The use of cultured human pluripotent stem cells (PSCs) to model human diseases has revolutionized the ways in which we study monogenic, multigenic and epigenetic disorders, by overcoming some of the limitations of animal models. PSC-based disease models are generated using various strategies and can be used for the discovery of new drugs and therapies.
Stem cells in translation
Stem-cell research is rapidly advancing towards potential therapeutic applications such as tissue and organ replacement, disease modelling and drug testing. This collection of articles published by Nature Publishing Group illustrates progress in bringing stem-cell research to the clinic.
Research Articles provide the latest insights into how cell differentiation can be directed to reconstitute tissues in vitro and into how stem-cell fates could be modulated to promote tissue repair in vivo. The articles also describe stem-cell-based models of disease that increase our understanding of disease onset and progression, providing a tool for drug screening and development.
News and Opinion articles include Reviews and Comments and discuss the potential and limitations of these findings in the context of regenerative medicine, highlighting the technical and regulatory challenges that lie ahead. This collection also includes a selection of peer-reviewed procedures from Nature Protocols that reflect how advances in stem-cell research are closely linked to the development of methods and techniques. Posters produced by the Nature Reviews Journals, which provide a visual overview of stem-cell-biology topics, can also be accessed and downloaded.
News and Opinion
Advances in the derivation of pluripotent stem cells (PSCs) and their differentiation to specific cell types could have diverse clinical applications. Trounson and DeWitt provide an overview of the progress in using embryonic stem cell and induced PSC derivatives for disease treatment and discuss the potential and limitations of such approaches.
Manipulating the stem cell niche could provide new ways of coaxing stem cells to repair damaged tissues.
Berninger and colleagues define milestones for in vivo reprogramming and discuss recent developments in reprogramming into pancreatic b-cells and neurons.
The use of patient-derived stem cells for in vitro neurodegenerative disease modeling has gained much traction in recent years. In this review, the authors examine the potential caveats and pitfalls of stem cell use and highlight insights from the literature that suggest methods for overcoming these difficulties.
Worldwide increases in life expectancy have been paralleled by a greater prevalence of chronic and age-associated disorders, particularly of the cardiovascular, neural and metabolic systems. Patient-specific induced pluripotent stem (iPS) cells are finding applications in disease modelling, drug testing and drug discovery, thus enabling researchers to undertake studies for treating diseases 'in a dish'.
Our understanding of stem cell biology is increasing, but the translation of this knowledge into regenerative medicine therapies for aged or diseased tissues is proving challenging. In this Perspective, four experts in the field discuss strategies for overcoming the major hurdles facing the translational regenerative field.
Elena Cattaneo and Gilberto Corbellini are among the academics working to protect patients from questionable stem-cell therapies. Here, they share their experiences and opinions of the long, hard fight for evidence to prevail.
Stem cells are being used as a wedge in calls to allow unproven medical interventions onto the market, warn Paolo Bianco and Douglas Sipp.
With thousands of people in need of heart transplants, researchers are trying to grow new organs.
Techniques that transfer DNA from diseased human eggs to healthy ones — creating offspring with three biological parents — are on the verge of clinical use.
Technologies are allowing doctors to do what was once unheard of: restore blind people's sight. Now the real challenges begin.
A decade ago, voters in California changed the biomedical research landscape by directly funding embryonic stem-cell research. Now the organization they created needs a hit to survive.
Moratorium on controversial therapy lifted as stem cells emerge as alternative source of treatment.
Standardized procedures and analyses should help to get stem-cell therapies to the clinic.
Diverse neurodegenerative diseases share a common pathological feature, namely the accumulation of misfolded proteins. However, both drug development and research need more standardization of the biomarkers for the protein types involved. The bold strategy of integrating high-throughput genetic and chemical screens in yeast with experiments in neurons derived from genetically modified human induced pluripotent stem cells (iPSCs) is producing many significant new molecular insights into disease mechanisms.
Human pluripotent stem cells (hPSCs) have great potential for regenerative medicine, yet producing billions of hPSCs suitable for clinical use needs defined culture conditions and scalable culture systems. This Review discusses the role of high-throughput materials discovery in the development of scalable growth substrates for hPSC culture.
The preclinical intersection of molecular imaging and gene- and cell-based therapies will enable more informed and effective clinical translation. We discuss how imaging can monitor cell and gene fate and function in vivo and overcome barriers associated with these therapies.
Materials-based control of stem cell fate is beginning to be rigorously combined with traditional soluble-factor approaches to better understand the cells' behaviour and maximize their potential for therapy.
