Biology subjects

Viswanathan, S.

Publications and source records attributed to Viswanathan, S..

At least 19 recordsLinked to original sources

bioRxiv2026

TGFB1-Engineered Induced Mesenchymal Stromal Cells Exhibit High Immunomodulatory Potency and Durably Reprogram Synovial Macrophages in Osteoarthritis

Clinical translation of mesenchymal stromal cell (MSC) therapies derived from primary tissue sources is limited by manufacturing inconsistencies driven by donor-to-donor variability, which reduces predictability of clinical response. Induced pluripotent stem cell (iPSC)-derived MSCs (iMSCs) offer a promising donor-independent, clonal alternative strategy that is also more amenable to engineering, but whether engineered iMSCs reproduce the potency attributes of primary MSCs remains unclear. Here, we benchmarked a doxycycline-inducible, hTERT-immortalized iMSC line engineered to overexpress TGFB1 (TGFB1-iMSCs), a key regulator of macrophage polarization, against multiple adipose tissue-derived MSC (MSC(AT)) donors across predefined immunomodulatory and angiogenic potency attributes. TGFB1-iMSCs were smaller and more circular with comparable or higher proliferative rates than primary MSC(AT) donors. Interestingly, they had a distinct angiogenic signature (EDIL3, EDN1, PDGFA), and nine differentially expressed microRNAs were predicted to target secretory trafficking and growth factor receptor signalling. Functionally, however, TGFB1-iMSCs secreted less VEGF and showed intermediate HUVEC tube formation, but matched or exceeded all primary MSC(AT) donors in a monocyte-macrophage transwell immunomodulatory assay. Notably, in a murine destabilization of the medial meniscus (DMM) model of post-traumatic osteoarthritis, a single intra-articular injection of TGFB1-iMSCs, but not MSC(AT), reduced total synovial macrophage numbers and lowered the MHCII/CD206 ratio at eight weeks, although it did not reduce cartilage degeneration, synovitis, or fibrosis. Together, these findings show that TGFB1-engineered iMSCs have a macrophage-directed potency profile distinct from that of primary MSC(AT). Immortalized iMSCs therefore provide a reproducible platform for mechanistically dissecting engineered MSC potency and its effects on the immune environment.

immunology↗

bioRxiv2026

Human knee osteoarthritis patient-specific cartilage-on-a-chip model captures donor differences to stressors and treatments

Knee Osteoarthritis (KOA) is a progressive whole-joint disease without approved disease modifying OA drugs (DMOADs). Effective treatments have been hindered by multiple layers of heterogeneity, including diverse disease etiology and patient-to-patient variability. Here, we present a scalable, KOA patient-derived (PD) cartilage-on-a-chip (CartChip) model integrating end-stage KOA cartilage tissue explants on a microengineered platform that, under mechanical overloading and hyperinflammatory stressors, mimics different KOA etiologies. These stressors drove distinct multivariable model features, including changes in a curated panel of anabolic and catabolic genes, extracellular matrix protein and soluble factors. Exploratory analysis of coordinated model readouts identified stressor-agnostic and -specific KOA disease signatures. Despite using KOA tissue, the model showed improvements to dexamethasone, a symptom-modifying, anti-inflammatory KOA treatment. The model responses to dexamethasone were dependent on both stressor and donor heterogeneity. Exploratory groupings of coordinated model readouts provided proof-of-concept for predicting categories of patient responsiveness to test therapeutics. Annotating patient data provided additional donor-dependent contexts for interpreting model responsiveness. PD-CartChip provides a powerful research platform to potentially surmount the donor and stressor heterogeneity barrier in developing DMOADs.

bioengineering↗

bioRxiv2026

Joint tissue explant model using psoriatic arthritis synovial fluid as a tool to capture patient-specific responses to treatments

