• Cell manufacturing
• Centralized manufacturing
• Decentralized manufacturing
• In-process control
• Industrialization
• Outscaling
• Process automation
• Process integration
• Quality control
• Upscaling

• Humans
• Genetic Therapy/methods
• Cell- and Tissue-Based Therapy/methods

• Stargardt disease
• age-related macular degeneration (AMD)
• embryonic stem cell (ES cell)
• iPSC (induced pluripotent stem cell)
• retina
• retinal pigment epithelium

• ANIMAL STUDIES
• CLINICAL TRIAL
• THERAPEUTIC APPROACHES FOR THE TREATMENT OF CNS INJURY
• spinal cord injury

Stem cells are undifferentiated cells that can self-renew and differentiate into diverse types of mature and functional cells while maintaining their original identity. This profound potential of stem cells has been thoroughly investigated for its significance in regenerative medicine and has laid the foundation for cell-based therapies. Regenerative medicine is rapidly progressing in healthcare with the prospect of repair and restoration of specific organs or tissue injuries or chronic disease conditions where the body’s regenerative process is not sufficient to heal. In this review, the recent advances in stem cell-based therapies in regenerative medicine are discussed, emphasizing mesenchymal stem cell-based therapies as these cells have been extensively studied for clinical use. Recent applications of artificial intelligence algorithms in stem cell-based therapies, their limitation, and future prospects are highlighted.

• Artificial intelligence
• Machine learning
• Mesenchymal stem cells
• Regenerative medicine
• Stem cells
• Therapy

• Cancer
• Cardiovascular disease
• Cell-labelling
• Diabetes
• Neurological disorders
• Signalling pathways
• Stem cell

• DNA methylation
• Infrapatellar fat pad-derived stem cells
• hypoxic sensitization/preconditioning
• neuronal differentiation
• neurotransmitter respecification

The rapid progress in the field of stem cell research has laid strong foundations for their use in regenerative medicine applications of injured or diseased tissues. Growing evidences indicate that some observed therapeutic outcomes of stem cell-based therapy are due to paracrine effects rather than long-term engraftment and survival of transplanted cells. Given their ability to cross biological barriers and mediate intercellular information transfer of bioactive molecules, extracellular vesicles are being explored as potential cell-free therapeutic agents. In this review, we first discuss the state of the art of regenerative medicine and its current limitations and challenges, with particular attention on pluripotent stem cell-derived products to repair organs like the eye, heart, skeletal muscle and skin. We then focus on emerging beneficial roles of extracellular vesicles to alleviate these pathological conditions and address hurdles and operational issues of this acellular strategy. Finally, we discuss future directions and examine how careful integration of different approaches presented in this review could help to potentiate therapeutic results in preclinical models and their good manufacturing practice (GMP) implementation for future clinical trials.

• acellular therapy
• cell therapy
• exosome
• extracellular vesicles
• pluripotent stem cells

The last 5 years have witnessed a significant increase in the number of clinical studies based on human pluripotent stem cells (hPSCs). In parallel, concern is increasing about the proliferation of unregulated stem cell treatments worldwide. Regulated clinical testing is a de facto standard to establish the safety and efficacy of new cell therapies, yet reliable information on clinical studies involving hPSCs is scattered. Our analysis of a multitude of resources found 54 clinical studies involving several types of hPSCs, which are performed in ten countries. While the majority of those studies is based on human embryonic stem cells (hESCs), clinical studies involving human induced pluripotent stem cells increased more strongly in the past 2 years than the number of hESC-based studies. A publicly accessible database was created using the human pluripotent stem cell registry (https://hpscreg.eu) platform, providing a steadily updated comprehensive overview on hPSC-based clinical studies performed worldwide.

