Surgery, Division of Plastic and Reconstructive Surgery (M.L.), and Department of Materials Science and Engineering (M.L., S.S.G.), Stanford University, 725 Welch Rd, Room 1665, Stanford, CA 94305-5614
| | - Hossein Nejadnik
- From the Department of Radiology, Molecular Imaging Program at Stanford (MIPS) (H.E.D.L., C.C., O.L., S.T., T.N., H.N., F.C., A.K., F.Y., L.P., M.L., S.S.G.), Department of Pediatrics (H.E.D.L.), Institute for Stem Cell Biology and Regenerative Medicine (H.E.D.L.), Department of Orthopaedic Surgery (X.T., F.Y.), Department of Bioengineering (F.Y., S.S.G.), Department of Surgery, Division of Plastic and Reconstructive Surgery (M.L.), and Department of Materials Science and Engineering (M.L., S.S.G.), Stanford University, 725 Welch Rd, Room 1665, Stanford, CA 94305-5614
| | - Fanny Chapelin
- From the Department of Radiology, Molecular Imaging Program at Stanford (MIPS) (H.E.D.L., C.C., O.L., S.T., T.N., H.N., F.C., A.K., F.Y., L.P., M.L., S.S.G.), Department of Pediatrics (H.E.D.L.), Institute for Stem Cell Biology and Regenerative Medicine (H.E.D.L.), Department of Orthopaedic Surgery (X.T., F.Y.), Department of Bioengineering (F.Y., S.S.G.), Department of Surgery, Division of Plastic and Reconstructive Surgery (M.L.), and Department of Materials Science and Engineering (M.L., S.S.G.), Stanford University, 725 Welch Rd, Room 1665, Stanford, CA 94305-5614
| | - Aman Khurana
- From the Department of Radiology, Molecular Imaging Program at Stanford (MIPS) (H.E.D.L., C.C., O.L., S.T., T.N., H.N., F.C., A.K., F.Y., L.P., M.L., S.S.G.), Department of Pediatrics (H.E.D.L.), Institute for Stem Cell Biology and Regenerative Medicine (H.E.D.L.), Department of Orthopaedic Surgery (X.T., F.Y.), Department of Bioengineering (F.Y., S.S.G.), Department of Surgery, Division of Plastic and Reconstructive Surgery (M.L.), and Department of Materials Science and Engineering (M.L., S.S.G.), Stanford University, 725 Welch Rd, Room 1665, Stanford, CA 94305-5614
| | - Xinming Tong
- From the Department of Radiology, Molecular Imaging Program at Stanford (MIPS) (H.E.D.L., C.C., O.L., S.T., T.N., H.N., F.C., A.K., F.Y., L.P., M.L., S.S.G.), Department of Pediatrics (H.E.D.L.), Institute for Stem Cell Biology and Regenerative Medicine (H.E.D.L.), Department of Orthopaedic Surgery (X.T., F.Y.), Department of Bioengineering (F.Y., S.S.G.), Department of Surgery, Division of Plastic and Reconstructive Surgery (M.L.), and Department of Materials Science and Engineering (M.L., S.S.G.), Stanford University, 725 Welch Rd, Room 1665, Stanford, CA 94305-5614
| | - Fan Yang
- From the Department of Radiology, Molecular Imaging Program at Stanford (MIPS) (H.E.D.L., C.C., O.L., S.T., T.N., H.N., F.C., A.K., F.Y., L.P., M.L., S.S.G.), Department of Pediatrics (H.E.D.L.), Institute for Stem Cell Biology and Regenerative Medicine (H.E.D.L.), Department of Orthopaedic Surgery (X.T., F.Y.), Department of Bioengineering (F.Y., S.S.G.), Department of Surgery, Division of Plastic and Reconstructive Surgery (M.L.), and Department of Materials Science and Engineering (M.L., S.S.G.), Stanford University, 725 Welch Rd, Room 1665, Stanford, CA 94305-5614
| | - Laura Pisani
- From the Department of Radiology, Molecular Imaging Program at Stanford (MIPS) (H.E.D.L., C.C., O.L., S.T., T.N., H.N., F.C., A.K., F.Y., L.P., M.L., S.S.G.), Department of Pediatrics (H.E.D.L.), Institute for Stem Cell Biology and Regenerative Medicine (H.E.D.L.), Department of Orthopaedic Surgery (X.T., F.Y.), Department of Bioengineering (F.Y., S.S.G.), Department of Surgery, Division of Plastic and Reconstructive Surgery (M.L.), and Department of Materials Science and Engineering (M.L., S.S.G.), Stanford University, 725 Welch Rd, Room 1665, Stanford, CA 94305-5614
| | - Michael Longaker
- From the Department of Radiology, Molecular Imaging Program at Stanford (MIPS) (H.E.D.L., C.C., O.L., S.T., T.N., H.N., F.C., A.K., F.Y., L.P., M.L., S.S.G.), Department of Pediatrics (H.E.D.L.), Institute for Stem Cell Biology and Regenerative Medicine (H.E.D.L.), Department of Orthopaedic Surgery (X.T., F.Y.), Department of Bioengineering (F.Y., S.S.G.), Department of Surgery, Division of Plastic and Reconstructive Surgery (M.L.), and Department of Materials Science and Engineering (M.L., S.S.G.), Stanford University, 725 Welch Rd, Room 1665, Stanford, CA 94305-5614
| | - Sanjiv Sam Gambhir
- From the Department of Radiology, Molecular Imaging Program at Stanford (MIPS) (H.E.D.L., C.C., O.L., S.T., T.N., H.N., F.C., A.K., F.Y., L.P., M.L., S.S.G.), Department of Pediatrics (H.E.D.L.), Institute for Stem Cell Biology and Regenerative Medicine (H.E.D.L.), Department of Orthopaedic Surgery (X.T., F.Y.), Department of Bioengineering (F.Y., S.S.G.), Department of Surgery, Division of Plastic and Reconstructive Surgery (M.L.), and Department of Materials Science and Engineering (M.L., S.S.G.), Stanford University, 725 Welch Rd, Room 1665, Stanford, CA 94305-5614
| |
Collapse
|
|
31
|
Miyagawa S, Fukushima S, Imanishi Y, Kawamura T, Mochizuki-Oda N, Masuda S, Sawa Y. Building A New Treatment For Heart Failure-Transplantation of Induced Pluripotent Stem Cell-derived Cells into the Heart. Curr Gene Ther 2016; 16:5-13. [PMID: 26785736 PMCID: PMC4997929 DOI: 10.2174/1566523216666160119094143] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2015] [Revised: 01/07/2016] [Accepted: 01/08/2016] [Indexed: 02/08/2023]
Abstract
Advanced cardiac failure is a progressive intractable disease and is the main cause of mortality and morbidity worldwide. Since this pathology is represented by a definite decrease in cardiomyocyte number, supplementation of functional cardiomyocytes into the heart would hypothetically be an ideal therapeutic option. Recently, unlimited in vitro production of human functional cardiomyocytes was established by using induced pluripotent stem cell (iPSC) technology, which avoids the use of human embryos. A number of basic studies including ours have shown that transplantation of iPSC-derived cardiomyocytes (iPSC-CMs) into the damaged heart leads to recovery of cardiac function, thereby establishing “proof-of-concept” of this iPSC-transplantation therapy. However, considering clinical application of this therapy, its feasibility, safety, and therapeutic efficacy need to be further investigated in the pre-clinical stage. This review summarizes up-to-date important topics related to safety and efficacy of iPSC-CMs transplantation therapy for cardiac disease and discusses the prospects for this treatment in clinical studies.