ObjectiveWe developed a patient- and joint-specific explant co-culture system to model active psoriatic arthritis (PsA) and capture donor-specific tissue responses to therapeutic interventions. MethodsBased on convergent joint pathology between end-stage osteoarthritis (OA) and PsA, OA cartilage-bone and synovium tissues from arthroplasty patients were exposed to synovial fluid (SF) obtained from PsA and OA patients. Histological outcomes (synovitis, proteoglycan distribution), curated gene expression, soluble mediators, and proteinase activity were assessed over 7-21-days. Model responses to dexamethasone (DEX) and the anti-tumor necrosis factor antibody adalimumab (ADA) were evaluated. ResultsPsA SF induced distinct inflammatory and tissue remodeling responses compared to OA SF and control conditions, including altered cartilage proteoglycan distribution, increased synovitis, and tissue-specific transcriptional changes. Multivariate analyses identified distinct osteochondral and synovial transcriptional responses to PsA SF, characterized by reduced osteochondral COL2A1 expression and increased synovial expression of inflammatory and matrix-remodeling genes, including MMP1 and CXCL8. DEX and ADA elicited donor-specific responses across histological, transcriptional, and protein readouts. Among multivariable model outputs, histologic synovitis scores emerged as the most clinically aligned parameter, demonstrating associations with baseline PsA donor disease activity, active joint counts, pain, high-sensitivity C-reactive protein (hsCRP), and radiographic scores. Synovitis score changes to DEX and ADA treatments also aligned with corresponding PsA SF donor clinical improvements to corticosteroid and TNF-modifying therapies. ConclusionThis osteochondral-synovial explant co-culture model captured donor-specific inflammatory and treatment-responsive features of PsA SF-induced pathology, thereby providing a clinically relevant ex vivo platform for studying patient-specific therapeutic responses in PsA.

immunology↗

bioRxiv2026

Combined computational and experimental analysis confirm donor-dependent optimization of critical processing parameters for improving mesenchymal stromal cell potency and expansion attributes

Mesenchymal Stromal Cells (MSC) face several heterogeneity challenges hindering clinical and commercial success. Employing a multiple response model, interplay between donor heterogeneity, and critical processing parameters (CPPs), effects on MSC potency and cell expansion attributes were investigated through computed composite attribute scores. Twelve unique CPP combinations were tested in thirteen marrow-derived MSC(M) and five adipose-tissue MSC(AT) training and test datasets, respectively. Donor heterogeneity and select CPP conditions affected a curated gene panel (surrogate for MSC potency); while MSC expansion was primarily influenced by CPPs. Model performances were evaluated against clinical effectiveness data from a previously deployed clinical trial; top-performing model predicted donor rankings coincided with clinical effectiveness data, validating the modeling approach used. Our model predicted that only 8% of tested donors were agnostic to CPPs; a majority (62%) of donors showed CPP-dependent optimal composite quality attributes, with MSC seeding density as a key driver; medium supplementation and oxygen preferences were highly donor dependent. Approximately 30% of donors performed poorly at all conditions tested and may be prospectively identified using a subset of genes (TGFB, VEGF, PDCD1LG1, PDCD1LG2, IDO). Model predicted optimal parameters worked for 69% of tested donors, while sub-optimal parameters worked for only 23% of donors and were confirmed in an independent CD14+ macrophage assay. Our integrated computational and experimental framework predictably identified interactive effects of donor heterogeneity and CPP conditions to optimize MSC potency attributes.

bioengineering↗

bioRxiv2025

Mesenchymal Stromal Cells Immunosuppress Osteoarthritis Synovial Fluid Tolerized Monocytes via IL-6