•

Establishment of a database for clinical studies based on pluripotent stem cells

• clinical study database
• embryonic stem cell
• pluripotent stem cell

• antibody discovery
• oncofetal
• oncology
• pluripotent stem cells
• regenerative cell therapy

• Cell- and Tissue-Based Therapy/methods
• Humans
• Pluripotent Stem Cells/metabolism
• Regenerative Medicine/methods

This study describes the use of a previously reported chimerised monoclonal antibody (mAb), ch2448, to kill human embryonic stem cells (hESCs) in vivo and prevent or delay the formation of teratomas. ch2448 was raised against hESCs and was previously shown to effectively kill ovarian and breast cancer cells in vitro and in vivo. The antigen target was subsequently found to be Annexin A2, an oncofetal antigen expressed on both embryonic cells and cancer cells. Against cancer cells, ch2448 binds and kills via antibody‐dependent cell‐mediated cytotoxicity (ADCC) and/or antibody‐drug conjugate (ADC) routes. Here, we investigate if the use of ch2448 can be extended to hESC. ch2448 was found to bind specifically to undifferentiated hESC but not differentiated progenitors. Similar to previous study using cancer cells, ch2448 kills hESC in vivo either indirectly by eliciting ADCC or directly as an ADC. The treatment with ch2448 post‐transplantation eliminated the in vivo circulating undifferentiated cells and prevented or delayed the formation of teratomas. This surveillance role of ch2448 adds an additional layer of safeguard to enhance the safety and efficacious use of pluripotent stem cell‐derived products in regenerative medicine. Thereby, translating the use of ch2448 in the treatment of cancers to a proof of concept study in hESC (or pluripotent stem cell [PSC]), we show that mAbs can also be used to eliminate teratoma forming cells in vivo during PSC‐derived cell therapies. We propose to use this strategy to complement existing methods to eliminate teratoma‐forming cells in vitro. Residual undifferentiated cells may escape in vitro removal methods and be introduced into patients together with the differentiated cells.

• antibody-dependent cell-mediated cytotoxicity
• antibody-drug conjugate
• cancer
• human embryonic stem cells
• monoclonal antibody
• pluripotent
• teratoma

The generation of human induced pluripotent stem cells (iPSCs) from somatic cells using gene transfer opens new areas for precision medicine with personalized cell therapy and encourages the discovery of essential platforms for targeted drug development. iPSCs retain the genome of the donor, may regenerate indefinitely, and undergo differentiation into virtually any cell type of interest using a range of published protocols. There has been enormous interest among researchers regarding the application of iPSC technology to regenerative medicine and human disease modeling, in particular, modeling of neurologic diseases using patient-specific iPSCs. For instance, Parkinson’s disease, Alzheimer’s disease, and spinal cord injuries may be treated with iPSC therapy or replacement tissues obtained from iPSCs. In this review, we discuss the work so far on generation and characterization of iPSCs and focus on recent advances in the use of human iPSCs in clinical setting.

• Cell-based therapy
• Induced pluripotent stem cells
• Precision medicine

• artificial pancreas
• automated insulin delivery
• continuous glucose monitoring
• encapsulation
• immunosuppression
• stem cells
• type 1 diabetes

• DAVID
• Human embryonic stem cells
• Major histocompatibility complex
• Microarray technology
• Reactome
• miRNA

• cell product
• cellular therapy
• clinical translation
• embryonic stem cells
• good medical practice
• induced pluripotent stem cells
• risks

• Ferumoxytol (Feraheme®)
• magnetic resonance imaging
• mesenchymal stem cells
• stem cell culture and expansion
• stem cell tracking

• culture conditions
• genetic instability
• genomic change
• hPSC
• human pluripotent stem cell
• teratoma
• tumorigenicity

• Apoptosis
• Human pluripotent stem cells
• Safe stem cell therapy
• Selective cell death
• Teratoma

• Animals
• Cell Death/drug effects
• Genes, Transgenic, Suicide
• Humans
• MicroRNAs/metabolism
• Mitochondria/drug effects
• Mitochondria/metabolism
• Pluripotent Stem Cells/cytology
• Pluripotent Stem Cells/drug effects
• Pluripotent Stem Cells/metabolism
• Small Molecule Libraries/pharmacology
• Stem Cell Transplantation/methods

• National Research Foundation of Korea

• Humans
• Phenotype
• Pluripotent Stem Cells/cytology
• Regeneration/physiology
• Signal Transduction
• Tissue Engineering/methods

• R21 NS082618 NINDS NIH HHS
• R33 NS082618 NINDS NIH HHS

Oligodendrocyte precursor cells (OPCs) offer considerable potential for the treatment of demyelinating diseases and injuries of the CNS. However, generating large quantities of high-quality OPCs remains a substantial challenge that impedes their therapeutic application. Here, we show that OPCs can be generated from human pluripotent stem cells (hPSCs) in a three-dimensional (3D), scalable, and fully defined thermoresponsive biomaterial system. We used CRISPR/Cas9 to create a NKX2.2-EGFP human embryonic stem cell reporter line that enabled fine-tuning of early OPC specification and identification of conditions that markedly increased the number of OLIG2⁺ and NKX2.2⁺ cells generated from hPSCs. Transplantation of 50-day-old OPCs into the brains of NOD/SCID mice revealed that progenitors generated in 3D without cell selection or purification subsequently engrafted, migrated, and matured into myelinating oligodendrocytes in vivo. These results demonstrate the potential of harnessing lineage reporter lines to develop 3D platforms for rapid and large-scale production of OPCs.

