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Cell reports
2022 Apr 12
Mauduit, O;Aure, MH;Delcroix, V;Basova, L;Srivastava, A;Umazume, T;Mays, JW;Bellusci, S;Tucker, AS;Hajihosseini, MK;Hoffman, MP;Makarenkova, HP;
PMID: 35417692 | DOI: 10.1016/j.celrep.2022.110663
Fibroblast growth factor 10 (FGF10) is well established as a mesenchyme-derived growth factor and a critical regulator of fetal organ development in mice and humans. Using a single-cell RNA sequencing (RNA-seq) atlas of salivary gland (SG) and a tamoxifen inducible Fgf10CreERT2:R26-tdTomato mouse, we show that FGF10pos cells are exclusively mesenchymal until postnatal day 5 (P5) but, after P7, there is a switch in expression and only epithelial FGF10pos cells are observed after P15. Further RNA-seq analysis of sorted mesenchymal and epithelial FGF10pos cells shows that the epithelial FGF10pos population express the hallmarks of ancient ionocyte signature Forkhead box i1 and 2 (Foxi1, Foxi2), Achaete-scute homolog 3 (Ascl3), and the cystic fibrosis transmembrane conductance regulator (Cftr). We propose that epithelial FGF10pos cells are specialized SG ionocytes located in ducts and important for the ionic modification of saliva. In addition, they maintain FGF10-dependent gland homeostasis via communication with FGFR2bpos ductal and myoepithelial cells.
Cell reports
2022 Apr 05
Gao, F;Li, C;Danopoulos, S;Al Alam, D;Peinado, N;Webster, S;Borok, Z;Kohbodi, GA;Bellusci, S;Minoo, P;
PMID: 35385750 | DOI: 10.1016/j.celrep.2022.110608
The lung alveolus is lined with alveolar type 1 (AT1) and type 2 (AT2) epithelial cells. During alveologenesis, increasing demand associated with expanding alveolar numbers is met by proliferating progenitor AT2s (pAT2). Little information exists regarding the identity of this population and their niche microenvironment. We show that during alveologenesis, Hedgehog-responsive PDGFRa(+) progenitors (also known as SCMFs) are a source of secreted trophic molecules that maintain a unique pAT2 population. SCMFs are in turn maintained by TGFβ signaling. Compound inactivation of Alk5 TβR2 in SCMFs reduced their numbers and depleted the pAT2 pool without impacting differentiation of daughter cells. In lungs of preterm infants who died with bronchopulmonary dysplasia, PDGFRa is reduced and the number of proliferative AT2s is diminished, indicating that an evolutionarily conserved mechanism governs pAT2 behavior during alveologenesis. SCMFs are a transient cell population, active only during alveologenesis, making them a unique stage-specific niche mesodermal cell type in mammalian organs.
Cell reports
2022 Apr 05
Phillips, RA;Tuscher, JJ;Black, SL;Andraka, E;Fitzgerald, ND;Ianov, L;Day, JJ;
PMID: 35385745 | DOI: 10.1016/j.celrep.2022.110616
The ventral tegmental area (VTA) is a complex brain region that is essential for reward function and frequently implicated in neuropsychiatric disease. While decades of research on VTA function have focused on dopamine neurons, recent evidence has identified critical roles for GABAergic and glutamatergic neurons in reward processes. Additionally, although subsets of VTA neurons express genes involved in the synthesis and transport of multiple neurotransmitters, characterization of these combinatorial populations has largely relied on low-throughput methods. To comprehensively define the molecular architecture of the VTA, we performed single-nucleus RNA sequencing on 21,600 cells from the rat VTA. Analysis of neuronal subclusters identifies selective markers for dopamine and combinatorial neurons, reveals expression profiles for receptors targeted by drugs of abuse, and demonstrates population-specific enrichment of gene sets linked to brain disorders. These results highlight the heterogeneity of the VTA and provide a resource for further exploration of VTA gene expression.
