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Cell Stem Cell Oct 2020Human pluripotent stem cells such as embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) provide unprecedented opportunities for cell therapies... (Review)
Review
Human pluripotent stem cells such as embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) provide unprecedented opportunities for cell therapies against intractable diseases and injuries. Both ESCs and iPSCs are already being used in clinical trials. However, we continue to encounter practical issues that limit their use, including their inherent properties of tumorigenicity, immunogenicity, and heterogeneity. Here, I review two decades of research aimed at overcoming these three difficulties.
Topics: Cell- and Tissue-Based Therapy; Embryonic Stem Cells; Humans; Induced Pluripotent Stem Cells; Pluripotent Stem Cells; Stem Cell Transplantation
PubMed: 33007237
DOI: 10.1016/j.stem.2020.09.014 -
Nature Cell Biology Sep 2019Cyclins, cyclin-dependent kinases and other components of the core cell cycle machinery drive cell division. Growing evidence indicates that this machinery operates in a... (Review)
Review
Cyclins, cyclin-dependent kinases and other components of the core cell cycle machinery drive cell division. Growing evidence indicates that this machinery operates in a distinct fashion in some mammalian stem cell types, such as pluripotent embryonic stem cells. In this Review, we discuss our current knowledge of how cell cycle proteins mechanistically link cell proliferation, pluripotency and cell fate specification. We focus on embryonic stem cells, induced pluripotent stem cells and embryonic neural stem/progenitor cells.
Topics: Animals; Cell Cycle; Cell Differentiation; Cell Proliferation; Embryonic Stem Cells; Humans; Induced Pluripotent Stem Cells; Pluripotent Stem Cells
PubMed: 31481793
DOI: 10.1038/s41556-019-0384-4 -
Stem Cell Reviews and Reports Feb 2020Over the past 20 years, and particularly in the last decade, significant developmental milestones have driven basic, translational, and clinical advances in the field of... (Review)
Review
Over the past 20 years, and particularly in the last decade, significant developmental milestones have driven basic, translational, and clinical advances in the field of stem cell and regenerative medicine. In this article, we provide a systemic overview of the major recent discoveries in this exciting and rapidly developing field. We begin by discussing experimental advances in the generation and differentiation of pluripotent stem cells (PSCs), next moving to the maintenance of stem cells in different culture types, and finishing with a discussion of three-dimensional (3D) cell technology and future stem cell applications. Specifically, we highlight the following crucial domains: 1) sources of pluripotent cells; 2) next-generation in vivo direct reprogramming technology; 3) cell types derived from PSCs and the influence of genetic memory; 4) induction of pluripotency with genomic modifications; 5) construction of vectors with reprogramming factor combinations; 6) enhancing pluripotency with small molecules and genetic signaling pathways; 7) induction of cell reprogramming by RNA signaling; 8) induction and enhancement of pluripotency with chemicals; 9) maintenance of pluripotency and genomic stability in induced pluripotent stem cells (iPSCs); 10) feeder-free and xenon-free culture environments; 11) biomaterial applications in stem cell biology; 12) three-dimensional (3D) cell technology; 13) 3D bioprinting; 14) downstream stem cell applications; and 15) current ethical issues in stem cell and regenerative medicine. This review, encompassing the fundamental concepts of regenerative medicine, is intended to provide a comprehensive portrait of important progress in stem cell research and development. Innovative technologies and real-world applications are emphasized for readers interested in the exciting, promising, and challenging field of stem cells and those seeking guidance in planning future research direction.
Topics: Biocompatible Materials; Cell Differentiation; Cellular Reprogramming; Genomic Instability; Humans; Induced Pluripotent Stem Cells; Pluripotent Stem Cells; Regenerative Medicine
PubMed: 31760627
DOI: 10.1007/s12015-019-09935-x -
Circulation Research Apr 2020Maturation is the last phase of heart development that prepares the organ for strong, efficient, and persistent pumping throughout the mammal's lifespan. This process is... (Review)
Review
Maturation is the last phase of heart development that prepares the organ for strong, efficient, and persistent pumping throughout the mammal's lifespan. This process is characterized by structural, gene expression, metabolic, and functional specializations in cardiomyocytes as the heart transits from fetal to adult states. Cardiomyocyte maturation gained increased attention recently due to the maturation defects in pluripotent stem cell-derived cardiomyocyte, its antagonistic effect on myocardial regeneration, and its potential contribution to cardiac disease. Here, we review the major hallmarks of ventricular cardiomyocyte maturation and summarize key regulatory mechanisms that promote and coordinate these cellular events. With advances in the technical platforms used for cardiomyocyte maturation research, we expect significant progress in the future that will deepen our understanding of this process and lead to better maturation of pluripotent stem cell-derived cardiomyocyte and novel therapeutic strategies for heart disease.