•

A defined and scalable 3D system accelerates the differentiation of OPCs from hPSCs

• CRISPR/Cas9 knockin
• NKX2.2-EGFP reporter cell line
• human pluripotent stem cells
• oligodendrocyte precursor cells
• scalable and defined oligodendrocyte differentiation
• three-dimensional culture systems

Utilization of small molecules in modulation of stem cell self-renewal is a promising approach to expand stem cells for regenerative therapy. Here, we identify Icaritin, a phytoestrogen molecule enhances self-renewal of mouse embryonic stem cells (mESCs). Icaritin increases mESCs proliferation while maintains their self-renewal capacity in vitro and pluripotency in vivo. This coincides with upregulation of key pluripotency transcription factors OCT4, NANOG, KLF4 and SOX2. The enhancement of mESCs self-renewal is characterized by increased population in S-phase of cell cycle, elevation of Cylin E and Cyclin-dependent kinase 2 (CDK2) and downregulation of p21, p27 and p57. PCR array screening reveals that caudal-related homeobox 2 (Cdx2) and Rbl2/p130 are remarkably suppressed in mESCs treated with Icaritin. siRNA knockdown of Cdx2 or Rbl2/p130 upregulates the expression of Cyclin E, OCT4 and SOX2, and subsequently increases cell proliferation and colony forming efficiency of mESCs. We then demonstrate that Icaritin co-localizes with estrogen receptor alpha (ERα) and activates its nuclear translocation in mESCs. The promotive effect of Icaritin on cell cycle and pluripotency regulators are eliminated by siRNA knockdown of ERα in mESCs. The results suggest that Icaritin enhances mESCs self-renewal by regulating cell cycle machinery and core pluripotency transcription factors mediated by ERα.

• Decision-making
• Phase 1 trials
• Policy
• Research ethics
• Risk/benefit
• Translational research

• Clinical Trials as Topic/ethics
• Clinical Trials as Topic/instrumentation
• Clinical Trials as Topic/methods
• Clinical Trials, Phase I as Topic/ethics
• Clinical Trials, Phase I as Topic/methods
• Decision Making/ethics
• Humans
• Public Policy
• Research Personnel/ethics
• Research Personnel/psychology
• Risk Assessment

Mesenchymal stem cells (MSCs) are among the major stem cells used for cell therapy and regenerative medicine. In-vivo cell-tracking by magnetic resonance imaging (MRI) is crucial for regenerative medicine, allowing verification that the transplanted cells reach the targeted sites. Cellular MRI combined with superparamagnetic iron-oxide (SPIO) contrast agents is an effective cell-tracking method. Here, we are reporting a new “bio-mimicry” method by making use of the “in-vivo environment” of MSCs to prepare native MSCs, so that (i) the phagocytic activity of cultured MSCs can be recovered and expanded MSCs can be ex-vivo labeled with Ferumoxytol, which is currently the only FDA approved SPIO nanoparticles for human use. Using our new method, 7-day cultured MSCs regain the capability to take up Ferumoxytol and exhibit an intracellular iron concentration of 2.50 ± 0.50 pg/MSC, comparable to that obtained by using Ferumoxytol-heparin-protamine nanocomplex; and (ii) cells can be re-sized to more native size, reducing from 32.0 ± 7.2 μm to 19.5 ± 5.2 μm. Our method can be very useful for expanding MSCs and labeling with Ferumoxytol, without the need for transfection agents and/or electroporation, allowing cell-tracking by MRI in both pre-clinical and clinical studies.