Differentiation of human pluripotent stem cells toward pancreatic beta cells yields cells of increased maturity.
Human pluripotent stem cells can be coaxed into a pure population of definitive hematopoietic cells.
Generation of differentiated kidney cell types from pluripotent stem cells would be enormously useful for research and therapeutic purposes, but progress towards this goal has so far been limited. In three recent reports, mature kidney cell types and three-dimensional nephron-like structures were generated from pluripotent cells rapidly and efficiently. A detailed understanding of the signals that drive nephrogenesis proved critical for these achievements.
Large copy number variants (CNVs) are strongly associated with morphogenetic processes and common neurodevelopmental disorders. A new study uses the example of Williams-Beuren syndrome (WBS) and Williams-Beuren region duplication syndrome to illustrate how induced pluripotent stem cells (iPSCs) and next-generation genomics can lead to a better understanding of complex genetics.
Prader-Willi syndrome (PWS) is caused by loss of paternally expressed genes at an imprinted locus on chromosome 15, including the long noncoding RNA IPW. A new study identifies a critical role for IPW in modulating the expression of maternally expressed genes in trans, which has important implications for the understanding of imprinted gene networks.
Two drugs, miconazole and clobetasol, have functions that modulate differentiation of oligodendrocyte progenitor cells directly, enhance remyelination, and significantly reduce disease severity in mouse models of multiple sclerosis.
J. B. Gurdon introduces this Focus issue by discussing the importance of the discovery of induced pluripotent stem cells 10 years ago and current challenges for the development of cell replacement therapies.
Combinatorial analysis of developmental cues efficiently converts human pluripotent stem cells into multiple neuronal subtypes
Combinatorial screening of developmental factors improves directed differentiation of human pluripotent stem cells into neuronal subtypes.
In this study, the authors show that they can induce the direct conversion of fibroblasts into nociceptor neurons via the expression of only five key transcription factors. They further confirm that these induced neurons are bona fide nociceptors by demonstrating that their expression profiles resemble that of their endogenous counterparts and show that they are responsive to common nociceptor agonists.
In this study, the authors show that expression of Brn3a with Ngn1 or 2 can induce the direct reprogramming of mouse and human fibroblasts into peripheral sensory neurons. They further demonstrate that these neurons exhibit the expression profiles and physiological properties of mature sensory neurons and are responsive to nociceptor agonists.
Some types of anaemia do not respond to erythropoietin (Epo) treatment because patients do not have sufficient numbers of Epo-sensitive erythroid precursor cells; here, two agonists of PPAR-α are found to synergize with glucocorticoid treatment to promote early erythroid progenitor self-renewal, increasing the production of mature red blood cells in both human and mouse cultures and alleviating anaemia in mouse models.
A method for 3D differentiation of human pluripotent stem cells yields brain cortical spheroids with functional neurons and astrocytes. The spheroids can be sliced for imaging and electrophysiological studies.
Optogenetics enables functional analysis of human embryonic stem cell–derived grafts in a Parkinson's disease model
Optogenetics helps unravel how neural cell grafts ameliorate symptoms in a mouse model of Parkinson's disease.
Articular cartilage cells, which maintain synovial joints, are generated in culture from human pluripotent stem cells.
This paper shows that microfluidic perfusion frequency can be optimized to improve the differentiation of human pluripotent stem cells along different lineages, and uses this principle to achieve functional hPSC differentiation directly on a chip.
7q11.23 dosage-dependent dysregulation in human pluripotent stem cells affects transcriptional programs in disease-relevant lineages
Giuseppe Testa and colleagues report the generation and transcriptional characterization of patient-derived induced pluripotent stem cells (iPSCs) with copy number variants at 7q11.23, which cause syndromes including neurocognitive phenotypes. They find that the dosage of the transcription factor gene GTF2I accounts for 10–20% of the transcriptional dysregulation observed in these cells.
The noncoding RNA IPW regulates the imprinted DLK1-DIO3 locus in an induced pluripotent stem cell model of Prader-Willi syndrome
Nissim Benvenisty and colleagues use induced pluripotent stem cells (iPSCs) derived from individuals with Prader-Willi syndrome (PWS) to model PWS in vitro. By comparison to parthenogenetic human iPSCs, they find that the PWS-associated noncoding RNA IPW regulates maternally expressed genes at the DLK1-DIO3 imprinted region through its effect on H3K9me3 histone marks in that region.
Wnt signaling controls the specification of definitive and primitive hematopoiesis from human pluripotent stem cells
Hematopoietic differentiation of human pluripotent stem cells is directed to either the definitive or primitive program, a step toward the generation of hematopoietic stem cells.