Topics: Animals; Cell Differentiation; Heart Diseases; Humans; Myocytes, Cardiac; Pluripotent Stem Cells
PubMed: 32271675
DOI: 10.1161/CIRCRESAHA.119.315862 -
Cells May 2020In the past five years, pluripotent stem cell (PSC)-derived kidney organoids and adult stem or progenitor cell (ASC)-based kidney tubuloids have emerged as advanced in... (Review)
Review
In the past five years, pluripotent stem cell (PSC)-derived kidney organoids and adult stem or progenitor cell (ASC)-based kidney tubuloids have emerged as advanced in vitro models of kidney development, physiology, and disease. PSC-derived organoids mimic nephrogenesis. After differentiation towards the kidney precursor tissues ureteric bud and metanephric mesenchyme, their reciprocal interaction causes self-organization and patterning in vitro to generate nephron structures that resemble the fetal kidney. ASC tubuloids on the other hand recapitulate renewal and repair in the adult kidney tubule and give rise to long-term expandable and genetically stable cultures that consist of adult proximal tubule, loop of Henle, distal tubule, and collecting duct epithelium. Both organoid types hold great potential for: (1) studies of kidney physiology, (2) disease modeling, (3) high-throughput screening for drug efficacy and toxicity, and (4) regenerative medicine. Currently, organoids and tubuloids are successfully used to model hereditary, infectious, toxic, metabolic, and malignant kidney diseases and to screen for effective therapies. Furthermore, a tumor tubuloid biobank was established, which allows studies of pathogenic mutations and novel drug targets in a large group of patients. In this review, we discuss the nature of kidney organoids and tubuloids and their current and future applications in science and medicine.
Topics: Adult Stem Cells; Animals; Humans; Kidney Tubules; Organogenesis; Organoids; Pluripotent Stem Cells; Regeneration
PubMed: 32466429
DOI: 10.3390/cells9061326 -
Cells Feb 2020The liver is a very complex organ that ensures numerous functions; it is thus susceptible to multiple types of damage and dysfunction. Since 1983, orthotopic liver... (Review)
Review
The liver is a very complex organ that ensures numerous functions; it is thus susceptible to multiple types of damage and dysfunction. Since 1983, orthotopic liver transplantation (OLT) has been considered the only medical solution available to patients when most of their liver function is lost. Unfortunately, the number of patients waiting for OLT is worryingly increasing, and extracorporeal liver support devices are not yet able to counteract the problem. In this review, the current and expected methodologies in liver regeneration are briefly analyzed. In particular, human pluripotent stem cells (hPSCs) as a source of hepatic cells for liver therapy and regeneration are discussed. Principles of hPSC differentiation into hepatocytes are explored, along with the current limitations that have led to the development of 3D culture systems and organoid production. Expected applications of these organoids are discussed with particular attention paid to bio artificial liver (BAL) devices and liver bio-fabrication.
Topics: Cell Differentiation; Cell- and Tissue-Based Therapy; Hepatocytes; Humans; Liver; Liver Diseases; Liver, Artificial; Organoids; Pluripotent Stem Cells; Regeneration
PubMed: 32059501
DOI: 10.3390/cells9020420 -
Theranostics 2022The advent of human pluripotent stem cells (hPSCs) presented a new paradigm to employ hPSC-derived cardiomyocytes (hPSC-CMs) in drug screening and disease modeling.... (Review)
Review
The advent of human pluripotent stem cells (hPSCs) presented a new paradigm to employ hPSC-derived cardiomyocytes (hPSC-CMs) in drug screening and disease modeling. However, hPSC-CMs differentiated in conventional two-dimensional systems are structurally and functionally immature. Moreover, these differentiation systems generate predominantly one type of cell. Since the heart includes not only CMs but other cell types, such monolayer cultures have limitations in simulating the native heart. Accordingly, three-dimensional (3D) cardiac tissues have been developed as a better platform by including various cardiac cell types and extracellular matrices. Two advances were made for 3D cardiac tissue generation. One type is engineered heart tissues (EHTs), which are constructed by 3D cell culture of cardiac cells using an engineering technology. This system provides a convenient real-time analysis of cardiac function, as well as a precise control of the input/output flow and mechanical/electrical stimulation. The other type is cardiac organoids, which are formed through self-organization of differentiating cardiac lineage cells from hPSCs. While mature cardiac organoids are more desirable, at present only primitive forms of organoids are available. In this review, we discuss various models of hEHTs and cardiac organoids emulating the human heart, focusing on their unique features, utility, and limitations.