Aging cell
2022 Apr 01
Chandra, A;Lagnado, AB;Farr, JN;Doolittle, M;Tchkonia, T;Kirkland, JL;LeBrasseur, NK;Robbins, PD;Niedernhofer, LJ;Ikeno, Y;Passos, JF;Monroe, DG;Pignolo, RJ;Khosla, S;
PMID: 35363946 | DOI: 10.1111/acel.13602
Cellular senescence, which is a major cause of tissue dysfunction with aging and multiple other conditions, is known to be triggered by p16Ink4a or p21Cip1 , but the relative contributions of each pathway toward inducing senescence are unclear. Here, we directly addressed this issue by first developing and validating a p21-ATTAC mouse with the p21Cip1 promoter driving a "suicide" transgene encoding an inducible caspase-8 which, upon induction, selectively kills p21Cip1 -expressing senescent cells. Next, we used the p21-ATTAC mouse and the established p16-INK-ATTAC mouse to directly compare the contributions of p21Cip1 versus p16Ink4a in driving cellular senescence in a condition where a tissue phenotype (bone loss and increased marrow adiposity) is clearly driven by cellular senescence-specifically, radiation-induced osteoporosis. Using RNA in situ hybridization, we confirmed the reduction in radiation-induced p21Cip1 - or p16Ink4a -driven transcripts following senescent cell clearance in both models. However, only clearance of p21Cip1 +, but not p16Ink4a +, senescent cells prevented both radiation-induced osteoporosis and increased marrow adiposity. Reduction in senescent cells with dysfunctional telomeres following clearance of p21Cip1 +, but not p16Ink4a +, senescent cells also reduced several of the radiation-induced pro-inflammatory senescence-associated secretory phenotype factors. Thus, by directly comparing senescent cell clearance using two parallel genetic models, we demonstrate that radiation-induced osteoporosis is driven predominantly by p21Cip1 - rather than p16Ink4a -mediated cellular senescence. Further, this approach can be used to dissect the contributions of these pathways in other senescence-associated conditions, including aging across tissues.
Cellular and molecular life sciences : CMLS
2022 Apr 19
Wu, F;Hill, K;Fang, Q;He, Z;Zheng, H;Wang, X;Xiong, H;Sha, SH;
PMID: 35438341 | DOI: 10.1007/s00018-022-04268-4
The Ca2+/calmodulin-dependent protein kinase kinases (CaMKKs) are serine/threonine-directed protein kinases that are activated following increases in intracellular calcium, playing a critical role in neuronal signaling. Inner-ear-trauma-induced calcium overload in sensory hair cells has been well documented in the pathogenesis of traumatic noise-induced hair cell death and hearing loss, but there are no established pharmaceutical therapies available due to a lack of specific therapeutic targets. In this study, we investigated the activation of CaMKKβ in the inner ear after traumatic noise exposure and assessed the prevention of noise-induced hearing loss (NIHL) with RNA silencing.Treatment with short hairpin RNA of CaMKKβ (shCaMKKβ) via adeno-associated virus transduction significantly knocked down CaMKKβ expression in the inner ear. Knockdown of CaMKKβ significantly attenuated noise-induced hair cell loss and hearing loss (NIHL). Additionally, pretreatment with naked CaMKKβ small interfering RNA (siCaMKKβ) attenuated noise-induced losses of inner hair cell synapses and OHCs and NIHL. Furthermore, traumatic noise exposure activates CaMKKβ in OHCs as demonstrated by immunolabeling for p-CaMKI. CaMKKβ mRNA assessed by fluorescence in-situ hybridization and immunolabeling for CaMKKβ in OHCs also increased after the exposure. Finally, pretreatment with siCaMKKβ diminished noise-induced activation of AMPKα in OHCs.These findings demonstrate that traumatic-noise-induced OHC loss and hearing loss occur primarily via activation of CaMKKβ. Targeting CaMKKβ is a key strategy for prevention of noise-induced hearing loss. Furthermore, our data suggest that noise-induced activation of AMPKα in OHCs occurs via the CaMKKβ pathway.