Collapse
Affiliation(s)
| | | | | | | | | | | | - Yoshiki Sawa
- Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
| |
Collapse
|
|
32
|
Bružauskaitė I, Bironaitė D, Bagdonas E, Bernotienė E. Scaffolds and cells for tissue regeneration: different scaffold pore sizes-different cell effects. Cytotechnology 2016. [PMID: 26091616 DOI: 10.1007/sl0616-0159895-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/12/2023] Open
Abstract
During the last decade biomaterial sciences and tissue engineering have become new scientific fields supplying rising demand of regenerative therapy. Tissue engineering requires consolidation of a broad knowledge of cell biology and modern biotechnology investigating biocompatibility of materials and their application for the reconstruction of damaged organs and tissues. Stem cell-based tissue regeneration started from the direct cell transplantation into damaged tissues or blood vessels. However, it is difficult to track transplanted cells and keep them in one particular place of diseased organ. Recently, new technologies such as cultivation of stem cell on the scaffolds and subsequently their implantation into injured tissue have been extensively developed. Successful tissue regeneration requires scaffolds with particular mechanical stability or biodegradability, appropriate size, surface roughness and porosity to provide a suitable microenvironment for the sufficient cell-cell interaction, cell migration, proliferation and differentiation. Further functioning of implanted cells highly depends on the scaffold pore sizes that play an essential role in nutrient and oxygen diffusion and waste removal. In addition, pore sizes strongly influence cell adhesion, cell-cell interaction and cell transmigration across the membrane depending on the various purposes of tissue regeneration. Therefore, this review will highlight contemporary tendencies in application of non-degradable scaffolds and stem cells in regenerative medicine with a particular focus on the pore sizes significantly affecting final recover of diseased organs.
Collapse
Affiliation(s)
- Ieva Bružauskaitė
- Department of Regenerative Medicine, State Research Institute Centre for Innovative Medicine, Zygimantu 9, 01102, Vilnius, Lithuania
| | - Daiva Bironaitė
- Department of Stem Cell Biology, State Research Institute Centre for Innovative Medicine, Zygimantu 9, 01102, Vilnius, Lithuania.
| | - Edvardas Bagdonas
- Department of Regenerative Medicine, State Research Institute Centre for Innovative Medicine, Zygimantu 9, 01102, Vilnius, Lithuania
| | - Eiva Bernotienė
- Department of Regenerative Medicine, State Research Institute Centre for Innovative Medicine, Zygimantu 9, 01102, Vilnius, Lithuania
| |
Collapse
|
|
33
|
Cui D, Wang J, Zeng Y, Rao L, Chen H, Li W, Li Y, Li H, Cui C, Xiao L. Generating hESCs with reduced immunogenicity by disrupting TAP1 or TAPBP. Biosci Biotechnol Biochem 2016; 80:1484-91. [PMID: 27068360 DOI: 10.1080/09168451.2016.1165601] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Human embryonic stem cells (hESCs) are thought to be a promising resource for cell therapy, while it has to face the major problem of graft immunological rejection. Major histocompatibility complex (MHC) class I expressed on the cell surface is the major cause of graft rejection. Transporter associated with antigen presentation 1 (TAP1) and TAP-associated glycoprotein (TAPBP) play important roles in regulating MHC class I expression. In this study, we generated TAP1- and TAPBP-deficient hESC lines, respectively, using transcription activator-like effector nucleases technique. These cells showed deficient expression of MHC class I on the cell surface and reduced immunogenicity compared with wild types, but maintained normal pluripotency, karyotypes, and differentiation ability. Thus, our findings are instrumental in developing a universal cell resource with both pluripotency and hypo-immunogenicity for transplantation therapy in the future.
