RESUMO
Acute myeloid leukemia (AML) and myeloid neoplasms develop through acquisition of somatic mutations that confer mutation-specific fitness advantages to hematopoietic stem and progenitor cells. However, our understanding of mutational effects remains limited to the resolution attainable within immunophenotypically and clinically accessible bulk cell populations. To decipher heterogeneous cellular fitness to preleukemic mutational perturbations, we performed single-cell RNA sequencing of eight different mouse models with driver mutations of myeloid malignancies, generating 269,048 single-cell profiles. Our analysis infers mutation-driven perturbations in cell abundance, cellular lineage fate, cellular metabolism, and gene expression at the continuous resolution, pinpointing cell populations with transcriptional alterations associated with differentiation bias. We further develop an 11-gene scoring system (Stem11) on the basis of preleukemic transcriptional signatures that predicts AML patient outcomes. Our results demonstrate that a single-cell-resolution deep characterization of preleukemic biology has the potential to enhance our understanding of AML heterogeneity and inform more effective risk stratification strategies.
RESUMO
Neurons coordinate their activity to produce an astonishing variety of motor behaviors. Our present understanding of motor control has grown rapidly thanks to new methods for recording and analyzing populations of many individual neurons over time. In contrast, current methods for recording the nervous system's actual motor output - the activation of muscle fibers by motor neurons - typically cannot detect the individual electrical events produced by muscle fibers during natural behaviors and scale poorly across species and muscle groups. Here we present a novel class of electrode devices ('Myomatrix arrays') that record muscle activity at unprecedented resolution across muscles and behaviors. High-density, flexible electrode arrays allow for stable recordings from the muscle fibers activated by a single motor neuron, called a 'motor unit,' during natural behaviors in many species, including mice, rats, primates, songbirds, frogs, and insects. This technology therefore allows the nervous system's motor output to be monitored in unprecedented detail during complex behaviors across species and muscle morphologies. We anticipate that this technology will allow rapid advances in understanding the neural control of behavior and identifying pathologies of the motor system.
Assuntos
Neurônios Motores , Primatas , Ratos , Camundongos , Animais , Neurônios Motores/fisiologia , Eletrodos , Fibras Musculares EsqueléticasRESUMO
Neurons coordinate their activity to produce an astonishing variety of motor behaviors. Our present understanding of motor control has grown rapidly thanks to new methods for recording and analyzing populations of many individual neurons over time. In contrast, current methods for recording the nervous system's actual motor output - the activation of muscle fibers by motor neurons - typically cannot detect the individual electrical events produced by muscle fibers during natural behaviors and scale poorly across species and muscle groups. Here we present a novel class of electrode devices ("Myomatrix arrays") that record muscle activity at unprecedented resolution across muscles and behaviors. High-density, flexible electrode arrays allow for stable recordings from the muscle fibers activated by a single motor neuron, called a "motor unit", during natural behaviors in many species, including mice, rats, primates, songbirds, frogs, and insects. This technology therefore allows the nervous system's motor output to be monitored in unprecedented detail during complex behaviors across species and muscle morphologies. We anticipate that this technology will allow rapid advances in understanding the neural control of behavior and in identifying pathologies of the motor system.
RESUMO
Adult hematopoietic stem cells (HSCs) are predominantly quiescent and can be activated in response to acute stress such as infection or cytotoxic insults. STAT1 is a pivotal downstream mediator of interferon (IFN) signaling and is required for IFN-induced HSC proliferation, but little is known about the role of STAT1 in regulating homeostatic hematopoietic stem/progenitor cells (HSPCs). Here, we show that loss of STAT1 altered the steady state HSPC landscape, impaired HSC function in transplantation assays, delayed blood cell regeneration following myeloablation, and disrupted molecular programs that protect HSCs, including control of quiescence. Our results also reveal STAT1-dependent functional HSC heterogeneity. A previously unrecognized subset of homeostatic HSCs with elevated major histocompatibility complex class II (MHCII) expression (MHCIIhi) displayed molecular features of reduced cycling and apoptosis and was refractory to 5-fluorouracil-induced myeloablation. Conversely, MHCIIlo HSCs displayed increased megakaryocytic potential and were preferentially expanded in CALR mutant mice with thrombocytosis. Similar to mice, high MHCII expression is a feature of human HSCs residing in a deeper quiescent state. Our results therefore position STAT1 at the interface of stem cell heterogeneity and the interplay between stem cells and the adaptive immune system, areas of broad interest in the wider stem cell field.
Assuntos
Células-Tronco Hematopoéticas , Megacariócitos , Fator de Transcrição STAT1 , Animais , Proliferação de Células , Fluoruracila/farmacologia , Células-Tronco Hematopoéticas/metabolismo , Humanos , Interferons , Megacariócitos/metabolismo , Camundongos , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT1/metabolismoRESUMO
A five-year-old male central bearded dragon (Pogona vitticeps) was presented for investigation of blood in the voided urates. A small cutaneous mass was detected in the gular region, but clinical examination was otherwise unremarkable. Fecal parasitology was negative. Initially, further diagnostics were declined, and antimicrobial treatment was initiated. At re-examination one month later, the gular mass had increased in size and an additional mass was detected within the celomic cavity. Both masses were surgically excised and diagnosed by histopathology as a high-grade anaplastic sarcoma (gular mass), resembling a histiocytic sarcoma, and a Sertoli cell tumor (coelomic mass). Neither of these have been previously reported in the central bearded dragon. Twenty months post-surgery, the lizard remains well with no recurrence of clinical signs or evidence of tumor re-growth.