Cellular and molecular gastroenterology and hepatology
2022 Apr 27
Gomez-Martinez, I;Bliton, RJ;Breau, KA;Czerwinski, MJ;Williamson, IA;Wen, J;Rawls, JF;Magness, ST;
PMID: 35489715 | DOI: 10.1016/j.jcmgh.2022.04.009
Fatty acid oxidation by absorptive enterocytes has been linked to the pathophysiology of type 2 diabetes, obesity, and dyslipidemia. Caco-2 and organoids have been used to study dietary lipid-handling processes including fatty acid oxidation but are limited in physiological relevance or preclude simultaneous apical and basal access. Here, we develop a high-throughput planar human absorptive enterocyte monolayer system for investigating lipid-handling, then evaluate the role of fatty acid oxidation in fatty acid export, using etomoxir, C75, and anti-diabetic drug, metformin.Single-cell RNA-sequencing (scRNAseq), transcriptomics, and lineage trajectory was performed on primary human jejunum. In vivo absorptive enterocyte maturational states informed conditions used to differentiate human intestinal stem cells (ISCs) that mimic in vivo absorptive enterocyte maturation. The system was scaled for high-throughput drug screening. Fatty acid oxidation (fatty acid oxidation) was pharmacologically modulated and BODIPYTM (B)-labelled fatty acids were used to evaluate fatty acid-handling via fluorescence and thin layer chromatography (TLC).ScRNAseq shows increasing expression of lipid-handling genes as absorptive enterocytes mature. Culture conditions promote ISC differentiation into confluent absorptive enterocyte monolayers. Fatty acid-handling gene expression mimics in vivo maturational states. Fatty acid oxidation inhibitor, etomoxir, decreased apical-to-basolateral export of medium-chain B-C12 and long-chain B-C16 fatty acids whereas CPT1 agonist, C75, and antidiabetic drug, metformin, increased apical-to-basolateral export. Short-chain B-C5 was unaffected by fatty acid oxidation inhibition and diffused through absorptive enterocytes.Primary human ISCs in culture undergo programmed maturation. Absorptive enterocyte monolayers demonstrate in vivo maturational states and lipid-handling gene expression profiles. Absorptive enterocytes create strong epithelial barriers in 96-Transwell format. Fatty acid export is proportional to fatty acid oxidation. Metformin enhances fatty acid oxidation and increases basolateral fatty acid export, supporting an intestine-specific role.
Molecular Therapy - Nucleic Acids
2022 Apr 01
Khoja, S;Liu, X;Truong, B;Nitzahn, M;Lambert, J;Eliav, A;Nasser, E;Randolph, E;Burke, K;White, R;Zhu, X;Martini, P;Nissim, I;Cederbaum, S;Lipshutz, G;
| DOI: 10.1016/j.omtn.2022.04.012
Arginase deficiency is associated with prominent neuromotor features including spastic diplegia, clonus, and hyperreflexia; intellectual disability and progressive neurological decline are other signs. In a constitutive murine model, we recently described leukodystrophy as a significant component of the central nervous system features of arginase deficiency. In the present studies, we sought to examine if the administration of a lipid nanoparticle carrying human ARG1 mRNA to constitutive knockout mice could prevent abnormalities in myelination associated with arginase deficiency. Imaging of the cingulum, striatum, and cervical segments of the corticospinal tract, revealed a drastic reduction of myelinated axons; signs of degenerating axons were also present with thin myelin layers. Lipid nanoparticle/ARG1 mRNA administration resulted in both light and electron microscopic evidence of a dramatic recovery of myelin density compared with age-matched controls; oligodendrocytes were seen to be extending processes to wrap many axons. Abnormally thin myelin layers, when myelination was present, was resolved with intermittent mRNA administration, indicative of not only a greater density of myelinated axons but also an increase in the thickness of the myelin sheath. In conclusion, lipid nanoparticle/ARG1 mRNA administration in arginase deficiency prevents the associated leukodystrophy and restores normal oligodendrocyte function.
Molecular Therapy - Nucleic Acids
2022 Jun 01
Bartesaghi, S;Wallenius, K;Hovdal, D;Liljeblad, M;Wallin, S;Dekker, N;Barlind, L;Davies, N;Seeliger, F;Winzell, M;Patel, S;Theisen, M;Brito, L;Bergenhem, N;Andersson, S;Peng, X;
| DOI: 10.1016/j.omtn.2022.04.010
Fibroblast growth factor 21 (FGF21) is a promising therapeutic agent for treatment of type 2 diabetes (T2D) and non-alcoholic steatohepatitis (NASH). We show that therapeutic levels of FGF21 were achieved following subcutaneous (s.c.) administration of mRNA encoding human FGF21 proteins. The efficacy of mRNA was assessed following 2-weeks repeated s.c. dosing in diet-induced obese (DIO), mice which resulted in marked decreases in body weight, plasma insulin levels, and hepatic steatosis. Pharmacokinetic/pharmacodynamic (PK/PD) modelling of several studies in both lean and DIO mice showed that mRNA encoding human proteins provided improved therapeutic coverage over recombinant dosed proteins in vivo. This study is the first example of s.c. mRNA therapy showing pre-clinical efficacy in a disease-relevant model, thus, showing the potential for this modality in the treatment of chronic diseases, including T2D and NASH.