Collapse
Affiliation(s)
- Di Cui
- a College of Animal Science, Stem Cell and Developmental Biology Research Center , Zhejiang University , Hangzhou , P.R. China.,b School of Medicine , Zhejiang University , Hangzhou , P.R. China
| | - Jinping Wang
- a College of Animal Science, Stem Cell and Developmental Biology Research Center , Zhejiang University , Hangzhou , P.R. China.,b School of Medicine , Zhejiang University , Hangzhou , P.R. China
| | - Yelin Zeng
- a College of Animal Science, Stem Cell and Developmental Biology Research Center , Zhejiang University , Hangzhou , P.R. China.,b School of Medicine , Zhejiang University , Hangzhou , P.R. China
| | - Lingjun Rao
- c Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences , Shanghai , P.R. China
| | - Haide Chen
- a College of Animal Science, Stem Cell and Developmental Biology Research Center , Zhejiang University , Hangzhou , P.R. China.,b School of Medicine , Zhejiang University , Hangzhou , P.R. China
| | - Wenling Li
- a College of Animal Science, Stem Cell and Developmental Biology Research Center , Zhejiang University , Hangzhou , P.R. China.,b School of Medicine , Zhejiang University , Hangzhou , P.R. China
| | - Yang Li
- a College of Animal Science, Stem Cell and Developmental Biology Research Center , Zhejiang University , Hangzhou , P.R. China.,b School of Medicine , Zhejiang University , Hangzhou , P.R. China
| | - Hui Li
- d Xiangtan Center Hospital , Hunan , P.R. China
| | - Chun Cui
- e Wuxi Medical School , Jiangnan University , Wuxi , P.R. China
| | - Lei Xiao
- a College of Animal Science, Stem Cell and Developmental Biology Research Center , Zhejiang University , Hangzhou , P.R. China.,b School of Medicine , Zhejiang University , Hangzhou , P.R. China
| |
Collapse
|
|
34
|
Sackett SD, Brown ME, Tremmel DM, Ellis T, Burlingham WJ, Odorico JS. Modulation of human allogeneic and syngeneic pluripotent stem cells and immunological implications for transplantation. Transplant Rev (Orlando) 2016; 30:61-70. [PMID: 26970668 DOI: 10.1016/j.trre.2016.02.001] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2015] [Accepted: 02/05/2016] [Indexed: 01/20/2023]
Abstract
Tissues derived from induced pluripotent stem cells (iPSCs) are a promising source of cells for building various regenerative medicine therapies; from simply transplanting cells to reseeding decellularized organs to reconstructing multicellular tissues. Although reprogramming strategies for producing iPSCs have improved, the clinical use of iPSCs is limited by the presence of unique human leukocyte antigen (HLA) genes, the main immunologic barrier to transplantation. In order to overcome the immunological hurdles associated with allogeneic tissues and organs, the generation of patient-histocompatible iPSCs (autologous or HLA-matched cells) provides an attractive platform for personalized medicine. However, concerns have been raised as to the fitness, safety and immunogenicity of iPSC derivatives because of variable differentiation potential of different lines and the identification of genetic and epigenetic aberrations that can occur during the reprogramming process. In addition, significant cost and regulatory barriers may deter commercialization of patient specific therapies in the short-term. Nonetheless, recent studies provide some evidence of immunological benefit for using autologous iPSCs. Yet, more studies are needed to evaluate the immunogenicity of various autologous and allogeneic human iPSC-derived cell types as well as test various methods to abrogate rejection. Here, we present perspectives of using allogeneic vs. autologous iPSCs for transplantation therapies and the advantages and disadvantages of each related to differentiation potential, immunogenicity, genetic stability and tumorigenicity. We also review the current literature on the immunogenicity of syngeneic iPSCs and discuss evidence that questions the feasibility of HLA-matched iPSC banks. Finally, we will discuss emerging methods of abrogating or reducing host immune responses to PSC derivatives.
Collapse
Affiliation(s)
- S D Sackett
- Division of Transplantation, Department of Surgery, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, USA
| | - M E Brown
- Division of Transplantation, Department of Surgery, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, USA
| | - D M Tremmel
- Division of Transplantation, Department of Surgery, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, USA
| | - T Ellis
- Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, USA
| | - W J Burlingham
- Division of Transplantation, Department of Surgery, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, USA
| | - J S Odorico
- Division of Transplantation, Department of Surgery, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, USA.
| |
Collapse
|
|
35
|
Scaffolds and cells for tissue regeneration: different scaffold pore sizes-different cell effects. Cytotechnology 2015. [PMID: 26091616 DOI: 10.1007/s10616-015-9895-4.] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/29/2022] Open
Abstract
During the last decade biomaterial sciences and tissue engineering have become new scientific fields supplying rising demand of regenerative therapy. Tissue engineering requires consolidation of a broad knowledge of cell biology and modern biotechnology investigating biocompatibility of materials and their application for the reconstruction of damaged organs and tissues. Stem cell-based tissue regeneration started from the direct cell transplantation into damaged tissues or blood vessels. However, it is difficult to track transplanted cells and keep them in one particular place of diseased organ. Recently, new technologies such as cultivation of stem cell on the scaffolds and subsequently their implantation into injured tissue have been extensively developed. Successful tissue regeneration requires scaffolds with particular mechanical stability or biodegradability, appropriate size, surface roughness and porosity to provide a suitable microenvironment for the sufficient cell-cell interaction, cell migration, proliferation and differentiation. Further functioning of implanted cells highly depends on the scaffold pore sizes that play an essential role in nutrient and oxygen diffusion and waste removal. In addition, pore sizes strongly influence cell adhesion, cell-cell interaction and cell transmigration across the membrane depending on the various purposes of tissue regeneration. Therefore, this review will highlight contemporary tendencies in application of non-degradable scaffolds and stem cells in regenerative medicine with a particular focus on the pore sizes significantly affecting final recover of diseased organs.
Collapse
|
|
36
|
Scaffolds and cells for tissue regeneration: different scaffold pore sizes-different cell effects. Cytotechnology 2015; 68:355-69. [PMID: 26091616 DOI: 10.1007/s10616-015-9895-4] [Citation(s) in RCA: 447] [Impact Index Per Article: 44.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2015] [Accepted: 06/12/2015] [Indexed: 12/12/2022] Open
Abstract
During the last decade biomaterial sciences and tissue engineering have become new scientific fields supplying rising demand of regenerative therapy. Tissue engineering requires consolidation of a broad knowledge of cell biology and modern biotechnology investigating biocompatibility of materials and their application for the reconstruction of damaged organs and tissues. Stem cell-based tissue regeneration started from the direct cell transplantation into damaged tissues or blood vessels. However, it is difficult to track transplanted cells and keep them in one particular place of diseased organ. Recently, new technologies such as cultivation of stem cell on the scaffolds and subsequently their implantation into injured tissue have been extensively developed. Successful tissue regeneration requires scaffolds with particular mechanical stability or biodegradability, appropriate size, surface roughness and porosity to provide a suitable microenvironment for the sufficient cell-cell interaction, cell migration, proliferation and differentiation. Further functioning of implanted cells highly depends on the scaffold pore sizes that play an essential role in nutrient and oxygen diffusion and waste removal. In addition, pore sizes strongly influence cell adhesion, cell-cell interaction and cell transmigration across the membrane depending on the various purposes of tissue regeneration. Therefore, this review will highlight contemporary tendencies in application of non-degradable scaffolds and stem cells in regenerative medicine with a particular focus on the pore sizes significantly affecting final recover of diseased organs.
