In recent years, the highly conserved Lin28 RNA-binding proteins have emerged as factors that define stemness in several tissue lineages. Lin28 proteins repress let-7 microRNAs and influence mRNA ...translation, thereby regulating the self-renewal of mammalian embryonic stem cells. Subsequent discoveries revealed that Lin28a and Lin28b are also important in organismal growth and metabolism, tissue development, somatic reprogramming, and cancer. In this review, we discuss the Lin28 pathway and its regulation, outline its roles in stem cells, tissue development, and pathogenesis, and examine the ramifications for re-engineering mammalian physiology.
This review discusses the highly conserved Lin28 family of RNA-binding proteins and outlines its role in stem cells, tissue development, and pathogenesis, and examines the ramifications for re-engineering mammalian physiology
Stem cells are the seeds of tissue repair and regeneration and a promising source for novel therapies. However, apart from hematopoietic stem cell (HSC) transplantation, essentially all other stem ...cell treatments remain experimental. High hopes have inspired numerous clinical trials, but it has been difficult to obtain unequivocal evidence for robust clinical benefit. In recent years, unproven therapies have been widely practiced outside the standard clinical trial network, threatening the cause of legitimate clinical investigation. Numerous challenges and technical barriers must be overcome before novel stem cell therapies can achieve meaningful clinical impact.
The field of stem-cell biology has been catapulted forward by the startling development of reprogramming technology. The ability to restore pluripotency to somatic cells through the ectopic ...co-expression of reprogramming factors has created powerful new opportunities for modelling human diseases and offers hope for personalized regenerative cell therapies. While the field is racing ahead, some researchers are pausing to evaluate whether induced pluripotent stem cells are indeed the true equivalents of embryonic stem cells and whether subtle differences between these types of cell might affect their research applications and therapeutic potential.
Pluripotent stem cells constitute a platform to model disease and developmental processes and can potentially be used in regenerative medicine. However, not all pluripotent cell lines are equal in ...their capacity to differentiate into desired cell types in vitro. Genetic and epigenetic variations contribute to functional variability between cell lines and heterogeneity within clones. These genetic and epigenetic variations could 'lock' the pluripotency network resulting in residual pluripotent cells or alter the signalling response of developmental pathways leading to lineage bias. The molecular contributors to functional variability and heterogeneity in both embryonic stem (ES) cells and induced pluripotent stem (iPS) cells are only beginning to emerge, yet they are crucial to the future of the stem cell field.
The derivation of induced pluripotent stem cells (iPSCs) over a decade ago sparked widespread enthusiasm for the development of new models of human disease, enhanced platforms for drug discovery and ...more widespread use of autologous cell-based therapy. Early studies using directed differentiation of iPSCs frequently uncovered cell-level phenotypes in monogenic diseases, but translation to tissue-level and organ-level diseases has required development of more complex, 3D, multicellular systems. Organoids and human-rodent chimaeras more accurately mirror the diverse cellular ecosystems of complex tissues and are being applied to iPSC disease models to recapitulate the pathobiology of a broad spectrum of human maladies, including infectious diseases, genetic disorders and cancer.
Although development leads unidirectionally toward more restricted cell fates, recent work in cellular reprogramming has proven that one cellular identity can strikingly convert into another, ...promising countless applications in biomedical research and paving the way for modeling diseases with patient-derived stem cells. To date, there has been little discussion of which disease models are likely to be most informative. Here, we review evidence demonstrating that, because environmental influences and epigenetic signatures are largely erased during reprogramming, patient-specific models of diseases with strong genetic bases and high penetrance are likely to prove most informative in the near term. We also discuss the implications of the new reprogramming paradigm in biomedicine and outline how reprogramming of cell identities is enhancing our understanding of cell differentiation and prospects for cellular therapies and in vivo regeneration.
Small, rapidly dividing pluripotent stem cells (PSCs) have unique energetic and biosynthetic demands compared with typically larger, quiescent differentiated cells. Shifts between glycolysis and ...oxidative phosphorylation with PSC differentiation or reprogramming to pluripotency are accompanied by changes in cell cycle, biomass, metabolite levels, and redox state. PSC and cancer cell metabolism are overtly similar, with metabolite levels influencing epigenetic/genetic programs. Here, we discuss the emerging roles for metabolism in PSC self-renewal, differentiation, and reprogramming.
Recent advances in metabolomics and computational analysis have deepened our appreciation for the role of specific metabolic pathways in dictating cell fate. Once thought to be a mere consequence of ...the state of a cell, metabolism is now known to play a pivotal role in dictating whether a cell proliferates, differentiates or remains quiescent. Here, we review recent studies of metabolism in stem cells that have revealed a shift in the balance between glycolysis, mitochondrial oxidative phosphorylation and oxidative stress during the maturation of adult stem cells, and during the reprogramming of somatic cells to pluripotency. These insights promise to inform strategies for the directed differentiation of stem cells and to offer the potential for novel metabolic or pharmacological therapies to enhance regeneration and the treatment of degenerative disease.
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