Cell death & disease
2022 Apr 13
Cen, Y;Fang, Y;Ren, Y;Hong, S;Lu, W;Xu, J;
PMID: 35418185 | DOI: 10.1038/s41419-022-04807-8
High grade serous ovarian cancer (HGSOC) is the most aggressive subtype of ovarian cancer and HGSOC patients often appear with metastasis, leading to the poor prognosis. Up to date, the extrachromosomal circular DNAs (eccDNAs) have been shown to be involved in cancer genome remodeling but the roles of eccDNAs in metastatic HGSOC are still not clear. Here we explored eccDNA profiles in HGSOC by Circle-Sequencing analysis using four pairs of primary and metastatic tissues of HGSOC patients. Within the differentially expressed eccDNAs screened out by our analysis, eight candidates were validated by outward PCR and qRT-PCR analysis. Among them, DNMT1circle10302690-10302961 was further confirmed by FISH assay and BaseScope assay, as the most significantly down-regulated eccDNA in metastatic tumors of HGSOC. Lower expression of DNMT1circle10302690-10302961 in both primary and metastatic tumors was associated with worse prognosis of HGSOC. Taken together, our finding firstly demonstrated the eccDNAs landscape of primary and metastatic tissues of HGSOC. The eccDNA DNMT1circle10302690-10302961 can be considered as a potential biomarker or a therapeutically clinical target of HGSOC metastasis and prognosis.
JCI insight
2022 Apr 19
Potluri, T;Taylor, MJ;Stulberg, JJ;Lieber, RL;Zhao, H;Bulun, SE;
PMID: 35439171 | DOI: 10.1172/jci.insight.152011
Greater than 25% of all men develop an inguinal hernia in their lifetime, and more than 20 million inguinal hernia repair surgeries are performed worldwide each year. The mechanisms causing abdominal muscle weakness, the formation of inguinal hernias, or their recurrence are largely unknown. We previously reported that excessively produced estrogen in the lower abdominal muscles (LAMs) triggers extensive LAM fibrosis, leading to hernia formation in a transgenic male mouse model expressing the human aromatase gene (Aromhum). To understand the cellular basis of estrogen-driven muscle fibrosis, we performed single-cell RNA sequencing on LAM tissue from Aromhum and wild-type littermates. We found a fibroblast-like cell group composed of 6 clusters, 2 of which were validated for their enrichment in Aromhum LAM tissue. One of the potentially novel hernia-associated fibroblast clusters in Aromhum was enriched for the estrogen receptor-α gene (Esr1hi). Esr1hi fibroblasts maximally expressed estrogen target genes and seemed to serve as the progenitors of another cluster expressing ECM-altering enzymes (Mmp3hi) and to upregulate expression of proinflammatory, profibrotic genes. The discovery of these 2 potentially novel and unique hernia-associated fibroblasts may lead to the development of novel treatments that can nonsurgically prevent or reverse inguinal hernias.