Collapse
|
|
37
|
Multipotent stromal cells derived from common marmoset Callithrix jacchus within alginate 3D environment: Effect of cryopreservation procedures. Cryobiology 2015; 71:103-11. [PMID: 25980899 DOI: 10.1016/j.cryobiol.2015.05.001] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2015] [Revised: 05/05/2015] [Accepted: 05/06/2015] [Indexed: 11/23/2022]
Abstract
Multipotent stromal cells derived from the common marmoset monkey Callithrix jacchus (cjMSCs) possess high phylogenetic similarity to humans, with a great potential for preclinical studies in the field of regenerative medicine. Safe and effective long-term storage of cells is of great significance to clinical and research applications. Encapsulation of such cell types within alginate beads that can mimic an extra-cellular matrix and provide a supportive environment for cells during cryopreservation, has several advantages over freezing of cells in suspension. In this study we have analysed the effect of dimethyl sulfoxide (Me2SO, 2.5-10%, v/v) and pre-freeze loading time of alginate encapsulated cjMSCs in Me2SO (0-45 min) on the viability and metabolic activity of the cells after freezing using a slow cooling rate (-1°C/min). It was found that these parameters affect the stability and homogeneity of alginate beads after thawing. Moreover, the cjMSCs can be frozen in alginate beads with lower Me2SO concentration of 7.5% after 30 min of loading, while retaining high cryopreservation outcome. We demonstrated the maximum viability, membrane integrity and metabolic activity of the cells under optimized, less cytotoxic conditions. The results of this study are another step forward towards the application of cryopreservation for the long-term storage and subsequent applications of transplants in cell-based therapies.
Collapse
|
|
38
|
Kruse V, Hamann C, Monecke S, Cyganek L, Elsner L, Hübscher D, Walter L, Streckfuss-Bömeke K, Guan K, Dressel R. Human Induced Pluripotent Stem Cells Are Targets for Allogeneic and Autologous Natural Killer (NK) Cells and Killing Is Partly Mediated by the Activating NK Receptor DNAM-1. PLoS One 2015; 10:e0125544. [PMID: 25950680 PMCID: PMC4423859 DOI: 10.1371/journal.pone.0125544] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2014] [Accepted: 03/25/2015] [Indexed: 02/07/2023] Open
Abstract
Human induced pluripotent stem cells (hiPSCs) could be used to generate autologous cells for therapeutic purposes, which are expected to be tolerated by the recipient. However, iPSC-derived grafts are at risk of giving rise to teratomas in the host, if residuals of tumorigenic cells are not rejected by the recipient. We have analyzed the susceptibility of hiPSC lines to allogeneic and autologous natural killer (NK) cells. IL-2-activated, in contrast to resting NK cells killed hiPSC lines efficiently (P = 1.69 x 10(-39)). Notably, the specific lysis of the individual hiPSC lines by IL-2-activated NK cells was significantly different (P = 1.72 x 10(-6)) and ranged between 46 % and 64 % in 51Cr-release assays when compared to K562 cells. The hiPSC lines were killed by both allogeneic and autologous NK cells although autologous NK cells were less efficient (P=8.63 x 10(-6)). Killing was partly dependent on the activating NK receptor DNAM-1 (P = 8.22 x 10(-7)). The DNAM-1 ligands CD112 and CD155 as well as the NKG2D ligands MICA and MICB were expressed on the hiPSC lines. Low amounts of human leukocyte antigen (HLA) class I proteins, which serve as ligands for inhibitory and activating NK receptors were also detected. Thus, the susceptibility to NK cell killing appears to constitute a common feature of hiPSCs. Therefore, NK cells might reduce the risk of teratoma formation even after autologous transplantations of pluripotent stem cell-derived grafts that contain traces of pluripotent cells.
Collapse
Affiliation(s)
- Vanessa Kruse
- Department of Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany
| | - Carina Hamann
- Department of Cellular and Molecular Immunology, University Medical Center Göttingen, Göttingen, Germany
- DZHK (German Center for Cardiovascular Research), Partner site Göttingen, Germany
| | - Sebastian Monecke
- Department of Cellular and Molecular Immunology, University Medical Center Göttingen, Göttingen, Germany
- DZHK (German Center for Cardiovascular Research), Partner site Göttingen, Germany
| | - Lukas Cyganek
- Department of Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany
- DZHK (German Center for Cardiovascular Research), Partner site Göttingen, Germany
| | - Leslie Elsner
- Department of Cellular and Molecular Immunology, University Medical Center Göttingen, Göttingen, Germany
| | - Daniela Hübscher
- Department of Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany
- DZHK (German Center for Cardiovascular Research), Partner site Göttingen, Germany
| | - Lutz Walter
- Primate Genetics Laboratory, German Primate Center, Göttingen, Germany
| | - Katrin Streckfuss-Bömeke
- Department of Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany
- DZHK (German Center for Cardiovascular Research), Partner site Göttingen, Germany
| | - Kaomei Guan
- Department of Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany
- DZHK (German Center for Cardiovascular Research), Partner site Göttingen, Germany
- * E-mail: (RD); (KG)
| | - Ralf Dressel
- Department of Cellular and Molecular Immunology, University Medical Center Göttingen, Göttingen, Germany
- DZHK (German Center for Cardiovascular Research), Partner site Göttingen, Germany
- * E-mail: (RD); (KG)
| |
Collapse
|
|
39
|
Controlling immune rejection is a fail-safe system against potential tumorigenicity after human iPSC-derived neural stem cell transplantation. PLoS One 2015; 10:e0116413. [PMID: 25706286 PMCID: PMC4338009 DOI: 10.1371/journal.pone.0116413] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2014] [Accepted: 12/09/2014] [Indexed: 02/07/2023] Open
Abstract
Our previous work reported functional recovery after transplantation of mouse and human induced pluripotent stem cell-derived neural stem/progenitor cells (hiPSC-NS/PCs) into rodent models of spinal cord injury (SCI). Although hiPSC-NS/PCs proved useful for the treatment of SCI, the tumorigenicity of the transplanted cells must be resolved before they can be used in clinical applications. The current study sought to determine the feasibility of ablation of the tumors formed after hiPSC-NS/PC transplantation through immunoregulation. Tumorigenic hiPSC-NS/PCs were transplanted into the intact spinal cords of immunocompetent BALB/cA mice with or without immunosuppressant treatment. In vivo bioluminescence imaging was used to evaluate the chronological survival and growth of the transplanted cells. The graft survival rate was 0% in the group without immunosuppressants versus 100% in the group with immunosuppressants. Most of the mice that received immunosuppressants exhibited hind-limb paralysis owing to tumor growth at 3 months after iPSC-NS/PC transplantation. Histological analysis showed that the tumors shared certain characteristics with low-grade gliomas rather than with teratomas. After confirming the progression of the tumors in immunosuppressed mice, the immunosuppressant agents were discontinued, resulting in the complete rejection of iPSC-NS/PC-derived masses within 42 days after drug cessation. In accordance with the tumor rejection, hind-limb motor function was recovered in all of the mice. Moreover, infiltration of microglia and lymphocytes was observed during the course of tumor rejection, along with apoptosis of iPSC-NS/PC-generated cells. Thus, immune rejection can be used as a fail-safe system against potential tumorigenicity after transplantation of iPSC-NS/PCs to treat SCI.
