Neural stem and progenitor cells (NSPCs) generate neurons throughout life in the mammalian hippocampus. We used chronic in vivo imaging and followed genetically labeled individual NSPCs and their ...progeny in the mouse hippocampus for up to 2 months. We show that NSPCs targeted by the endogenous Achaete-scute homolog 1 (Ascl1) promoter undergo limited rounds of symmetric and asymmetric divisions, eliciting a burst of neurogenic activity, after which they are lost. Further, our data reveal unexpected asymmetric divisions of nonradial glia-like NSPCs. Cell fates of Ascl1-labeled lineages suggest a developmental-like program involving a sequential transition from a proliferative to a neurogenic phase. By providing a comprehensive description of lineage relationships, from dividing NSPCs to newborn neurons integrating into the hippocampal circuitry, our data offer insight into how NSPCs support life-long hippocampal neurogenesis.
Hippocampal neurogenesis is important for certain forms of cognition, and failing neurogenesis has been implicated in neuropsychiatric diseases. The neurogenic capacity of hippocampal neural ...stem/progenitor cells (NSPCs) depends on a balance between quiescent and proliferative states. Here, we show that the rate of fatty acid oxidation (FAO) regulates the activity of NSPCs. Quiescent NSPCs show high levels of carnitine palmitoyltransferase 1a (Cpt1a)-dependent FAO, which is downregulated in proliferating NSPCs. Pharmacological inhibition and conditional deletion of Cpt1a in vitro and in vivo leads to altered NSPC behavior, showing that Cpt1a-dependent FAO is required for stem cell maintenance and proper neurogenesis. Strikingly, manipulation of malonyl-CoA, the metabolite that regulates levels of FAO, is sufficient to induce exit from quiescence and to enhance NSPC proliferation. Thus, the data presented here identify a shift in FAO metabolism that governs NSPC behavior and suggest an instructive role for fatty acid metabolism in regulating NSPC activity.
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•A metabolic shift defines NSPC quiescence versus proliferation•Quiescent NSPCs require high levels of FAO•Changing levels of a single metabolite is sufficient to induce NSPC proliferation
Controlled balance between proliferation and quiescence of neural stem/progenitor cells (NSPCs) is required for lifelong neurogenesis. Knobloch et al. identify a metabolic shift in fatty acid oxidation (FAO) that governs the proliferation of NSPCs. Further, their data suggest an instructive role for FAO in regulating NSPC activity. Thus, Knobloch et al. identify FAO as a key metabolic pathway to regulate NSPC activity.
Evolution of the mammalian brain encompassed a remarkable increase in size of the cerebral cortex, which includes tangential and radial expansion. However, the mechanisms underlying these key ...features are still largely unknown. Here, we identified the DNA-associated protein Trnp1 as a regulator of cerebral cortex expansion in both of these dimensions. Gain- and loss-of-function experiments in the mouse cerebral cortex in vivo demonstrate that high Trnp1 levels promote neural stem cell self-renewal and tangential expansion. In contrast, lower levels promote radial expansion, with a potent increase of the number of intermediate progenitors and basal radial glial cells leading to folding of the otherwise smooth murine cerebral cortex. Remarkably, TRNP1 expression levels exhibit regional differences in the cerebral cortex of human fetuses, anticipating radial or tangential expansion. Thus, the dynamic regulation of Trnp1 is critical to control tangential and radial expansion of the cerebral cortex in mammals.
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•Trnp1 is a nuclear regulator of radial glial cell fate•Knockdown of Trnp1 results in gyrification (folding) of a naturally smooth brain•Regulation of a single factor orchestrates most characteristics of gyrated brains•Trnp1 associates with DNA and regulates gene expression but has no known motifs
Trnp1 is a DNA-associated protein that regulates cortical expansion—both radial and tangential—and gyrification during development. Its expression pattern in the human brain correlates with regional folding levels, and its conservation among mammals suggests that it may have played a role during the evolution of the mammalian brain.
The mechanisms governing the expansion of neuron number in specific brain regions are still poorly understood. Enlarged neuron numbers in different species are often anticipated by increased numbers ...of progenitors dividing in the subventricular zone. Here we present live imaging analysis of radial glial cells and their progeny in the ventral telencephalon, the region with the largest subventricular zone in the murine brain during neurogenesis. We observe lineage amplification by a new type of progenitor, including bipolar radial glial cells dividing at subapical positions and generating further proliferating progeny. The frequency of this new type of progenitor is increased not only in larger clones of the mouse lateral ganglionic eminence but also in cerebral cortices of gyrated species, and upon inducing gyrification in the murine cerebral cortex. This implies key roles of this new type of radial glia in ontogeny and phylogeny.
Neural stem cells (NSCs) generate neurons throughout life in the mammalian hippocampus. However, the potential for long-term self-renewal of individual NSCs within the adult brain remains unclear. We ...used two-photon microscopy and followed NSCs that were genetically labeled through conditional recombination driven by the regulatory elements of the stem cell-expressed genes GLI family zinc finger 1 (Gli1) or achaete-scute homolog 1 (Ascl1). Through intravital imaging of NSCs and their progeny, we identify a population of Gli1-targeted NSCs showing long-term self-renewal in the adult hippocampus. In contrast, once activated, Ascl1-targeted NSCs undergo limited proliferative activity before they become exhausted. Using single-cell RNA sequencing, we show that Gli1- and Ascl1-targeted cells have highly similar yet distinct transcriptional profiles, supporting the existence of heterogeneous NSC populations with diverse behavioral properties. Thus, we here identify long-term self-renewing NSCs that contribute to the generation of new neurons in the adult hippocampus.