• TAP-associated glycoprotein (TAPBP)
• immune rejection
• major histocompatibility complex (MHC) class I
• transcription activator-like effector nucleases (TALEN)
• transporter associated with antigen presentation 1 (TAP1)

• animal models
• chimera
• cloning
• cultured meat
• induced pluripotent stem cells (iPSC)
• nuclear transfer
• pig
• regenerative medicine
• severe combined immunodeficiency (SCID)

• Cell Differentiation
• Humans
• Immunity, Cellular/immunology
• Induced Pluripotent Stem Cells/cytology
• Induced Pluripotent Stem Cells/immunology
• Stem Cell Transplantation

• TL1TR000429 NCATS NIH HHS
• UL1 TR000427 NCATS NIH HHS
• T32 GM007215 NIGMS NIH HHS
• R01-AI066219 NIAID NIH HHS
• TL1 TR000429 NCATS NIH HHS
• R01 AI066219 NIAID NIH HHS
• UL1TR000427 NCATS NIH HHS
• T32 AI125231 NIAID NIH HHS

In principle, induced pluripotent stem cells (iPSCs) are generated from somatic cells by reprogramming and gaining the capacity to self-renew indefinitely as well as the ability to differentiate into cells of different lineages. Human iPSCs have absolute advantages over human embryonic stem cells (ESCs) and animal models in disease modeling, drug screening, and cell replacement therapy. Since Takahashi and Yamanaka first described in 2007 that iPSCs can be generated from human adult somatic cells by retroviral transduction of the four transcription factors, Oct3/4, Sox2, Klf4, and c-Myc, disease specific iPSC lines have sprung up worldwide like bamboo shoots after a spring rain, making iPSC one of the hottest and fastest moving topics in modern science. The craze for iPSCs has spread throughout main branches of clinical medicine, covering neurology, hematology, cardiology, endocrinology, hepatology, ophthalmology, and so on. Here in this paper, we will focus on the clinical application of human iPSCs in disease modeling, drug screening, and cell replacement therapy for neurological diseases.

• Cell transplantation
• DRG neurons
• Interferon gamma
• Lipopolysaccharide
• Proinflammatory mediators
• Spinal cord injury

• Animals
• Cell- and Tissue-Based Therapy/methods
• Clinical Trials as Topic
• Humans
• Parkinson Disease/physiopathology
• Parkinson Disease/surgery
• Parkinson Disease/therapy

• 97922 Wellcome Trust
• Department of Health

• Differentiation and characterization
• Human leukocyte antigen class I
• Immunogenicity of human embryonic stem cells
• β2-Microglobulin gene targeting strategy

• Alleles
• Animals
• CD8-Positive T-Lymphocytes/immunology
• Cell Self Renewal
• Cell Survival
• Cell Transplantation/adverse effects
• Cytotoxicity, Immunologic
• Exons/genetics
• Gene Expression Profiling
• Gene Knockdown Techniques
• Genetic Vectors
• Genomic Instability
• Graft Rejection/prevention & control
• HLA Antigens
• Heterografts
• Histocompatibility
• Human Embryonic Stem Cells/cytology
• Human Embryonic Stem Cells/immunology
• Human Embryonic Stem Cells/transplantation
• Humans
• Interferon-gamma/pharmacology
• Killer Cells, Natural/immunology
• Mice
• Mice, SCID
• Pluripotent Stem Cells/cytology
• Pluripotent Stem Cells/immunology
• Pluripotent Stem Cells/transplantation
• Sequence Deletion
• Teratoma/etiology
• Teratoma/immunology
• beta 2-Microglobulin/genetics
• beta 2-Microglobulin/physiology

• R21 HL102833-01 NHLBI NIH HHS

Since the 1960s and the therapeutic use of hematopoietic stem cells of bone marrow origin, there has been an increasing interest in the study of undifferentiated progenitors that have the ability to proliferate and differentiate into various tissues. Stem cells (SC) with different potency can be isolated and characterised. Despite the promise of embryonic stem cells, in many cases, adult or even fetal stem cells provide a more interesting approach for clinical applications. It is undeniable that mesenchymal stem cells (MSC) from bone marrow, adipose tissue, or Wharton's Jelly are of potential interest for clinical applications in regenerative medicine because they are easily available without ethical problems for their uses. During the last 10 years, these multipotent cells have generated considerable interest and have particularly been shown to escape to allogeneic immune response and be capable of immunomodulatory activity. These properties may be of a great interest for regenerative medicine. Different clinical applications are under study (cardiac insufficiency, atherosclerosis, stroke, bone and cartilage deterioration, diabetes, urology, liver, ophthalmology, and organ's reconstruction). This review focuses mainly on tissue and organ regeneration using SC and in particular MSC.