RESUMO
We examined activin receptor type IIA (ActRIIA) activation in chronic kidney disease (CKD) by signal analysis and inhibition in mice with Alport syndrome using the ActRIIA ligand trap RAP-011 initiated in 75-day-old Alport mice. At 200 days of age, there was severe CKD and associated Mineral and Bone Disorder (CKD-MBD), consisting of osteodystrophy, vascular calcification, cardiac hypertrophy, hyperphosphatemia, hyperparathyroidism, elevated FGF23, and reduced klotho. The CKD-induced bone resorption and osteoblast dysfunction was reversed, and bone formation was increased by RAP-011. ActRIIA inhibition prevented the formation of calcium apatite deposits in the aortic adventitia and tunica media and significantly decreased the mean aortic calcium concentration from 0.59 in untreated to 0.36 mg/g in treated Alport mice. Aortic ActRIIA stimulation in untreated mice increased p-Smad2 levels and the transcription of sm22α and αSMA. ActRIIA inhibition reversed aortic expression of the osteoblast transition markers Runx2 and osterix. Heart weight was significantly increased by 26% in untreated mice but remained normal during RAP-011 treatment. In 150-day-old mice, GFR was significantly reduced by 55%, but only by 30% in the RAP-011-treated group. In 200-day-old mice, the mean BUN was 100 mg/dl in untreated mice compared to 60 mg/dl in the treated group. In the kidneys of 200-day-old mice, ActRIIA and p-Smad2 were induced and MCP-1, fibronectin, and interstitial fibrosis were stimulated; all were attenuated by RAP-011 treatment. Hence, the activation of ActRIIA signaling during early CKD contributes to the CKD-MBD components of osteodystrophy and cardiovascular disease and to renal fibrosis. Thus, the inhibition of ActRIIA signaling is efficacious in improving and delaying CKD-MBD in this model of Alport syndrome.
Assuntos
Receptores de Activinas Tipo II/metabolismo , Reabsorção Óssea/metabolismo , Cardiomegalia/metabolismo , Distúrbio Mineral e Ósseo na Doença Renal Crônica/metabolismo , Nefrite Hereditária/metabolismo , Insuficiência Renal Crônica/metabolismo , Calcificação Vascular/metabolismo , Actinas/metabolismo , Receptores de Activinas Tipo II/antagonistas & inibidores , Receptores de Activinas Tipo II/genética , Animais , Vasos Sanguíneos/metabolismo , Vasos Sanguíneos/patologia , Vasos Sanguíneos/fisiopatologia , Remodelação Óssea , Reabsorção Óssea/genética , Reabsorção Óssea/fisiopatologia , Reabsorção Óssea/prevenção & controle , Osso e Ossos/metabolismo , Osso e Ossos/patologia , Osso e Ossos/fisiopatologia , Cardiomegalia/genética , Cardiomegalia/fisiopatologia , Cardiomegalia/prevenção & controle , Distúrbio Mineral e Ósseo na Doença Renal Crônica/genética , Distúrbio Mineral e Ósseo na Doença Renal Crônica/fisiopatologia , Distúrbio Mineral e Ósseo na Doença Renal Crônica/prevenção & controle , Colágeno Tipo IV/deficiência , Colágeno Tipo IV/genética , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Modelos Animais de Doenças , Fator de Crescimento de Fibroblastos 23 , Fibrose , Taxa de Filtração Glomerular , Rim/metabolismo , Rim/patologia , Rim/fisiopatologia , Camundongos Knockout , Proteínas dos Microfilamentos/metabolismo , Proteínas Musculares/metabolismo , Miocárdio/metabolismo , Miocárdio/patologia , Nefrite Hereditária/tratamento farmacológico , Nefrite Hereditária/genética , Nefrite Hereditária/fisiopatologia , Fosforilação , Proteínas Recombinantes de Fusão/farmacologia , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/fisiopatologia , Insuficiência Renal Crônica/prevenção & controle , Transdução de Sinais , Proteína Smad2/metabolismo , Fator de Transcrição Sp7/metabolismo , Calcificação Vascular/genética , Calcificação Vascular/fisiopatologia , Calcificação Vascular/prevenção & controle , Remodelação VascularRESUMO
Maintenance of the specialised environment of the central nervous system requires barriers provided by the endothelium of brain microvessels (the blood-brain barrier (BBB)) or the epithelium lining the ventricles (CSF-brain barrier) or the choroid plexus (blood-CSF barrier). Inter-endothelial junctions are more extensive in the BBB than in other tissues, with elaborate tight junctions. However, few differences in the molecular composition of these junctions have been described. Here, we show, in both human and mouse brain, that the type II classical cadherin, cadherin-10, is expressed in BBB and retinal endothelia, but not in the leaky microvessels of brain circumventricular organs (CVO), or in those of non-CNS tissues. This expression pattern is distinct from, and reciprocal to, VE-cadherin, which is reduced or absent in tight cortical microvessels, but present in leaky CVO vessels. In CVO, the barrier function is switched from the microvasculature to the adjacent ventricular epithelium, which we also find to express cadherin-10. In the vessels of gliobastoma multiforme tumours, where BBB is lost, cadherin-10 is not detected. This demonstration of a distinctive expression pattern of cadherin-10 suggests that it has a pivotal role in the development and maintenance of brain barriers.