Topics: Cell Differentiation; Humans; Myocytes, Cardiac; Organoids; Pluripotent Stem Cells; Tissue Engineering
PubMed: 35401829
DOI: 10.7150/thno.67661 -
Nature Reviews. Cardiology Jun 2020Our knowledge of pluripotent stem cell (PSC) biology has advanced to the point where we now can generate most cells of the human body in the laboratory. PSC-derived... (Review)
Review
Our knowledge of pluripotent stem cell (PSC) biology has advanced to the point where we now can generate most cells of the human body in the laboratory. PSC-derived cardiomyocytes can be generated routinely with high yield and purity for disease research and drug development, and these cells are now gradually entering the clinical research phase for the testing of heart regeneration therapies. However, a major hurdle for their applications is the immature state of these cardiomyocytes. In this Review, we describe the structural and functional properties of cardiomyocytes and present the current approaches to mature PSC-derived cardiomyocytes. To date, the greatest success in maturation of PSC-derived cardiomyocytes has been with transplantation into the heart in animal models and the engineering of 3D heart tissues with electromechanical conditioning. In conventional 2D cell culture, biophysical stimuli such as mechanical loading, electrical stimulation and nanotopology cues all induce substantial maturation, particularly of the contractile cytoskeleton. Metabolism has emerged as a potent means to control maturation with unexpected effects on electrical and mechanical function. Different interventions induce distinct facets of maturation, suggesting that activating multiple signalling networks might lead to increased maturation. Despite considerable progress, we are still far from being able to generate PSC-derived cardiomyocytes with adult-like phenotypes in vitro. Future progress will come from identifying the developmental drivers of maturation and leveraging them to create more mature cardiomyocytes for research and regenerative medicine.
Topics: Animals; Cell Culture Techniques; Cell Differentiation; Humans; Metabolome; Myocytes, Cardiac; Pluripotent Stem Cells; Proteome; Regenerative Medicine; Stem Cell Transplantation; Tissue Engineering; Transcriptome
PubMed: 32015528
DOI: 10.1038/s41569-019-0331-x -
Cell Stem Cell Mar 2021Pluripotent cells emerge as a naive founder population in the blastocyst, acquire capacity for germline and soma formation, and then undergo lineage priming. Mouse...
Pluripotent cells emerge as a naive founder population in the blastocyst, acquire capacity for germline and soma formation, and then undergo lineage priming. Mouse embryonic stem cells (ESCs) and epiblast-derived stem cells (EpiSCs) represent the initial naive and final primed phases of pluripotency, respectively. Here, we investigate the intermediate formative stage. Using minimal exposure to specification cues, we derive stem cells from formative mouse epiblast. Unlike ESCs or EpiSCs, formative stem (FS) cells respond directly to germ cell induction. They colonize somatic tissues and germline in chimeras. Whole-transcriptome analyses show similarity to pre-gastrulation formative epiblast. Signal responsiveness and chromatin accessibility features reflect lineage capacitation. Furthermore, FS cells show distinct transcription factor dependencies, relying critically on Otx2. Finally, FS cell culture conditions applied to human naive cells or embryos support expansion of similar stem cells, consistent with a conserved staging post on the trajectory of mammalian pluripotency.
Topics: Animals; Blastocyst; Cell Differentiation; Embryonic Stem Cells; Germ Layers; Humans; Mice; Pluripotent Stem Cells
PubMed: 33271069
DOI: 10.1016/j.stem.2020.11.005 -
Molecules (Basel, Switzerland) Apr 2020Neurodegenerative diseases represent a significant unmet medical need in our aging society. There are no effective treatments for most of these diseases, and we know... (Review)
Review
Neurodegenerative diseases represent a significant unmet medical need in our aging society. There are no effective treatments for most of these diseases, and we know comparatively little regarding pathogenic mechanisms. Among the challenges faced by those involved in developing therapeutic drugs for neurodegenerative diseases, the syndromes are often complex, and small animal models do not fully recapitulate the unique features of the human nervous system. Human induced pluripotent stem cells (iPSCs) are a novel technology that ideally would permit us to generate neuronal cells from individual patients, thereby eliminating the problem of species-specificity inherent when using animal models. Specific phenotypes of iPSC-derived cells may permit researchers to identify sub-types and to distinguish among unique clusters and groups. Recently, iPSCs were used for drug screening and testing for neurologic disorders including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), spinocerebellar atrophy (SCA), and Zika virus infection. However, there remain many challenges still ahead, including how one might effectively recapitulate sporadic disease phenotypes and the selection of ideal phenotypes and for large-scale drug screening. Fortunately, quite a few novel strategies have been developed that might be combined with an iPSC-based model to solve these challenges, including organoid technology, single-cell RNA sequencing, genome editing, and deep learning artificial intelligence. Here, we will review current applications and potential future directions for iPSC-based neurodegenerative disease models for critical drug screening.
Topics: Animals; Cell Differentiation; Disease Susceptibility; Drug Discovery; Drug Evaluation, Preclinical; Humans; Induced Pluripotent Stem Cells; Neurodegenerative Diseases; Neuroglia; Neurons; Phenotype
PubMed: 32344649
DOI: 10.3390/molecules25082000