Collapse
|
|
40
|
Wang X, Qin J, Zhao RC, Zenke M. Reduced immunogenicity of induced pluripotent stem cells derived from Sertoli cells. PLoS One 2014; 9:e106110. [PMID: 25166861 PMCID: PMC4148392 DOI: 10.1371/journal.pone.0106110] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2014] [Accepted: 08/02/2014] [Indexed: 12/12/2022] Open
Abstract
Sertoli cells constitute the structural framework in testis and provide an immune-privileged environment for germ cells. Induced pluripotent stem cells (iPS cells) resemble embryonic stem cells (ES cells) and are generated from somatic cells by expression of specific reprogramming transcription factors. Here, we used C57BL/6 (B6) Sertoli cells to generate iPS cells (Ser-iPS cells) and compared the immunogenicity of Ser-iPS cells with iPS cells derived from mouse embryonic fibroblast (MEF-iPS cells). Ser-iPS cells were injected into syngeneic mice to test for their in vivo immunogenicity in teratoma assay. Teratoma assay allows assessing in vivo immunogenicity of iPS cells and of their differentiated progeny simultaneously. We observed that early-passage Ser-iPS cells formed more teratomas with less immune cell infiltration and tissue damage and necrosis than MEF-iPS cells. Differentiating Ser-iPS cells in embryoid bodies (EBs) showed reduced T cell activation potential compared to MEF-iPS cells, which was similar to syngeneic ES cells. However, Ser-iPS cells lost their reduced immunogenicity in vivo after extended passaging in vitro and late-passage Ser-iPS cells exhibited an immunogenicity similar to MEF-iPS cells. These findings indicate that early-passage Ser-iPS cells retain some somatic memory of Sertoli cells that impacts on immunogenicity of iPS cells and iPS cell-derived cells in vivo and in vitro. Our data suggest that immune-privileged Sertoli cells might represent a preferred source for iPS cell generation, if it comes to the use of iPS cell-derived cells for transplantation.
Collapse
Affiliation(s)
- Xiaoying Wang
- Institute for Biomedical Engineering, Department of Cell Biology, RWTH Aachen University Medical School, Aachen, Germany
- Helmholtz Institute for Biomedical Engineering, RWTH Aachen University, Aachen, Germany
| | - Jie Qin
- Institute for Biomedical Engineering, Department of Cell Biology, RWTH Aachen University Medical School, Aachen, Germany
- Helmholtz Institute for Biomedical Engineering, RWTH Aachen University, Aachen, Germany
| | - Robert Chunhua Zhao
- Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China
- Center of Excellence in Tissue Engineering, Peking Union Medical College Hospital, Beijing, China
| | - Martin Zenke
- Institute for Biomedical Engineering, Department of Cell Biology, RWTH Aachen University Medical School, Aachen, Germany
- Helmholtz Institute for Biomedical Engineering, RWTH Aachen University, Aachen, Germany
- * E-mail:
| |
Collapse
|
|
41
|
Willinger T, Flavell RA. ESCaping rejection: A step forward for embryonic-stem-cell-based regenerative medicine. Cell Stem Cell 2014; 14:3-4. [PMID: 24388169 DOI: 10.1016/j.stem.2013.12.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
The use of human embryonic stem cells (hESCs) for regenerative medicine currently faces several hurdles, including immune rejection of transplanted cells. Now in Cell Stem Cell, Rong et al. (2014) describe a strategy to protect hESCs from immune rejection while avoiding systemic immunosuppression, potentially facilitating clinical implementation of hESC-based therapies.
Collapse
Affiliation(s)
- Tim Willinger
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Richard A Flavell
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA; Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520, USA.
| |
Collapse
|
|
42
|
Rong Z, Wang M, Hu Z, Stradner M, Zhu S, Kong H, Yi H, Goldrath A, Yang YG, Xu Y, Fu X. An effective approach to prevent immune rejection of human ESC-derived allografts. Cell Stem Cell 2014; 14:121-30. [PMID: 24388175 DOI: 10.1016/j.stem.2013.11.014] [Citation(s) in RCA: 191] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2013] [Revised: 10/07/2013] [Accepted: 11/15/2013] [Indexed: 01/03/2023]
Abstract
Human embryonic stem cells (hESCs) hold great promise for cell therapy as a source of diverse differentiated cell types. One key bottleneck to realizing such potential is allogenic immune rejection of hESC-derived cells by recipients. Here, we optimized humanized mice (Hu-mice) reconstituted with a functional human immune system that mounts a vigorous rejection of hESCs and their derivatives. We established knockin hESCs that constitutively express CTLA4-Ig and PD-L1 before and after differentiation, denoted CP hESCs. We then demonstrated that allogenic CP hESC-derived teratomas, fibroblasts, and cardiomyocytes are immune protected in Hu-mice, while cells derived from parental hESCs are effectively rejected. Expression of both CTLA4-Ig, which disrupts T cell costimulatory pathways, and PD-L1, which activates T cell inhibitory pathway, is required to confer immune protection, as neither was sufficient on their own. These findings are instrumental for developing a strategy to protect hESC-derived cells from allogenic immune responses without requiring systemic immune suppression.
