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Key Points Human induced pluripotent stem cell (iPSC) technology has evolved rapidly since its inception in 2007. Human iPSC technology has been widely used for disease modelling; for example, for neurodegenerative and psychiatric disorders. Human iPSC technology has yielded several drug candidates that are currently in clinical trials. The first clinical trial using human iPSC-derived products has been initiated for age-related macular degeneration. The combination with gene editing and 3D organoid technologies makes the iPSC platform more powerful. The continued development of iPSC technology and its integration with other technologies has the potential to make substantial contributions to disease modelling, drug discovery and regenerative medicine. Since the advent of induced pluripotent stem cell (iPSC) technology a decade ago, human iPSCs have been widely used for disease modelling, drug discovery and cell therapy development. This article discusses progress in applications of iPSC technology that are particularly relevant to drug discovery and regenerative medicine, including the powerful combination of human iPSC technology with recent developments in gene editing. Since the advent of induced pluripotent stem cell (iPSC) technology a decade ago, enormous progress has been made in stem cell biology and regenerative medicine. Human iPSCs have been widely used for disease modelling, drug discovery and cell therapy development. Novel pathological mechanisms have been elucidated, new drugs originating from iPSC screens are in the pipeline and the first clinical trial using human iPSC-derived products has been initiated. In particular, the combination of human iPSC technology with recent developments in gene editing and 3D organoids makes iPSC-based platforms even more powerful in each area of their application, including precision medicine. In this Review, we discuss the progress in applications of iPSC technology that are particularly relevant to drug discovery and regenerative medicine, and consider the remaining challenges and the emerging opportunities in the field.

\"The discovery of cells--and the reframing of the human body as a cellular ecosystem--announced the birth of a new kind of medicine based on the therapeutic manipulations of cells. A hip fracture, a cardiac arrest, Alzheimer's, dementia, AIDS, pneumonia, lung cancer, kidney failure, arthritis, COVID--all could be viewed as the results of cells, or systems of cells, functioning abnormally. And all could be perceived as loci of cellular therapies. In The Song of the Cell, Mukherjee tells the story of how scientists discovered cells, began to understand them, and are now using that knowledge to create new treatments and new humans\"--Dust jacket flap.

Embryonic stem cells (ESCs) are derived from the inner cell mass of preimplantation blastocysts. From agricultural and biomedical perspectives, the derivation of stable ESCs from domestic ungulates is important for genomic testing and selection, genome engineering, and modeling human diseases. Cattle are one of the most important domestic ungulates that are commonly used for food and bioreactors. To date, however, it remains a challenge to produce stable pluripotent bovine ESC lines. Employing a culture system containing fibroblast growth factor 2 and an inhibitor of the canonical Wnt-signaling pathway, we derived pluripotent bovine ESCs (bESCs) with stable morphology, transcriptome, karyotype, population-doubling time, pluripotency marker gene expression, and epigenetic features. Under this condition bESC lines were efficiently derived (100% in optimal conditions), were established quickly (3–4 wk), and were simple to propagate (by trypsin treatment). When used as donors for nuclear transfer, bESCs produced normal blastocyst rates, thereby opening the possibility for genomic selection, genome editing, and production of cattle with high genetic value.

Documents the story of how scientists took cells from an unsuspecting descendant of freed slaves and created a human cell line that has been kept alive indefinitely, enabling discoveries in such areas as cancer research, in vitro fertilization, and gene mapping.

Aberrant epithelial reprogramming can induce metaplastic differentiation at sites of tissue injury that culminates in transformed barriers composed of scar and metaplastic epithelium. While the plasticity of epithelial stem cells is well characterized, the identity and role of the niche has not been delineated in metaplasia. Here, we show that Gli1+ mesenchymal stromal cells (MSCs), previously shown to contribute to myofibroblasts during scarring, promote metaplastic differentiation of airway progenitors into KRT5+ basal cells. During fibrotic repair, Gli1+ MSCs integrate hedgehog activation signalling to upregulate BMP antagonism in the progenitor niche that promotes metaplasia. Restoring the balance towards BMP activation attenuated metaplastic KRT5+ differentiation while promoting adaptive alveolar differentiation into SFTPC+ epithelium. Finally, fibrotic human lungs demonstrate altered BMP activation in the metaplastic epithelium. These findings show that Gli1+ MSCs integrate hedgehog signalling as a rheostat to control BMP activation in the progenitor niche to determine regenerative outcome in fibrosis.Cassandras et al. show that Gli1-expressing mesenchymal stromal cells promote metaplastic differentiation of airway progenitors into basal cells by antagonizing BMP signalling in lung fibrosis.

\"In proving the existence of stem cells, Ernest Armstrong McCulloch and James Edgar Till formed the most important partnership in Canadian medical research since Frederick Banting and Charles Best, the discoverers of insulin. Together, Till and McCulloch instructed, influenced, and inspired successive generations of researchers who have used their findings to make huge advances against disease. Thousands of people who would have died from leukemia and immunological disorders now owe their lives to therapies supported by their seminal discoveries\"-- Dust jacket flap.