• Huntington's disease
• Parkinson's disease
• cell therapy
• embryonic stem cells
• fetal human tissue
• induced neurons
• induced pluripotent stem cells

• cell transplantation
• glial scar
• inflammation
• nodes of Ranvier
• oligodendrocytes

• Biomedical Research/instrumentation
• Biomedical Research/methods
• Biomedical Research/standards
• Biomedical Research/trends
• Drug Evaluation, Preclinical/economics
• Drug Evaluation, Preclinical/methods
• Drug Evaluation, Preclinical/standards
• Drug Evaluation, Preclinical/trends
• Humans
• Pluripotent Stem Cells
• Reference Standards

• MR/L01324X/1 Medical Research Council

• Adult stem cells
• Autologous stem cell transplantation
• Cellular therapy
• In vivo tracking
• Pluripotent stem cells
• Stem cell
• Stem cell expansion
• Stem cell transplantation

• Cell- and Tissue-Based Therapy/adverse effects
• Cell- and Tissue-Based Therapy/methods
• Humans
• Pluripotent Stem Cells/transplantation
• Stem Cell Transplantation
• Stem Cells/cytology
• Transplantation, Autologous

• MR/K026739/1 Medical Research Council
• MR/L006758/1 Medical Research Council
• MR/L012537/1 Medical Research Council
• G0700654 Medical Research Council
• MR/L01324X/1 Medical Research Council

• embryonic stem cells
• human
• feeder layers
• 3-d culture
• hydrogel
• cell adhesion
• ecm (extracellular matrix)
• tissue regeneration
• differentiation
• pluripotent

• Animals
• Cell Culture Techniques/history
• Cell Culture Techniques/trends
• Cell Proliferation
• Coculture Techniques
• Culture Media
• Feeder Cells
• History, 20th Century
• History, 21st Century
• Human Embryonic Stem Cells
• Humans
• Mice
• Stem Cell Research/history

• Huntington's disease
• regenerative medicine
• stem cell
• transplantation

• Adult
• Animals
• Animals, Genetically Modified
• Cell Differentiation
• Cell Transplantation/methods
• Central Nervous System/pathology
• Child
• Clinical Trials as Topic
• Disease Progression
• Embryonic Stem Cells/cytology
• Humans
• Huntington Disease/therapy
• Immune System
• Mesenchymal Stem Cell Transplantation
• Mesenchymal Stem Cells/metabolism
• Nerve Growth Factors/chemistry
• Neurons/metabolism
• Neuroprotection
• Stem Cell Transplantation

• R01 GM099688 NIGMS NIH HHS
• R01 NS102486 NINDS NIH HHS
• R24 OD021606 NIH HHS
• S10 RR026825 NCRR NIH HHS

• Animals
• Decompression, Surgical/methods
• Embryonic Stem Cells/transplantation
• Humans
• Neuronal Plasticity/physiology
• Recovery of Function/physiology
• Spinal Cord Injuries/diagnosis
• Spinal Cord Injuries/physiopathology
• Spinal Cord Injuries/therapy

• FPP216158 Canadian Institutes of Health Research
• G1002055 Medical Research Council

The heart is a continuously pumping organ with an average lifespan of eight decades. It develops from the onset of embryonic cardiogenesis under biomechanical load, performs optimally within a defined range of hemodynamic load, and fails if acutely or chronically overloaded. Unloading of the heart leads to defective cardiogenesis in utero, but can also lead to a desired therapeutic outcome (for example, in patients with heart failure under left ventricular assist device therapy). In light of the well-documented relevance of mechanical loading for cardiac physiology and pathology, it is plausible that tissue engineers have integrated mechanical stimulation regimens into protocols for heart muscle construction. To achieve optimal results, physiological principles of beat-to-beat myocardial loading and unloading should be simulated. In addition, heart muscle engineering, in particular if based on pluripotent stem cell-derived cardiomyocytes, may benefit from staggered tonic loading protocols to simulate viscoelastic properties of the prenatal and postnatal myocardial stroma. This review will provide an overview of heart muscle mechanics, summarize observations on the role of mechanical loading for heart development and postnatal performance, and discuss how physiological loading regimens can be exploited to advance myocardial tissue engineering towards a therapeutic application.