Collapse
Affiliation(s)
- Zhili Rong
- Section of Molecular Biology, Division of Biological Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0322, USA
| | - Meiyan Wang
- Shenzhen Children's Hospital, Shenzhen, Guangdong 518026, China; Section of Molecular Biology, Division of Biological Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0322, USA
| | - Zheng Hu
- First Hospital of Jilin University, Changchun, Jilin 130021, China
| | - Martin Stradner
- Section of Molecular Biology, Division of Biological Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0322, USA
| | - Shengyun Zhu
- Shenzhen Children's Hospital, Shenzhen, Guangdong 518026, China; Section of Molecular Biology, Division of Biological Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0322, USA
| | - Huijuan Kong
- Section of Molecular Biology, Division of Biological Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0322, USA
| | - Huanfa Yi
- First Hospital of Jilin University, Changchun, Jilin 130021, China
| | - Ananda Goldrath
- Section of Molecular Biology, Division of Biological Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0322, USA
| | - Yong-Guang Yang
- First Hospital of Jilin University, Changchun, Jilin 130021, China; Columbia Center for Translational Immunology, Columbia University Medical School, New York, NY 10032, USA
| | - Yang Xu
- Section of Molecular Biology, Division of Biological Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0322, USA.
| | - Xuemei Fu
- Shenzhen Children's Hospital, Shenzhen, Guangdong 518026, China; Children's Hospital, Chongqing Medical University, Chongqing 400016, China.
| |
Collapse
|
|
43
|
Tan Y, Ooi S, Wang L. Immunogenicity and tumorigenicity of pluripotent stem cells and their derivatives: genetic and epigenetic perspectives. Curr Stem Cell Res Ther 2014; 9:63-72. [PMID: 24160683 PMCID: PMC3873036 DOI: 10.2174/1574888x113086660068] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2013] [Revised: 10/19/2013] [Accepted: 10/22/2013] [Indexed: 12/18/2022]
Abstract
One aim of stem cell-based therapy is to utilize pluripotent stem cells (PSCs) as a supplementary source of cells
to repair or replace tissues or organs that have ceased to function due to severe tissue damage. However, PSC-based therapy
requires extensive research to ascertain if PSC derivatives are functional without the risk of tumorigenicity, and also
do not engender severe immune rejection that threatens graft survival and function. Recently, the suitability of induced
pluripotent stem cells applied for patient-tailored cell therapy has been questioned since the discovery of several genetic
and epigenetic aberrations during the reprogramming process. Hence, it is crucial to understand the effect of these abnormalities
on the immunogenicity and survival of PSC grafts. As induced PSC-based therapy represents a hallmark for the
potential solution to prevent and arrest immune rejection, this review also summarizes several up-to-date key findings in
the field.
Collapse
Affiliation(s)
| | | | - Lisheng Wang
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa K1H8M5, Canada.
| |
Collapse
|
|
44
|
Dolezalova D, Hruska-Plochan M, Bjarkam CR, Sørensen JCH, Cunningham M, Weingarten D, Ciacci JD, Juhas S, Juhasova J, Motlik J, Hefferan MP, Hazel T, Johe K, Carromeu C, Muotri A, Bui J, Strnadel J, Marsala M. Pig models of neurodegenerative disorders: Utilization in cell replacement-based preclinical safety and efficacy studies. J Comp Neurol 2014; 522:2784-801. [DOI: 10.1002/cne.23575] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2013] [Revised: 02/13/2014] [Accepted: 02/14/2014] [Indexed: 12/12/2022]
Affiliation(s)
- Dasa Dolezalova
- Department of Anesthesiology; University of California; San Diego La Jolla CA USA
| | | | - Carsten R. Bjarkam
- Department of Neurosurgery; Aalborg University Hospital; Aalborg Denmark
- Department of Biomedicine; Institute of Anatomy, University of Aarhus; Aarhus Denmark
| | | | - Miles Cunningham
- MRC 312, McLean Hospital, Harvard Medical School; Belmont MA 02478 USA
| | - David Weingarten
- UCSD Division of Neurosurgery; University of California; San Diego CA USA
| | - Joseph D. Ciacci
- UCSD Division of Neurosurgery; University of California; San Diego CA USA
| | - Stefan Juhas
- Institute of Animal Physiology and Genetics, Czech Academy of Sciences; 277 21 Libechov Czech Republic
| | - Jana Juhasova
- Institute of Animal Physiology and Genetics, Czech Academy of Sciences; 277 21 Libechov Czech Republic
| | - Jan Motlik
- Institute of Animal Physiology and Genetics, Czech Academy of Sciences; 277 21 Libechov Czech Republic
| | | | | | | | - Cassiano Carromeu
- Department of Cellular and Molecular Medicine; University of California; San Diego CA USA
| | - Alysson Muotri
- Department of Cellular and Molecular Medicine; University of California; San Diego CA USA
| | - Jack Bui
- Department of Pathology; University of California; San Diego CA USA
| | - Jan Strnadel
- Department of Pathology; University of California; San Diego CA USA
| | - Martin Marsala
- Department of Anesthesiology; University of California; San Diego La Jolla CA USA
- Institute of Neurobiology, Slovak Academy of Sciences; Kosice Slovakia
| |
Collapse
|
|
45
|
Stamegna JC, Girard SD, Veron A, Sicard G, Khrestchatisky M, Feron F, Roman FS. A unique method for the isolation of nasal olfactory stem cells in living rats. Stem Cell Res 2014; 12:673-9. [PMID: 24681208 DOI: 10.1016/j.scr.2014.02.010] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2013] [Revised: 01/23/2014] [Accepted: 02/27/2014] [Indexed: 12/23/2022] Open
Abstract
Stem cells are attractive tools to develop new therapeutic strategies for a variety of disorders. While ethical and technical issues, associated with embryonic, fetal and neural stem cells, limit the translation to clinical applications, the nasal stem cells identified in the human olfactory mucosa stand as a promising candidate for stem cell-based therapies. Located in the back of the nose, this multipotent stem cell type is readily accessible in humans, a feature that makes these cells highly suitable for the development of autologous cell-based therapies. However, preclinical studies based on autologous transplantation of rodent olfactory stem cells are impeded because of the narrow opening of the nasal cavity. In this study, we report the development of a unique method permitting to quickly and safely biopsy olfactory mucosa in rats. Using this newly developed technique, rat stem cells expressing the stem cell marker Nestin were successfully isolated without requiring the sacrifice of the donor animal. As an evidence of the self-renewal capacity of the isolated cells, several millions of rat cells were amplified from a single biopsy within four weeks. Using an olfactory discrimination test, we additionally showed that this novel biopsy method does not affect the sense of smell and the learning and memory abilities of the operated animals. This study describes for the first time a methodology allowing the derivation of rat nasal cells in a way that is suitable for studying the effects of autologous transplantation of any cell type present in the olfactory mucosa in a wide variety of rat models.
