Frontiers in Cell and Developmental Biology

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Genomic manipulation of human pluripotent stem cells (hPSCs) has become essential to introduce genetic modifications and transgenes, and develop reporter lines. One of the major bottlenecks in gene editing is at the stage of single-cell cloning, which is thought to be variable across hPSC lines and is substantially reduced following a transfection. Due to the difficulty of performing fluorescent-assisted cell sorting (FACS) for single-cell isolation of hPSCs, previous approaches rely on manual colony picking, which is both time-consuming and labor-intensive...

Neuron-Glia related cell adhesion molecule (NrCAM) is a candidate autism risk factor that promotes axon guidance through cytoskeletal linkages in developing brain but its role in limbic circuitry has not been investigated. In situ hybridization (ISH) and immunofluorescence staining showed that NrCAM is expressed in the developing amygdalar pathway of mouse embryos during outgrowth of projections in the stria terminalis, a major limbic tract that interconnects the central amygdala (CeA) with key targets in the bed nucleus of the stria terminalis (BNST)...

We recently identified lamin A/C as a docking molecule for human histone deacetylase 2 (HDAC2) and showed involvement of HDAC2-lamin A/C complexes in the DNA damage response. We further showed that lamin A/C-HDAC2 interaction is altered in Hutchinson-Gilford Progeria syndrome and other progeroid laminopathies. Here, we show that both inhibitors of lamin A maturation and small molecules inhibiting HDAC activity affect lamin A/C interaction with HDAC2. While statins, which inhibit prelamin A processing, reduce protein interaction, HDAC inhibitors strengthen protein binding...

The mitochondrial carrier family (MCF) is a group of transport proteins that are mostly localized to the inner mitochondrial membrane where they facilitate the movement of various solutes across the membrane. Although these carriers represent potential targets for therapeutic application and are repeatedly associated with human disease, research on the MCF has not progressed commensurate to their physiologic and pathophysiologic importance. Many of the 53 MCF members in humans are orphans and lack known transport substrates...

While oxygen is critical to the continued existence of complex organisms, extreme levels of oxygen within a system, known as hypoxia (low levels of oxygen) and hyperoxia (excessive levels of oxygen), potentially promote stress within a defined biological environment. The consequences of tissue hypoxia, a result of a defective oxygen supply, vary in response to the gravity, extent and environment of the malfunction. Persistent pathological hypoxia is incompatible with normal biological functions, and as a result, multicellular organisms have been compelled to develop both organism-wide and cellular-level hypoxia solutions...

Human innate immune cells exposed to certain infections or stimuli develop enhanced immune responses upon re-infection with a different second stimulus, a process termed trained immunity. Recent studies have revealed that hematopoietic stem cells (HSCs) are integral to trained immune responses as they are able to "remember" transcriptional responses and transmit this state to their progeny to educate them how to respond to future infections. The macrophages that arise from trained HSCs are epigenetically reprogrammed and as a result robustly express immune genes, enhancing their capability to resolve infection...

Stromal cells in spleen organize tissue into red pulp, white pulp and marginal zone, and also interact with hematopoietic cells to regulate immune responses. This study has used phenotypic information of a previously described spleen stromal cell line called 5G3, which supports restricted hematopoiesis in vitro , to identify an equivalent stromal cell subset in vivo and to test its capacity to support hematopoiesis. Using stromal cell fractionation, phenotypic analysis, as well as cell growth and hematopoietic support assays, the Sca-1+ gp38+ Thy1...

CDK8 and its paralog, CDK19, collectively termed 'Mediator Kinase,' are cyclin-dependent kinases that have been implicated as key rheostats in cellular homeostasis and developmental programming. CDK8 and CDK19 are incorporated, in a mutually exclusive manner, as part of a 4-protein complex called the Mediator kinase module. This module reversibly associates with the Mediator, a 26 subunit protein complex that regulates RNA Polymerase II mediated gene expression. As part of this complex, the Mediator kinases have been implicated in diverse process such as developmental signaling, metabolic homeostasis and in innate immunity...

Cancer is a disease of the elderly, and old age is its largest risk factor. With age, DNA damage accumulates continuously, increasing the chance of malignant transformation. The zebrafish has emerged as an important vertebrate model to study these processes. Key mechanisms such as DNA damage responses and cellular senescence can be studied in zebrafish throughout its life course. In addition, the zebrafish is becoming an important resource to study telomere biology in aging, regeneration and cancer. Here we review some of the tools and resources that zebrafish researchers have developed and discuss their potential use in the study of DNA damage, cancer and aging related diseases...

Targeting the mitotic pathways of rapidly proliferating tumor cells has been an effective strategy in traditional cancer therapy. Chemotherapeutics such as taxanes and vinca alkaloids, which disrupt microtubule function, have enjoyed clinical success; however, the accompanying side effects, toxicity and multi drug resistance remain as serious concerns. The emerging classes of inhibitors targeting mitotic kinases and proteasome face their own set of challenges. It is hoped that elucidation of the regulatory interface between mitotic checkpoints, mitochondria and mitotic death will aid the development of more efficacious anti-mitotic agents and improved treatment protocols...

