In this article, Kiskinis and coworkers use all-optical electrophysiology to characterize an iPSC-based model of ALS. By performing high-throughput optical measurements of excitability in motor neurons derived from patients with a SOD1 (A4V) mutations and genome-corrected controls, the authors identify differences in firing consistent with a deficit in KV7 current in the mutants.
Schroeder and colleagues show that GSK3 and MEK inhibition (2i) has several simultaneous effects on murine ESC cultures. They applied long-term time-lapse imaging to quantify cell death, proliferation, and Nanog expression dynamics in single ESCs. This demonstrated that 2i treatment of ESCs leads to more uniform and high Nanog expression due to both selective and inductive effects.
Medelnik and colleagues identify lysophosphatidic acid as a serum factor that has a major effect on the expansion of the apical domain of human ESC-derived neural progenitor cells, resulting in the formation of very large neural rosette-like structures that can be maintained for many passages in the absence of neuronal and glial differentiation if constantly supplied with LPA.
In this paper, Bertrand and colleagues show that kit signaling is necessary to the development of zebrafish hematopoietic stem cells, as well as for their expansion. Moreover, they characterize a new zebrafish cytokine, oncostatin M (osm), which acts upstream of kit signaling during HSC specification but synergizes with kitlgb to promote HSC expansion in the caudal hematopoietic tissue.
Human embryonic stem cells have the capacity to turn into any cell type within the adult. Peter Andrews and colleagues have shown that subtle differences between individual cells can functionally bias the resulting cell type that is produced. Generating and purifying these biased cells may therefore improve the derivation of medically relevant cell types.
In this article, Tuoc and colleagues show that inactivation of BAF complexes in late cortical development leads to H3K27me3-linked silencing of neuronal differentiation-related genes, with concurrent H3K4me2-mediated activation of proliferation-associated genes via de-repression of Wnt signaling. The deletion of BAF complexes increased proliferation of neuroepithelial-like progenitors, impaired neuronal differentiation, and exerted a Wnt-dependent effect on neocortical and hippocampal development.
In this article, Dr. Zhang and colleagues describe an episomal vector system for one-step generation and genome editing (knockin) of integration-free iPSCs from peripheral blood mononuclear cells (PB MNCs). Up to 40% knockin editing efficiencies in bulk iPSCs can be achieved by co-expression of Cas9 and KLF4 in a single vector and with addition of SV40LT.
In this article, Wielockx and colleagues reveal that chronic erythropoietic stress induces distinct differences in the behavior of HSCs and their closely related MPPs. In particular, HSCs show greater commitment to an erythroid progenitor profile with heightened cell division, whereas MPPs are characterized by erythroid and immune signatures and an accumulation of uncommitted cells.
Kusumoto et al. developed an automated system to identify endothelial cells derived from induced pluripotent stem cells, based only on morphology. Performance, as assessed by F1 score and accuracy, was correlated with network depth and pixel size of training images. K-fold validation confirmed that endothelial cells are identified automatically with high accuracy using only generalized morphological features.
Shaheen and Shiti et al. combine hiPSC-CMs, two-dimensional cardiac tissue models, and optical mapping of a genetically encoded voltage indicator (ArcLight) to enable both short-term and repeated tissue electrophysiological phenotyping (over weeks). This allowed tracking of electrophysiological tissue remodeling over time; drug effects on conduction, repolarization, and pro-arrhythmia; and investigation of arrhythmia mechanisms and treatments.
We are pleased to introduce a new feature in this issue of Stem Cell Reports in which we invite an author to share a personal narrative about his or her paper, also published in this edition. In this Q&A format, the author shares perspectives and insights into the research and its broader impact in the field, addressing questions the research may raise and its implications.
We have seen important advances in stem cell science in recent years, many the results of new technologies and applications that are propelling research forward and collaborations that are moving science closer to the clinic. Just in the past year, several significant studies such as a trial using a stem cell-based therapy to treat epidermis bullosa (https://www.closerlookatstemcells.org/blog/blog/2018/02/13/Novel-Stem-Cell-Therapy-Grows-New-Skin), and retinal therapy using stem cells (https://www.sciencedaily.com/releases/2018/03/180319124218.htm) have shown initial success, with trials in other areas beginning to get underway.
Joseph Itskovitz-Eldor gives his personal perspective and experience related to events in the US and Israel surrounding the early days of hESC derivation in 1998; the major role reproductive medicine, specifically IVF, played in successful isolation of hESC lines; and how early distribution of hESCs from his laboratory contributed to the development of hESC research.
Stem cell-based clinical interventions are increasingly advancing through preclinical testing and approaching clinical trials. The complexity and diversity of these approaches, and the confusion created by unproven and untested stem cell-based “therapies,” create a growing need for a more comprehensive review of these early-stage human trials to ensure they place the patients at minimal risk of adverse events but are also based on solid evidence of preclinical efficacy with a clear scientific rationale for that effect.
In this article, Hochedlinger and colleagues reprogrammed mouse fibroblasts into induced myogenic progenitors (iMPCs) by transient expression of MyoD and treatment with small molecules. iMPCs can be extensively propagated in vitro and exhibit skeletal muscle stem/progenitor cell characteristics, including the requirement for Pax7 function as well as the ability to sustain muscle regeneration upon repeated injury.
In this Perspective, Elaine Fuchs describes her laboratory's contributions to the field of skin stem cells, giving a historical overview of their first isolation and characterization, the discovery of extrinsic and intrinsic factors regulating skin stem cell states, and their role in skin disease.
Bhatia and colleagues reveal that human PSC-derived hematopoietic progenitor cells fail to survive even 24 hr following in vivo bone marrow transplantation, while these same progenitors survive and proliferate for weeks in vitro. They link these observations to deficiencies in CXCR4 signaling, which, when rectified, lead to enhanced progenitor function and survival in the bone marrow and a transcriptional shift toward somatic hematopoietic stem cells gene profiles.
In this report, Lowry and colleagues found that loss of MECP2 has a more profound effect as pluripotent stem cells are terminally differentiated toward neurons. The loss of MECP2 leads to induction of P53 protein and subsequent senescence pathways including an SASP gene program, which appears to be a cause of diminished dendritic branching in Rett neurons.
In this article, Darbar and colleagues identify a mechanism by which RA-guided differentiation of hiPSCs generates an atrial-like electrophysiologic signature through the downstream regulation of calcium channel gene expression by COUP-TFII. The study provides important insights into the underlying molecular mechanisms that regulate atrial-like hiPSC-CM electrophysiology and support the use of atrial-like hiPSC-CMs to model AF.
To reveal the pathophysiology of a proteasome-associated autoinflammatory syndrome, Honda-Ozaki et al. established a panel of immortalized myeloid cell lines from pluripotent stem cells harboring a Nakajo-Nishimura syndrome (NNS)-associated mutation in the PSMB8 gene. The lines recapitulated disease phenotypes and revealed the role of oxidative stress and the p38 MAPK pathway on autoinflammation.