The 2nd SY-Stem Symposium - a symposium for 'the next generation of stem cell researchers' - was held on the 21-23 March 2019 at the Vienna BioCenter in Austria. After the great success of the ...initial SY-Stem meeting in 2018, this year's event again focused on the work of young scientists. Here, we summarize the impressive amount of new research covering stem cell-related fields that was discussed at the meeting.
ABSTRACT
Implementation of lung cancer screening and improvements in imaging are expected to increase the proportion of lung cancer diagnosed at an early stage. The standard of care has historically ...been anatomic lobectomy; however, there is now an array of surgical and non‐surgical approaches for management of local disease either in active use or under investigation. By their nature, these new modalities offer a theoretical trade‐off of reduced morbidity in exchange for reduced efficacy in the setting of advanced disease. It is therefore critical that patients being considered for these approaches (e.g. surgical segmentectomy and SABR) be accurately staged to maximize the potential for definitive treatment. In this article, we will review current approaches to the staging of patients being considered for segmentectomy or ablation. This will serve as a foundation to highlight important questions deserving further investigation.
Little is known about the metabolism of quiescent endothelial cells (QECs). Nonetheless, when dysfunctional, QECs contribute to multiple diseases. Previously, we demonstrated that proliferating ...endothelial cells (PECs) use fatty acid β-oxidation (FAO) for de novo dNTP synthesis. We report now that QECs are not hypometabolic, but upregulate FAO >3-fold higher than PECs, not to support biomass or energy production but to sustain the tricarboxylic acid cycle for redox homeostasis through NADPH regeneration. Hence, endothelial loss of FAO-controlling CPT1A in CPT1AΔEC mice promotes EC dysfunction (leukocyte infiltration, barrier disruption) by increasing endothelial oxidative stress, rendering CPT1AΔEC mice more susceptible to LPS and inflammatory bowel disease. Mechanistically, Notch1 orchestrates the use of FAO for redox balance in QECs. Supplementation of acetate (metabolized to acetyl-coenzyme A) restores endothelial quiescence and counters oxidative stress-mediated EC dysfunction in CPT1AΔEC mice, offering therapeutic opportunities. Thus, QECs use FAO for vasculoprotection against oxidative stress-prone exposure.
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•QECs reprogram their metabolism to enhance redox homeostasis•QECs rely on fatty acid β-oxidation (FAO) to increase NADPH regeneration•Inhibition of FAO in QECs results in QEC dysfunction, which is rescued by acetate•Notch signaling upregulates transcription of CPT1A, a rate-controlling step in FAO
Kalucka et al. show that fatty acid β-oxidation in quiescent endothelial cells (QECs) is indispensable to maintain redox balance and prevent EC dysfunction. In contrast to proliferating ECs (PECs), QECs reprogram their metabolism to increase regeneration of NAPDH, which is then used by vasculoprotective (NADPH-consuming) enzymes for redox homeostasis.
Diagnosis and resection of indeterminate pulmonary nodules (IPNs) is a growing challenge with increased utilization of chest computed tomography. Photoacoustic (PA) -guided surgical resection with ...local injection of indocyanine green (ICG) may have utility for IPNs that are suspicious for lung cancer. This preclinical study explores the potential of PA imaging (PAI) to detect ICG-labeled tumors.
ICG uptake by H460 lung cancer cells was evaluated in vitro. A phantom study was performed to analyze PA signal intensity according to ICG concentration and tissue thickness/depth using chicken breast. PA signals were measured up to 48 hours after injection of ICG (mixed with 5% agar) into healthy subcutaneous tissue, subcutaneous H460 tumors and right healthy lung in nude mice.
Intracellular ICG fluorescence was detected in H460 cells co-incubated with ICG in vitro. The concentration dependence of the PA signal was logarithmic, and PA signal decline was exponential with increasing tissue depth. The PA signal of 2 mg/mL ICG was still detectable at a depth of 22 mm in chicken breast. The PA signal from ICG mixed with agar was detectable 48 hours post injection into subcutaneous tissue and subcutaneous H460 tumors in nude mice. Similar features of PA signals from ICG-agar in mice lung were obtained.
The results from this preclinical study suggests that PAI of injected ICG-agar may be beneficial for identifying deeply located tumors. These features may be valuable for IPNs.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The developmental mechanisms regulating the number of adult neural stem cells (aNSCs) are largely unknown. Here we show that the cleavage plane orientation in murine embryonic radial glia cells ...(RGCs) regulates the number of aNSCs in the lateral ganglionic eminence (LGE). Randomizing spindle orientation in RGCs by overexpression of Insc or a dominant-negative form of Lgn (dnLgn) reduces the frequency of self-renewing asymmetric divisions while favoring symmetric divisions generating two SNPs. Importantly, these changes during embryonic development result in reduced seeding of aNSCs. Interestingly, no effects on aNSC numbers were observed when Insc was overexpressed in postnatal RGCs or aNSCs. These data suggest a new mechanism for controlling aNSC numbers and show that the role of spindle orientation during brain development is highly time and region dependent.
•Randomization of the spindle orientation changes the progenitor pool composition•Overexpression of Insc or dnLgn reduces asymmetric self-renewing division of aRGCs•The change in embryonic progenitor pool leads to reduced seeding of adult NSCs•Insc influences the seeding of adult NSCs in a narrow developmental time window
Falk et al. uncover a new concept where the control of the division type in progenitor cells during embryonic development regulates the number of embryonic progenitor cells destined to become adult neural stem cells.
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