This year marks the 100th anniversary of one of the deadliest pandemic outbreaks, commonly referred as the Spanish Flu, that was caused by influenza A virus (IAV). Since then, IAV has been in governmental agendas worldwide, and a lot of effort has been put into understanding the pathogen's lifecycle, predict and mitigate the emergence of the strains that provoke yearly epidemics and pandemic events. Despite decades of research and seminal contributions there is still a lot to be investigated. In particular for this review, IAV lifecycle that takes place inside the host cell is not fully understood...

Every year stroke claims more than 6 million lives worldwide. The majority of them are ischemic stroke. Small molecule-based therapeutics for ischemic stroke has attracted a lot of attention, but none has been shown to be clinically useful so far. Hypoxia-inducible factor-1 (HIF-1) plays a crucial role in the transcriptional adaptation of cells to hypoxia. Small molecule-based hypoxia-mimetic agents either stabilize HIF-1α via HIF-prolyl hydroxylases (PHDs) inhibition or through other mechanisms. In both the cases, these agents have been shown to confer ischemic neuroprotection in vitro and in vivo ...

Wnt signaling plays a central regulatory role across a remarkably diverse range of functions during embryonic development, including those involved in the formation of bone and cartilage. Wnt signaling continues to play a critical role in adult osteogenic differentiation of mesenchymal stem cells. Disruptions in this highly-conserved and complex system leads to various pathological conditions, including impaired bone healing, autoimmune diseases and malignant degeneration. For reconstructive surgeons, critically sized skeletal defects represent a major challenge...

Hematopoiesis is a precisely orchestrated process regulated by the activity of hematopoietic cytokines and their respective receptors. Due to an extra round of whole genome duplication during vertebrate evolution in teleost fish, zebrafish have two paralogs of many important genes, including genes involved in hematopoiesis. Importantly, these duplication events brought increased level of complexity in such cases, where both ligands and receptors have been duplicated in parallel. Therefore, precise understanding of binding specificities between duplicated ligand-receptor signalosomes as well as understanding of their differential expression provide an important basis for future studies to better understand the role of duplication of these genes...

Thy-1 is possibly the smallest of cell surface proteins - 110 amino acids folded into an Immunoglobulin variable domain, tethered to the outer leaflet of the cell surface membrane via just the two saturated fatty acids of its glycosylphosphatidylinositol (GPI) anchor. Yet Thy-1 is emerging as a key regulator of differentiation in cells of endodermal, mesodermal, and ectodermal origin, acting as both a ligand (for certain integrins and other receptors), and as a receptor, able to modulate signaling and hence differentiation in the Thy-1-expressing cell...

Laminopathies are a group of rare degenerative disorders that manifest with a wide spectrum of clinical phenotypes, including both systemic multi-organ disorders, such as the Hutchinson-Gilford Progeria Syndrome (HGPS), and tissue-restricted diseases, such as Emery-Dreifuss muscular dystrophy, dilated cardiomyopathy and lipodystrophies, often overlapping. Despite their clinical heterogeneity, which remains an open question, laminopathies are commonly caused by mutations in the LMNA gene, encoding the nuclear proteins Lamin A and C...

Hypoxia is the most critical factor for maintaining stemness. During embryonic development, neural stem cells (NSCs) reside in hypoxic niches, and different levels of oxygen pressure and time of hypoxia exposure play important roles in the development of NSCs. Such hypoxic niches exist in adult brain tissue, where the neural precursors originate. Hypoxia-inducible factors (HIFs) are key transcription heterodimers consisting of regulatory α-subunits (HIF-1α, HIF-2α, HIF-3α) and a constitutive β-subunit (HIF-β)...

Immune cells are one of the most versatile cell types, as they can tailor their metabolic activity according to their required function. In response to diverse environmental cues, immune cells undergo metabolic reprogramming to support their differentiation, proliferation and pro-inflammatory effector functions. To meet a dramatic surge in energetic demand, immune cells rewire their metabolism to utilize aerobic glycolysis. This preferential use of glycolysis even under aerobic conditions is well established in tumor cells, and is known as the "Warburg effect...

Microtubule-associated protein tau (MAPT) hyperphosphorylation and aggregation, are two hallmarks of a family of neurodegenerative disorders collectively referred to as tauopathies. In many tauopathies, including Alzheimer's disease (AD), progressive supranuclear palsy (PSP) and Pick's disease, tau aggregates are found associated with highly sulfated polysaccharides known as heparan sulfates (HSs). In AD, amyloid beta (Aβ) peptide aggregates associated with HS are also characteristic of disease. Heparin, an HS analog, promotes misfolding, hyperphosphorylation and aggregation of tau protein in vitro ...