BackgroundMesenchymal stromal cell (MSC) interactions with monocytes/macrophages are central to their therapeutic effects in knee osteoarthritis (KOA); however, mechanisms of these interactions are not fully understood. HypothesisWe hypothesize that MSC soluble factors, particularly interleukin-6 (IL-6) and C-C motif chemokine ligand (CCL2) modulate monocytes in KOA environment. MethodsUsing healthy donor CD14+ monocytes exposed to KOA synovial fluid (SF) in the presence or absence of marrow-derived MSC(M) directly or conditioned medium (CM), we evaluated cell surface markers and signaling via signal transducer and activator of transcription (STAT3), nuclear factor kappa-light-chain-enhancer of activated B (NF-{kappa}B) and c-Jun Terminal Kinase (JNK); functional responses were measured by secretion of tumor necrosis factor (TNF) and IL-1, and by phagocytosis of pHrodo Red E-coli. ResultsCD14+ monocytes demonstrated a mixed phenotype in KOA SF with increased CD163, CD206 and unchanged HLA-DR, CD86 marker expression. This was accompanied by activated STAT3, JNK and NF-{kappa}B signaling. TNF and IL-1 secreted levels were unchanged, but phagocytosis was impaired, indicative of a net dysfunctional repair phenotype and functionality. CD14+ monocytes in KOA SF were hyporesponsive to additional lipopolysaccharide re-challenge, based on TNF and IL-1 secretion. Addition of MSC(M) to KOA SF programmed CD14+ monocytes resolved the dysfunctional phenotype and functionality, with significant increases in CD163, CD206; significant reductions in HLA-DR and CD86 expression; this was accompanied by significantly increased activated STAT3, and decreased activated JNK and NF-{kappa}B. TNF and IL-1 secretion were also significantly reduced, and phagocytic capacity restored. Blocking IL-6, or to a lesser extent, CCL2, partially abrogated MSC(M) soluble factor effects. MSC(M) experienced apoptosis in KOA SF; however, apoptotic bodies did not fully recapitulate MSC(M) soluble factor effects. ConclusionIL-6, CCL2, other soluble factors and apoptotic bodies from MSC(M) secretome mitigate the dysfunctional effects of KOA SF on CD14+ monocytes resulting in immunosuppressed phenotype and functionality.

immunology↗

bioRxiv2025

Dicer is essential for proper maturation, composition, and function in the postnatal retina.

microRNAs (miRNAs) play a pivotal role during the early phases of retinal development, but their impact on late-phase retinogenesis is unknown. We depleted miRNAs in late retinal progenitor/precursor cells (RPCs/PCs) via a conditional Dicer knock-out. Optical coherence tomography (OCT), electroretinography (ERG), histological, and transcriptional analyses were conducted in young and adult mice. Alterations in gene expression of late-born cells were observed as early as postnatal day 7 (P7), resulting in impaired rod function, a significantly reduced number of rod bipolar cells and their associated function, and a decreased Muller glia population at adult age. These defects appear to be caused by a delay in differentiation/ incomplete maturation, as indicated by an enlarged progenitor/precursor population at young ages that persists into adulthood. Notably, an increased population of HuC/D+ amacrine cells was found. Luciferase assays led us to speculate that this increase may be due to the absence of Elavl3 suppression via RPC-miRNAs. This suggests that Dicer/miRNAs in late RPC/PCs are essential for the proper formation and maturation of late RPC progenies and may also play a role in regulating cell state. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=109 SRC="FIGDIR/small/635135v1_ufig1.gif" ALT="Figure 1"> View larger version (22K): org.highwire.dtl.DTLVardef@9e0950org.highwire.dtl.DTLVardef@1757e2corg.highwire.dtl.DTLVardef@aeb5ecorg.highwire.dtl.DTLVardef@29accb_HPS_FORMAT_FIGEXP M_FIG C_FIG Summary statementLate-retinal progenitor microRNAs are essential for proper postnatal retinogenesis and retinal function.

developmental biology↗

bioRxiv2025

Responders vs. non-responders to mesenchymal stromal cells in knee osteoarthritis patients: mechanistic correlates of donor cell attributes and patient features

Mesenchymal stromal cell (MSC) injection has afforded heterogenous outcomes in knee osteoarthritis (KOA). Herein, a framework that dually correlates KOA patient responsiveness to baseline autologous bone marrow-derived MSC(M) donor batch attributes and baseline clinical and biomarker features is provided. Using clinical trial data, we demonstrated that MSC(M) with increased immunomodulatory potency are more efficacious. Multivariable MSC(M) genes correlated strongly with responder status and to 12- and 24-month improvements in Knee Injury and Osteoarthritis Outcome Scores. Responder MSC(M) donor batches had unique microRNA expression and ability to polarize CD14+ monocytes in vitro. KOA Responders had lower baseline physical activity and trended toward more severe baseline KOA. Baseline local but not systemic biomarkers showed trending correlations to patient responsiveness. 42% of KOA patients were Responders at 24 months, emphasizing durability of single MSC(M) injections. Together, our analytical methodology defines critical quality attributes of potent MSC(M) donor batches and identifies putative KOA patient theratypes to MSC treatments. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=159 HEIGHT=200 SRC="FIGDIR/small/665028v4_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@18bbb07org.highwire.dtl.DTLVardef@a406e8org.highwire.dtl.DTLVardef@c18c8corg.highwire.dtl.DTLVardef@f2731c_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2025