Alveolar epithelium plays a pivotal role in protecting the lungs from inhaled infectious agents. Therefore, the regenerative capacity of the alveolar epithelium is critical for recovery from these insults in order to rebuild the epithelial barrier and restore pulmonary functions. Here, we show that sublethal infection of mice with Streptococcus pneumoniae, the most common pathogen of community-acquired pneumonia, led to exclusive damage in lung alveoli, followed by alveolar epithelial regeneration and resolution of lung inflammation. We show that surfactant protein C-expressing (SPC-expressing) alveolar epithelial type II cells (AECIIs) underwent proliferation and differentiation after infection, which contributed to the newly formed alveolar epithelium. This increase in AECII activities was correlated with increased nuclear expression of Yap and Taz, the mediators of the Hippo pathway. Mice that lacked Yap/Taz in AECIIs exhibited prolonged inflammatory responses in the lung and were delayed in alveolar epithelial regeneration during bacterial pneumonia. This impaired alveolar epithelial regeneration was paralleled by a failure to upregulate IκBa, the molecule that terminates NF-κB-mediated inflammatory responses. These results demonstrate that signals governing resolution of lung inflammation were altered in Yap/Taz mutant mice, which prevented the development of a proper regenerative niche, delaying repair and regeneration of alveolar epithelium during bacterial pneumonia.

The heart switches its energy substrate from glucose to fatty acids at birth, and maternal hyperglycemia is associated with congenital heart disease. However, little is known about how blood glucose impacts heart formation. Using a chemically defined human pluripotent stem-cell-derived cardiomyocyte differentiation system, we found that high glucose inhibits the maturation of cardiomyocytes at genetic, structural, metabolic, electrophysiological, and biomechanical levels by promoting nucleotide biosynthesis through the pentose phosphate pathway. Blood glucose level in embryos is stable in utero during normal pregnancy, but glucose uptake by fetal cardiac tissue is drastically reduced in late gestational stages. In a murine model of diabetic pregnancy, fetal hearts showed cardiomyopathy with increased mitotic activity and decreased maturity. These data suggest that high glucose suppresses cardiac maturation, providing a possible mechanistic basis for congenital heart disease in diabetic pregnancy. Congenital heart disease is the most common type of birth defect, affecting nearly 1 in 100 children born. It can involve a weak heart, narrowed arteries, narrowed heart valves, or the main arteries of the heart switching places. These conditions can be fatal if untreated and often need surgery to correct. The mother’s blood sugar levels during pregnancy can have a large effect on how likely the baby is to have congenital heart disease. If a pregnant woman has poorly controlled diabetes with rapidly fluctuating sugar levels, she may be at a higher risk of having a child with the condition. High sugar levels in the mother’s blood make the baby up to five times more likely to have congenital heart disease. It has been difficult to find out exactly how sugar levels interfere with heart development because diabetes can affect the fetus in many ways. Nakano et al. used stem cells and experiments in pregnant mice with diabetes to hone in on how high sugar levels affect the fetus’s heart development. First, heart cells were grown from human stem cells, and exposed to high levels of glucose in a dish. This revealed a new mechanism for how high sugar levels affect heart formation: the cells created too many nucleotides, the building blocks of molecules such as DNA. It turns out that high glucose levels boosted a chemical process in the cell known as the pentose phosphate pathway. Some of the products of this pathway are nucleotides. This made the cells divide rapidly, but did not allow them to mature well compared with cells exposed to normal levels of sugar. In another experiment, Nakano et al. found similar results in pregnant diabetic mice. The heart cells in mouse fetuses also divided quickly but matured slowly when exposed to high sugar levels. An estimated 60 million women at an age to have children have diabetes. These new findings help us to understand why and how these women are more likely to have children with congenital heart disease, and further study will hopefully lead to a better way to prevent this condition.

Until recently, complex multi-parameters were required for the isolation and identification of haematopoietic stem cells, complicating study of their biology in situ ; here the authors have found that expression of a single gene, Hoxb5 , defines haematopoietic stem cells with long-term reconstitution capacity, and that these cells are mainly found in direct contact with endothelial cells. Haematopoietic stem cell niche characterized Until recently, the isolation and recognition of haematopoietic stem cells (HSCs) has been a complex process involving the manipulation of multiple parameters, and this complicates the study of HSC biology in situ . In particular, it has been difficult to establish their relationship to the HSC niche, and how their self-renewal and differentiation properties are modulated by their environment. Here Irving Weissman and colleagues demonstrate that expression of a single gene, Hoxb5 , defines cells with long-term reconstitution capacity, and show that these cells are mainly found directly in contact with endothelial cells. Haematopoietic stem cells (HSCs) are arguably the most extensively characterized tissue stem cells. Since the identification of HSCs by prospective isolation 1 , complex multi-parameter flow cytometric isolation of phenotypic subsets has facilitated studies on many aspects of HSC biology, including self-renewal 2 , 3 , 4 , differentiation, ageing, niche 5 , and diversity 6 , 7 , 8 . Here we demonstrate by unbiased multi-step screening, identification of a single gene, homeobox B5 ( Hoxb5 , also known as Hox-2.1 ), with expression in the bone marrow that is limited to long-term (LT)-HSCs in mice. Using a mouse single-colour tri-mCherry reporter driven by endogenous Hoxb5 regulation, we show that only the Hoxb5 + HSCs exhibit long-term reconstitution capacity after transplantation in primary transplant recipients and, notably, in secondary recipients. Only 7–35% of various previously defined immunophenotypic HSCs are LT-HSCs. Finally, by in situ imaging of mouse bone marrow, we show that >94% of LT-HSCs (Hoxb5 + ) are directly attached to VE-cadherin + cells, implicating the perivascular space as a near-homogenous location of LT-HSCs.