JCI insight
2022 Apr 14
Wilson, C;Mertens, TC;Shivshankar, P;Bi, W;Collum, SD;Wareing, N;Ko, J;Weng, T;Naikawadi, RP;Wolters, PJ;Maire, P;Jyothula, SS;Thandavarayan, RA;Ren, D;Elrod, ND;Wagner, EJ;Huang, HJ;Dickey, BF;Ford, HL;Karmouty-Quintana, H;
PMID: 35420997 | DOI: 10.1172/jci.insight.142984
Idiopathic pulmonary fibrosis (IPF) is a fatal disease with limited treatment options. The role of the developmental transcription factor Sine Oculis homeobox homolog 1 (SIX1) in the pathophysiology of lung fibrosis is not known. IPF lung tissue samples and IPF-derived alveolar type II cells (AT2) showed a significant increase in SIX1 mRNA and protein levels, and the SIX1 transcriptional co-activators EYA1 and EYA2 were elevated. Six1 was also upregulated in bleomycin (BLM)-treated mice and in a model of spontaneous lung fibrosis driven by deletion of Telomeric Repeat Binding Factor 1 (Trf1) in AT2 cells. Conditional deletion of Six1 in AT2 cells prevented or halted BLM-induced lung fibrosis as measured by a significant reduction in histological burden of fibrosis, reduced fibrotic mediator expression and improved lung function. These effects were associated with increased macrophage migration inhibitory factor (MIF) in lung epithelial cells in vivo following SIX1 overexpression in BLM-induced fibrosis. A MIF promoter-driven luciferase assay demonstrated direct binding of Six1 to the 5'-TCAGG-3' consensus sequence of the MIF promoter, identifying a likely mechanism of SIX1-driven MIF expression in the pathogenesis of lung fibrosis, and providing a novel pathway for targeting in IPF therapy.
JCI insight
2022 Apr 12
Cross, RW;Bornholdt, ZA;Prasad, AN;Woolsey, C;Borisevich, V;Agans, KN;Deer, DJ;Abelson, DM;Kim, DH;Shestowsky, WS;Campbell, LA;Bunyan, E;Geisbert, JB;Dobias, NS;Fenton, KA;Porter, DP;Zeitlin, L;Geisbert, TW;
PMID: 35413016 | DOI: 10.1172/jci.insight.159090
A major challenge in managing acute viral infections is ameliorating disease when treatment is delayed. Previously, we reported the success of a two-pronged monoclonal antibody (mAb) and antiviral remdesivir therapeutic approach to treat advanced illness in Marburg virus (MARV)-infected rhesus monkeys. Here, we explored the benefit of a similar combination therapy for Sudan ebolavirus (SUDV) infection. Importantly, no licensed anti-SUDV therapeutics currently exist, and infection of rhesus macaques with SUDV results in a rapid disease course similar to MARV with a mean time-to-death of 8.3 days. When initiation of therapy with either remdesivir or a pan ebolavirus mAb cocktail (MBP431) was delayed until 6 days post inoculation (dpi), only 20% of macaques survived. In contrast, when remdesivir and MBP431 treatment were combined beginning 6 dpi, significant protection (80%) was achieved. Our results suggest that combination therapy may be a viable treatment for patients with advanced filovirus disease that warrants further clinical testing in future outbreaks.
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| Description | ||
|---|---|---|
| sense Example: Hs-LAG3-sense | Standard probes for RNA detection are in antisense. Sense probe is reverse complent to the corresponding antisense probe. | |
| Intron# Example: Mm-Htt-intron2 | Probe targets the indicated intron in the target gene, commonly used for pre-mRNA detection | |
| Pool/Pan Example: Hs-CD3-pool (Hs-CD3D, Hs-CD3E, Hs-CD3G) | A mixture of multiple probe sets targeting multiple genes or transcripts | |
| No-XSp Example: Hs-PDGFB-No-XMm | Does not cross detect with the species (Sp) | |
| XSp Example: Rn-Pde9a-XMm | designed to cross detect with the species (Sp) | |
| O# Example: Mm-Islr-O1 | Alternative design targeting different regions of the same transcript or isoforms | |
| CDS Example: Hs-SLC31A-CDS | Probe targets the protein-coding sequence only | |
| EnEm | Probe targets exons n and m | |
| En-Em | Probe targets region from exon n to exon m | |
| Retired Nomenclature | ||
| tvn Example: Hs-LEPR-tv1 | Designed to target transcript variant n | |
| ORF Example: Hs-ACVRL1-ORF | Probe targets open reading frame | |
| UTR Example: Hs-HTT-UTR-C3 | Probe targets the untranslated region (non-protein-coding region) only | |
| 5UTR Example: Hs-GNRHR-5UTR | Probe targets the 5' untranslated region only | |
| 3UTR Example: Rn-Npy1r-3UTR | Probe targets the 3' untranslated region only | |
| Pan Example: Pool | A mixture of multiple probe sets targeting multiple genes or transcripts | |
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