Dicer loss in Muller glia leads to a defined sequence of pathological events beginning with cone dysfunction

PurposeThe loss of Dicer in Muller glia (MG) results in severe photoreceptor degeneration as it occurs in retinitis pigmentosa or AMD. However, the sequence of events leading to this severe degenerative state is unknown. The aim of this study was to conduct a chronological functional and structural characterization of the pathological events in MG-specific Dicer-cKO mice in vivo and histologically. MethodsTo delete Dicer and mature microRNAs (miRNAs) in MG, two conditional Dicer1 knock-out mouse strains namely RlbpCre:Dicer-cKOMG and GlastCre:Dicer-cKOMG, were created. Optical coherence tomography (OCT), electroretinograms (ERGs) as well as histological analyses were conducted to investigate structural and functional changes up to six months after Dicer deletion. ResultsDicer/miRNA loss in MG leads to 1) impairments of the external limiting membrane (ELM) - retinal pigment epithelium (RPE), 2) cone photoreceptor dysfunction and 3) retinal remodeling and functional loss of the inner retina, 1, 3 and 6 months after Dicer loss, respectively, in both strains. Furthermore, in the Rlbp:Dicer-cKOMG strain, rod photoreceptor impairment was found 4 months after Dicer depletion (4) accompanied by alteration of RPE integrity (5). ConclusionsMG Dicer loss in the adult mouse retina impacts cone function prior to any measurable changes in rod function, suggesting a pivotal role for MG Dicer and miRNAs in supporting cone health. A partially impaired RPE however seems to accelerate rod degeneration and overall degenerative events.

neuroscience↗

bioRxiv2024

A framework for target discovery in rare cancers

Functional genetic screens have uncovered dependencies in many cancers, but experimentally screened models for most cancers are far outnumbered by molecularly-profiled tumors, particularly for rare cancers. We used machine learning to infer gene dependencies from tumor transcriptional profiles, applying our model to the TCGA (11,373 tumors; 28 lineages), rare cancers (1,034 tumors, including 17 kidney cancer subtypes), and 509 previously unscreened cancer cell lines. Besides recovering dependencies previously identified in functional screens, we inferred drug response and synthetic essential relationships directly from tumors, including those associated with RB1 inactivation, KRAS mutation, and microsatellite instability. Via dependency prediction, we discovered and validated a shared reliance on oxidative phosphorylation in two previously unscreened rare cancers both driven by TFE3 gene fusions. We also nominate additional actionable vulnerabilities across various rare kidney cancers lacking experimental models. Our approach enables discovery of cancer vulnerabilities from transcriptomes, even in the absence of functional screening.

cancer biology↗

bioRxiv2023

Inhibition of an immunometabolic axis of mTORC1 activation extends mammalian healthspan

Human ageing is associated with metabolic dysfunction, sarcopenia and frailty that taken together reduce healthspan. For age-associated diseases and lifespan, ERK, AMPK and mTORC1 represent critical pathways, across species1-7. Here we examined the hypothesis that IL11, recently shown to regulate ERK/mTORC1, is an inflammaging factor important for healthspan. As mice age, IL11 is progressively upregulated in liver, skeletal muscle, and fat to stimulate an ERK/AMPK/mTORC1 axis of cellular, tissue- and organismal-level ageing pathologies. In old mice, deletion of Il11 or Il11ra1 protects against metabolic multi-morbidity, sarcopenia, and frailty. Administration of anti-IL11 therapy to elderly mice for six months reactivates an age-repressed program of white fat beiging, reverses metabolic dysfunction, restores muscle function, and reduces frailty. Across studies, inhibition of IL11 lowers epigenetic age, reduces telomere attrition, and preserves mitochondrial function. Towards clinical translation, we generated, humanised, and engineered a neutralising, high-affinity IL11 antibody. These studies identify IL11 as a key inflammaging factor and therapeutic target for mammalian healthspan.

molecular biology↗

bioRxiv2023

Successful Modulation of Temporoparietal Junction Activity and Stimulus-Driven Attention by fNIRS-based Neurofeedback - a Randomized Controlled Proof-of-Concept Study