Collapse
Affiliation(s)
| | - Stéphane D Girard
- Aix Marseille Université, CNRS, NICN, UMR7259, 13344 Marseille, France
| | - Antoine Veron
- Aix Marseille Université, CNRS, NICN, UMR7259, 13344 Marseille, France
| | - Gilles Sicard
- Aix Marseille Université, CNRS, NICN, UMR7259, 13344 Marseille, France
| | | | - François Feron
- Aix Marseille Université, CNRS, NICN, UMR7259, 13344 Marseille, France; APHM, Centre d'Investigations Cliniques en Biothérapie CIC-BT 510, Marseille, France
| | - François S Roman
- Aix Marseille Université, CNRS, NICN, UMR7259, 13344 Marseille, France.
| |
Collapse
|
|
46
|
Maynard KM, Arvindam U, Cross M, Firpo MT. Potentially immunogenic proteins expressed similarly in human embryonic stem cells and induced pluripotent stem cells. Exp Biol Med (Maywood) 2014; 239:484-8. [DOI: 10.1177/1535370214522936] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Abstract
A major limitation of the use of cellular therapies is the loss of donor-derived cells because of immune incompatibility. While induced pluripotent stem (iPS) cells offer the potential for autologous transplant therapies, questions have been raised using a mouse model that specific antigens mediate the rejection of grafts after syngeneic transplants with iPS, but not embryonic stem (ES) cells. In this study, we examined whether the human homologs of these markers, HORMAD1, ZG16, and Cyp3A, are differentially expressed in human iPS versus ES cells, as well as undifferentiated and in vitro-differentiated cells. Both qRT-PCR and flow cytometric analyses demonstrated similar gene and protein expression profiles for iPS and ES cells regardless of differentiation state. Our data are consistent with a recent study in mice that showed no evidence of rejection of differentiated syngeneic iPS cells. Furthermore, our results suggest that expression of these gene products cannot predict differences in clinical outcomes between human iPS and ES-derived cells.
Collapse
Affiliation(s)
- Kristen M Maynard
- Stem Cell Institute, Division of Endocrinology, Department of Medicine, Schulze Diabetes Institute, Department of Surgery, University of Minnesota, Minneapolis, MN 55455, USA
| | - Upasana Arvindam
- Stem Cell Institute, Division of Endocrinology, Department of Medicine, Schulze Diabetes Institute, Department of Surgery, University of Minnesota, Minneapolis, MN 55455, USA
| | - Madeline Cross
- Stem Cell Institute, Division of Endocrinology, Department of Medicine, Schulze Diabetes Institute, Department of Surgery, University of Minnesota, Minneapolis, MN 55455, USA
| | - Meri T Firpo
- Stem Cell Institute, Division of Endocrinology, Department of Medicine, Schulze Diabetes Institute, Department of Surgery, University of Minnesota, Minneapolis, MN 55455, USA
| |
Collapse
|
|
47
|
Low immunogenicity of neural progenitor cells differentiated from induced pluripotent stem cells derived from less immunogenic somatic cells. PLoS One 2013; 8:e69617. [PMID: 23922758 PMCID: PMC3724937 DOI: 10.1371/journal.pone.0069617] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2013] [Accepted: 06/12/2013] [Indexed: 01/29/2023] Open
Abstract
The groundbreaking discovery of induced pluripotent stem cells (iPS cells) provides a new source for cell therapy. However, whether the iPS derived functional lineages from different cell origins have different immunogenicity remains unknown. It had been known that the cells isolated from extra-embryonic tissues, such as umbilical cord mesenchymal cells (UMCs), are less immunogenic than other adult lineages such as skin fibroblasts (SFs). In this report, we differentiated iPS cells from human UMCs and SFs into neural progenitor cells (NPCs) and analyzed their immunogenicity. Through co-culture with allologous peripheral blood mononuclear cells (PBMCs), we showed that UMCs were indeed less immunogenic than skin cells to simulate proliferation of PBMCs. Surprisingly, we found that the NPCs differentiated from UMC-iPS cells retained low immunogenicity as the parental UMCs based on the PBMC proliferation assay. In cytotoxic expression assay, reactions in most kinds of immune effector cells showed more perforin and granzyme B expression with SF-NPCs stimulation than that with UMC-NPCs stimulation in PBMC co-culture system, in T cell co-culture system as well. Furthermore, through whole genome expression microarray analysis, we showed that over 70 immune genes, including all members of HLA-I, were expressed at lower levels in NPCs derived from UMC-iPS cells than that from SF-iPS cells. Our results demonstrated a phenomenon that the low immunogenicity of the less immunogenic cells could be retained after cell reprogramming and further differentiation, thus provide a new concept to generate functional lineages with lower immunogenicity for regenerative medicine.
Collapse
|
|
48
|
Fink KD, Rossignol J, Lu M, Lévêque X, Hulse TD, Crane AT, Nerriere-Daguin V, Wyse RD, Starski PA, Schloop MT, Dues DJ, Witte SJ, Song C, Vallier L, Nguyen TH, Naveilhan P, Anegon I, Lescaudron L, Dunbar GL. Survival and differentiation of adenovirus-generated induced pluripotent stem cells transplanted into the rat striatum. Cell Transplant 2013; 23:1407-23. [PMID: 23879897 DOI: 10.3727/096368913x670958] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Induced pluripotent stem cells (iPSCs) offer certain advantages over embryonic stem cells in cell replacement therapy for a variety of neurological disorders. However, reliable procedures, whereby transplanted iPSCs can survive and differentiate into functional neurons, without forming tumors, have yet to be devised. Currently, retroviral or lentiviral reprogramming methods are often used to reprogram somatic cells. Although the use of these viruses has proven to be effective, formation of tumors often results following in vivo transplantation, possibly due to the integration of the reprogramming genes. The goal of the current study was to develop a new approach, using an adenovirus for reprogramming cells, characterize the iPSCs in vitro, and test their safety, survivability, and ability to differentiate into region-appropriate neurons following transplantation into the rat brain. To this end, iPSCs were derived from bone marrow-derived mesenchymal stem cells and tail-tip fibroblasts using a single cassette lentivirus or a combination of adenoviruses. The reprogramming efficiency and levels of pluripotency were compared using immunocytochemistry, flow cytometry, and real-time polymerase chain reaction. Our data indicate that adenovirus-generated iPSCs from tail-tip fibroblasts are as efficient as the method we used for lentiviral reprogramming. All generated iPSCs were also capable of differentiating into neuronal-like cells in vitro. To test the in vivo survivability and the ability to differentiate into region-specific neurons in the absence of tumor formation, 400,000 of the iPSCs derived from tail-tip fibroblasts that were transfected with the adenovirus pair were transplanted into the striatum of adult, immune-competent rats. We observed that these iPSCs produced region-specific neuronal phenotypes, in the absence of tumor formation, at 90 days posttransplantation. These results suggest that adenovirus-generated iPSCs may provide a safe and viable means for neuronal replacement therapies.