Fanconi anaemia (FA) is a genetic disease associated with low levels of blood stem cells. Here Liu et al. report an improved method to generate genetically corrected induced pluripotent stem cells from an FA patient, and perform a screening to identify drugs that improve their differentiation into blood stem cells.
iPSC-derived neurons from GBA1-associated Parkinson’s disease patients show autophagic defects and impaired calcium homeostasis
Mutations in the gene, GBA1, cause Gaucher’s disease, and are a strong risk factor for the development of Parkinson’s disease. Here the authors use cells derived from Parkinson’s patients with GBA1 mutations to model the disease, and reveal changes in cellular recycling systems that may promote neurodegeneration.
Role of astroglia in Down’s syndrome revealed by patient-derived
human-induced pluripotent stem cells
Down’s syndrome is characterized by intellectual disability and other neuropathological symptoms. Here, the authors show that astroglia derived from induced pluripotent stem cells from Down’s syndrome patients impair the development of neurons, and that this can be attenuated with the drug minocycline.
Shen and colleagues report the in vitro generation of organoids from mouse luminal epithelial progenitor cells and normal or transformed prostate tissue, and extend this approach to the formation of normal and tumour organoids of human origin
Generation of functional T-cells for therapeutic purposes requires a thymic epithelium. Blackburn and colleagues show that FOXN1 expression in fibroblasts triggers the formation of functional thymic epithelial cells that support T-cell differentiation from haematopoietic progenitors.
Directing human embryonic stem cell differentiation towards a renal lineage generates a self-organizing kidney
Differentiation of pluripotent cells into renal lineages has had limited success so far. Melissa Little and colleagues have used defined medium conditions that induce posterior primitive streak and intermediate mesoderm using growth factors used during normal embryogenesis. This results in the synchronous induction of both components of the kidney, the ureteric bud and metanephric mesenchyme, which form a self-organizing nephron structure in vitro.
Here the authors present a human pluripotent stem cell-derived three-dimensional organoid culture system that is able to recapitulate several aspects of human brain development in addition to modelling the brain disorder microcephaly, which has been difficult to achieve using mouse models.
Reversal of diabetes with insulin-producing cells derived in vitro from human pluripotent stem cells
A seven-stage protocol enables differentiation of human embryonic stem cells into cells similar to pancreatic beta cells.
Differentiation of human pluripotent stem cells to cells similar to cord-blood endothelial colony–forming cells
Endothelial cells with properties of cord-blood endothelial colony-forming cells are generated from human pluripotent stem cells.
The ability to generate epicardial cells from human pluripotent stem cells will facilitate studies of heart regeneration.
High-throughput screening platform for the testing of small bioactive molecules that promote oligodendrocyte differentiation and remyelination: a new path to the discovery of potential drugs for multiple sclerosis.
Although human pluripotent stem cells (hPSCs) can be used to regenerate neural tissues, inefficient protocols and poorly defined culture conditions have hindered their use. It is now shown that soft, micropatterned culture substrates can induce hPSCs to differentiate into motor neurons with significantly improved yields and purity in comparison to rigid substrates, and that such mechanotransductive process involves the Hippo/YAP pathway and phosphorylation of the intracellular protein Smad.
Medial ganglionic eminence–like cells derived from human embryonic stem cells correct learning and memory deficits
Human embryonic stem cells differentiated to medial ganglionic eminence–like cells ameliorate learning and memory deficits in a mouse model.
Multiple sclerosis is associated with a deficiency in generation of mature oligodendroctyes; an image-based screen for oligodendrocyte differentiation inducers identified the compound benztropine, which enhances remyelination acting through muscarinic receptors and decreases clinical severity in a multiple sclerosis model system.
In this study, the authors show that MGE-derived interneuron progenitors, when engrafted into the adult hippocampus, can migrate long distances and functionally integrate into the host tissue. In addition, if these cells are engrafted into the brain after the initiation of epilepsy, seizure frequency and behavioral deficits are reduced.
Differentiation of pluripotent cells into renal lineages has so far demonstrated limited success. Juan Carlos Ispizua Belmonte and colleagues have used defined medium conditions to obtain committed renal progenitor cells that are able to integrate into a ureteric bud in a three-dimensional culture system.
A new protocol enables efficient differentiation of human pluripotent stem cells to lung cells, including type II alveolar epithelial cells.
In this study, the authors direct human iPS and ES cells to adopt cortical progenitor and, subsequently, mature projection neurons with functional synaptic connections. This protocol is able to generate both deep and upper layer neurons in proper temporal order.