The right temporoparietal junction (rTPJ) is a core hub in neural networks associated with reorienting of attention and social cognition. However, it remains unknown whether participants can learn to actively modulate their rTPJ activity via neurofeedback. Here, we explored the feasibility of functional near-infrared spectroscopy (fNIRS)-based neurofeedback in modulating rTPJ activity and its effect on rTPJ functions such as reorienting of attention and visual perspective taking. In a bidirectional regulation control group design, 50 healthy participants were either reinforced to up- or downregulate rTPJ activation over four days of training. Both groups showed an increase in rTPJ activity right from the beginning of the trainingbut only the upregulation group maintained this effect, while the downregulation group showed a decline from the initial rTPJ activation. This suggests a learning effect in the downregulation exclusively, making it challenging to draw definitive conclusions about the effectiveness of rTPJ upregulation training. However, we observed group-specific effects on the behavioral level. We found a significant group x time interaction effect in the performance of the reorienting of attention task and group-specific changes, with decreased reaction times (RTs) in the upregulation group and increased RTs in the downregulation group across all conditions after the neurofeedback training. Those with low baseline performance showed greater improvements. In the perspective-taking task, however, only time effects were observed that were non-group-specific.These findings demonstrate that fNIRS-based neurofeedback is a feasible method to modulate rTPJ functions with preliminary evidence of neurophysiologically specific effects, thus paving the way for future applications of non-invasive rTPJ modulation in neuropsychiatric disorders. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=96 SRC="FIGDIR/small/532169v2_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@1061186org.highwire.dtl.DTLVardef@168b06forg.highwire.dtl.DTLVardef@17795forg.highwire.dtl.DTLVardef@1215c6e_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIthe right temporoparietal junction (rTPJ) as a core hub for attentive and socio-cognitive functions is a promising target for neuromodulatory interventions C_LIO_LIfirst single-blinded, randomized controlled study demonstrates feasibility and effectiveness of the fNIRS-based neurofeedback training of the rTPJ in healthy adults C_LIO_LIsubjects are able to regulate the rTPJ with different learning characteristics C_LIO_LIfirst evidence of a neurophysiologically specific effect on stimulus-driven attention C_LIO_LIfindings have important implications for clinical translation of neurofeedback interventions targeting the rTPJ C_LI

neuroscience↗

bioRxiv2022

Interleukin-11 causes alveolar type 2 cell dysfunction and prevents alveolar regeneration

Following lung injury, alveolar regeneration is characterized by the transformation of alveolar type 2 (AT2) cells, via a transitional KRT8+ state, into alveolar type 1 (AT1) cells. In lung disease, dysfunctional intermediate cells accumulate, AT1 cells are diminished and fibrosis occurs. Using single cell RNA sequencing datasets of human interstitial lung disease, we found that interleukin-11 (IL11) is specifically expressed in aberrant KRT8 expressing KRT5-/KRT17+ and basaloid cells. Stimulation of AT2 cells with IL11 or TGF{beta}1 caused EMT, induced KRT8+ and stalled AT1 differentiation, with TGF{beta}1 effects being IL11 dependent. In bleomycin injured mouse lung, IL11 was increased in AT2-derived KRT8+ cells and deletion of Il11ra1 in lineage labeled AT2 cells reduced KRT8+ expression, enhanced AT1 differentiation and promoted alveolar regeneration, which was replicated in therapeutic studies using anti-IL11. These data show that IL11 maintains AT2 cells in a dysfunctional transitional state, impairs AT1 differentiation and blocks alveolar regeneration across species. TeaserInterleukin-11 stalls type 2-to-type 1 alveolar epithelial cell differentiation and prevents lung regeneration