Collapse
Affiliation(s)
- Kyle D Fink
- Program in Neuroscience, Field Neurosciences Laboratory for Restorative Neurology Brain Research and Integrative Neuroscience Center, Central Michigan University, Mount Pleasant, MI, USA
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
49
|
Shaharuddin B, Ahmad S, Ali S, Meeson A. Limbal side population cells: a future treatment for limbal stem cell deficiency. Regen Med 2013; 8:319-31. [DOI: 10.2217/rme.13.18] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Corneal blindness carries a morbidity that affects quality of life and is often associated with an increased economic burden. In this review, we focus on the severe and painful condition of limbal stem cell deficiency, an important cause of corneal blindness. Conventional corneal transplantation usually results in graft failure and is contraindicated in this condition. Ex vivo-expanded limbal epithelial transplantation has been used as a cellular-based therapy to regenerate and reconstruct the ocular surface as a mode of treatment. Enrichment methods for stem cells are a strategy to improve the outcome of limbal stem cell transplantation. Here we discuss the side population assay as a functional assay to enrich for stem cells as an important source of limbal stem cells. The challenges in ex vivo-expanded limbal stem cell transplantation are wide and varied and will be addressed in this review with regard to improving the clinical outcomes of cultivated limbal stem cell transplantation.
Collapse
Affiliation(s)
- Bakiah Shaharuddin
- Advanced Medical & Dental Institute, Universiti Sains Malaysia, 13200 Pulau Pinang, Malaysia
| | - Sajjad Ahmad
- St Paul’s Eye Unit, Royal Liverpool University Hospital, Prescot Street, Liverpool, L7 8XP, UK
- Department of Eye & Vision Sciences, Institute of Ageing & Chronic Disease, University of Liverpool, 4th Floor UCD Building, Daulby Street, Liverpool, L69 3GA, UK
| | - Simi Ali
- Institute of Cellular Medicine, William-Leech Building, Newcastle University, Newcastle upon Tyne, NE1 7RU, UK
| | - Annette Meeson
- Institute of Genetic Medicine, Newcastle University, International Centre for Life, Newcastle upon Tyne, NE1 3BZ, UK
| |
Collapse
|
|
50
|
Kramer AS, Harvey AR, Plant GW, Hodgetts SI. Systematic Review of Induced Pluripotent Stem Cell Technology as a Potential Clinical Therapy for Spinal Cord Injury. Cell Transplant 2013; 22:571-617. [DOI: 10.3727/096368912x655208] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Transplantation therapies aimed at repairing neurodegenerative and neuropathological conditions of the central nervous system (CNS) have utilized and tested a variety of cell candidates, each with its own unique set of advantages and disadvantages. The use and popularity of each cell type is guided by a number of factors including the nature of the experimental model, neuroprotection capacity, the ability to promote plasticity and guided axonal growth, and the cells' myelination capability. The promise of stem cells, with their reported ability to give rise to neuronal lineages to replace lost endogenous cells and myelin, integrate into host tissue, restore functional connectivity, and provide trophic support to enhance and direct intrinsic regenerative ability, has been seen as a most encouraging step forward. The advent of the induced pluripotent stem cell (iPSC), which represents the ability to “reprogram” somatic cells into a pluripotent state, hails the arrival of a new cell transplantation candidate for potential clinical application in therapies designed to promote repair and/or regeneration of the CNS. Since the initial development of iPSC technology, these cells have been extensively characterized in vitro and in a number of pathological conditions and were originally reported to be equivalent to embryonic stem cells (ESCs). This review highlights emerging evidence that suggests iPSCs are not necessarily indistinguishable from ESCs and may occupy a different “state” of pluripotency with differences in gene expression, methylation patterns, and genomic aberrations, which may reflect incomplete reprogramming and may therefore impact on the regenerative potential of these donor cells in therapies. It also highlights the limitations of current technologies used to generate these cells. Moreover, we provide a systematic review of the state of play with regard to the use of iPSCs in the treatment of neurodegenerative and neuropathological conditions. The importance of balancing the promise of this transplantation candidate in the light of these emerging properties is crucial as the potential application in the clinical setting approaches. The first of three sections in this review discusses (A) the pathophysiology of spinal cord injury (SCI) and how stem cell therapies can positively alter the pathology in experimental SCI. Part B summarizes (i) the available technologies to deliver transgenes to generate iPSCs and (ii) recent data comparing iPSCs to ESCs in terms of characteristics and molecular composition. Lastly, in (C) we evaluate iPSC-based therapies as a candidate to treat SCI on the basis of their neurite induction capability compared to embryonic stem cells and provide a summary of available in vivo data of iPSCs used in SCI and other disease models.
Collapse
Affiliation(s)
- Anne S. Kramer
- Spinal Cord Repair Laboratory, School of Anatomy, Physiology and Human Biology, The University of Western Australia, Perth, Western Australia
| | - Alan R. Harvey
- Spinal Cord Repair Laboratory, School of Anatomy, Physiology and Human Biology, The University of Western Australia, Perth, Western Australia
| | - Giles W. Plant
- Stanford Partnership for Spinal Cord Injury and Repair, Stanford Institute for Neuro-Innovation and Translational Neurosciences, Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USA
| | - Stuart I. Hodgetts
- Spinal Cord Repair Laboratory, School of Anatomy, Physiology and Human Biology, The University of Western Australia, Perth, Western Australia
| |
Collapse
|