immunology↗

bioRxiv2022

IL11 stimulates IL33 expression and proinflammatory fibroblast activation

Interleukin 11 (IL11) is upregulated in inflammatory conditions where it is believed to have anti-inflammatory activity. However, recent studies suggest instead that IL11 may promote inflammation, via the stroma. Here, we assessed whether IL11 is pro- or anti-inflammatory in fibroblasts. Primary cultures of human kidney, lung or skin fibroblasts were stimulated with IL11 that resulted in transient STAT3 phosphorylation and bi-modal ERK activation. RNA sequencing over a time course of IL11 stimulation revealed a robust short-lived transcriptional response, which was enriched for gene set hallmarks of inflammation and characterized by upregulation of SERPINB2, TNFRSF18, IL33, CCL20, IL1RL1, CXCL3/5/8, ICAM1 and IL11 itself. IL33 was the most upregulated signaling factor (38-fold, P=9.8x10-5) and IL1RL1, its cognate receptor, was similarly increased (18-fold, P=1.1x10-34). In proteomic studies, IL11 triggered a proinflammatory secretome with notable upregulation of IL8, IL6, MCP1, CCL20 and CXCL1/5/6, which are important chemotaxins for neutrophils, monocytes and lymphocytes. IL11 induced IL33 expression across fibroblast types and inhibition of STAT3, but not MEK/ERK, prevented this. These data establish IL11 as pro-inflammatory with specific importance for priming the IL33 alarmin response in inflammatory fibroblasts.

molecular biology↗

bioRxiv2022

IL11 stimulates ERK/P90RSK to inhibit LKB1/AMPK and activate mTOR in hepatocytes, the stroma and cancer cells

Interleukin 11 (IL11) stimulates stromal cell activation but also causes hepatocyte metabolic dysfunction. The mechanisms underlying these seemingly unrelated processes are not known. Here we report that IL11-stimulated ERK/P90RSK activity causes the sequential phosphorylation of LKB1 (STK11) at S325 and S428, leading to its inactivation. This leads to a reduction in AMPK activity whilst concomitantly activating mTOR in human fibroblasts, hepatic stellate cells, hepatocytes and cancer cells. In fibroblasts and hepatic stellate cells, IL11-mediated LKB1/AMPK inhibition causes myofibroblast transformation whereas in hepatocytes it inhibits autophagy and fatty acid oxidation and is toxic. Across cell types, the self-amplifying loop of autocrine IL11 activity was inhibited by AMPK activation with metformin, AICAR or 991. In mice on a western diet with fructose, anti-IL11 therapy or hepatocyte-specific deletion of Il11ra1 rescues LKB1/AMPK activity and reduces NASH. In contrast, restoration of IL11 signalling in hepatocytes of mice with global Il11ra1 deletion inactivates LKB1/AMPK and exacerbates NASH. These data show that LKB1, an important tumour suppressor and master kinase, is not constitutively active and identify the IL11/LKB1/AMPK/mTOR axis as a point of signalling convergence for epithelial homeostasis, fibrogenesis, immunometabolism and cancer.

molecular biology↗

bioRxiv2021

N-myc Downstream Regulated Gene 1 (NDRG1) functions as a molecular switch for cellular adaptation to hypoxia

Lack of oxygen (hypoxia and anoxia) is detrimental to cell function and survival and underlies many disease conditions. Hence, metazoans have evolved mechanisms to adapt to low oxygen. One such mechanism, metabolic suppression, decreases the cellular demand for oxygen by downregulating ATP-demanding processes. However, the molecular mechanisms underlying this adaptation are poorly understood. Here, we report on the role of ndrg1a in hypoxia adaptation of the anoxia-tolerant zebrafish embryo. ndrg1a is expressed in the kidney and ionocytes, cell types that use large amounts of ATP to maintain ion homeostasis. ndrg1a mutants are viable and develop normally when raised under normal oxygen. However, their survival and kidney function is reduced relative to WT embryos following exposure to prolonged anoxia. We further demonstrate that Ndrg1a binds to the energy-demanding sodium-potassium ATPase (NKA) pump under anoxia and is required for its degradation, which may preserve ATP in the kidney and ionocytes and contribute to energy homeostasis. Lastly, we show that sodium azide treatment, which increased lactate levels, was sufficient to trigger NKA degradation in an Ndrg1a-dependent manner. These findings support a model whereby Ndrg1a is essential for hypoxia adaptation and functions downstream of lactate signaling to induce NKA degradation, a process known to conserve cellular energy.

developmental biology↗

bioRxiv2021

An individualized fMRI-based protocol to assess semantic memory in a heterogeneous multilingual population

The cognitive stimulation induced by multilingualism may slow down age-related memory impairment. However, a suitable neuroscientific framework to assess the influence of multilingualism on age-related memory processes is missing. We propose an experimental paradigm that assesses the effects of semantic congruency on episodic memory using functional magnetic resonance imaging (fMRI). To this end, we modified the picture-word interference (PWI) task to be suitable for the assessment of older multilingual subjects undergoing functional magnetic resonance imaging (fMRI). In particular, stimulus materials were prepared in multiple languages (French, German, Luxembourgish, English) and closely matched in semantic properties, thus enabling participants to perform the experiment in a language of their choice. This paradigm was validated in a group (n = 62) of healthy, older participants (over 64 years) who were multilingual, all practicing three or more languages. Consistent with the engagement of semantic congruency processes, we found that the encoding and recognition of semantically related vs. unrelated picture-word pairs evoked robust differences in behavior and the neural activity of parietal-temporal networks. These effects were negligibly modulated by the language used to perform the task. Based on this validation in a multilingual population, we conclude that the proposed paradigm will allow future studies to evaluate whether multilingualism aptitude engages neural systems in a manner that protects long-term memory from aging-related decline.

neuroscience↗

bioRxiv2021

Molecular dissection of pro-fibrotic signaling identifies the mechanism underlying IL11-driven fibrosis gene translation, reveals non-specific effects of STAT3 and suggests a new mechanism of action for nintedanib

In fibroblasts, TGF{beta}1 stimulates IL11 upregulation that leads to an autocrine loop of IL11-dependent pro-fibrotic protein translation. The signalling pathways downstream of IL11 are contentious and both STAT3 and ERK have been implicated. Here we show that TGF{beta}1- or IL11-induced ERK activation is consistently associated with fibrogenesis whereas STAT3 phosphorylation (pSTAT3) is unrelated to fibroblast activation. Surprisingly, recombinant human IL11, which has been used extensively in mouse experiments to infer STAT3 activity downstream of IL11, non-specifically increases pSTAT3 in Il11ra1 null mouse fibroblasts. Pharmacologic inhibition of STAT3 prevents TGF{beta}1-induced fibrogenesis but this effect was found to reflect fibroblast dysfunction due to severe proteotoxic ER stress. In contrast, inhibition of MEK/ERK prevented fibrosis in the absence of ER stress. TGF{beta}1-stimulated ERK/mTOR/P70RSK-driven protein translation was IL11-dependent and selectivity for pro-fibrotic protein synthesis was ascribed to an EPRS-related mechanism. In TGF{beta}1-stimulated fibroblasts, the anti-fibrotic drug nintedanib caused dose-dependent ER stress, reduced pSTAT/pERK and inhibited pro-fibrotic protein translation, similarly to generic STAT3 inhibitors or ER stressors. Pirfenidone, while anti-fibrotic, had no effect on ER stress whereas anti-IL11 inhibited the ERK/mTOR axis while reducing ER stress. These studies discount a specific role for STAT3 in pro-fibrotic signaling, suggest a novel mechanism of action for nintedanib and prioritise further the IL11 pathway as a therapeutic target for fibrosis.

molecular biology↗

bioRxiv2021

Overturning the paradigm that IL6 signaling drives liver regrowth while shining light on a new therapeutic target for regenerative medicine

It is accepted that IL6 signaling in hepatocytes, mediated via glycoprotein 130 (gp130), is beneficial and that HyperIL6 promotes liver regeneration by activating STAT3. Recently, autocrine IL11 activity, which also signals via gp130 and ERK, was found to be hepatotoxic. Here we examined whether the beneficial effects of HyperIL6 could reflect unappreciated competitive inhibition of IL11 signaling. In hepatocytes, HyperIL6 inhibited N-acetyl-p-aminophenol (APAP)-induced cell death that mimicked inhibition of IL11 signaling and was unrelated to STAT3 phosphorylation. In mice, expression of HyperIL6 reduced liver damage due to IL11 dosing or APAP and promoted hepatic regeneration in a STAT3-independent manner. Following APAP, mice deleted for Il11 were protected from liver failure and exhibited spontaneous regeneration. Despite robustly activating STAT3, HyperIL6 had no beneficial effect in Il11 null mice. These data overturn the premise that IL6 promotes liver regeneration, show STAT3 activation to be redundant and suggest IL11 as a focus for regenerative medicine.

cell biology↗