Biology subjects

Basak, N.

Publications and source records attributed to Basak, N..

4 recordsLinked to original sources

bioRxiv2025

Pretreatment with estrogen enhances the therapeutic efficacy of cardiac progenitor cells and improves cardiac recovery in a failing heart model

BackgroundIn recent years, cardiac progenitor cells (CPCs) are considered as a potential source of cell therapy for the treatment of heart failure. Despite the encouraging results of clinical trials showing that transplantation of CPCs improves function of infarcted hearts, reduced cell survival and inefficient engraftment into host tissue are still challenging issues. MethodsCPCs were isolated from a male mouse heart and incubated with estrogen (10-7M for 48 hours) in vitro. The heart failure model was generated by intraperitoneally isoproterenol (ISO) treatment (200mg/kg for 6 days) in the female mouse. Either estrogen pretreated-CPC (E2-CPC) or untreated-CPCs (Control-CPC) were intramyocardially transplanted into the failure heart. Engraftment of transplanted cells were visualized by in vivo imaging, Y-chromosome staining (by Fluorescence In Situ Hybridization) and SRY gene for expression analysis. Cardiac functions were determined by analyzing electrophysiological changes. Pathological changes following the transplantation were also examined at the molecular level by immunostaining and western blotting from isolated heart samples and on heart tissue sections to address the efficiency of the E2-CPC transplantation. In addition to regenerative outcomes at animal level, the enhancing effect of estrogen on the therapeutic potential of CPC was examined through changes in migration, proliferation and mitochondrial energetics by in vitro experiments. The effects of estrogen in transcriptome profiling was also evaluated by RNA sequencing (RNA-seq) in CPCs. ResultsIn vivo results demonstrated that estrogen pretreatment increased the retention rate of transplanted CPCs in failing heart. E2-CPC transplantation enhanced cardiac function and ameliorated pathological cardiac remodelling via inducing revascularization, proliferation while attenuating collagen formation and hypertrophy in failing heart. Our in vitro results have shown that estrogen treatment promotes migration, angiogenesis and proliferation capacities and adenosine triphosphate (ATP) production of CPCs in vitro. RNA sequencing provided further evidence that the change in the transcriptome profile of CPCs upon estrogen treatment improved their ability to cause reverse cardiac remodelling in the failing heart after transplantation. ConclusionOur data indicated that estrogen-pretreatment significantly improves cardiac recovery in a failing heart through enhancing efficacy of CPC transplantation. This study also emphasized underyling mechanisms of the improvement in function in CPC-based therapies which remain poorly understood.

molecular biology↗

bioRxiv2024

Sex-specific DNA methylation differences in Amyotrophic lateral sclerosis

Sex is an important covariate in all genetic and epigenetic research due to its role in the incidence, progression and outcome of many phenotypic characteristics and human diseases. Amyotrophic lateral sclerosis (ALS) is a motor neuron disease with a sex bias towards higher incidence in males. Here, we report for the first time a blood-based epigenome-wide association study meta-analysis in 9274 individuals after stringent quality control (5529 males and 3975 females). We identified a total of 226 ALS saDMPs (sex-associated DMPs) annotated to a total of 159 unique genes. These ALS saDMPs were depleted at transposable elements yet significantly enriched at enhancers and slightly enriched at 3UTRs. These ALS saDMPs were enriched for transcription factor motifs such as ESR1 and REST. Moreover, we identified an additional 10 genes associated with ALS saDMPs through chromatin loop interactions, suggesting a potential regulatory role for these saDMPs on distant genes. Furthermore, we investigated the relationship between DNA methylation at specific CpG sites and overall survival in ALS using Cox proportional hazards models. We identified two ALS saDMPs, cg14380013 and cg06729676, that showed significant associations with survival. Overall, our study reports a reliable catalogue of sex-associated ALS saDMPs in ALS and elucidates several characteristics of these sites using a large-scale dataset. This resource will benefit future studies aiming to investigate the role of sex in the incidence, progression and risk for ALS.

genomics↗

bioRxiv2024

Directed differentiation of functional corticospinal-like neurons from endogenous SOX6+/NG2+ cortical progenitors

Corticospinal neurons (CSN) centrally degenerate in amyotrophic lateral sclerosis (ALS), along with spinal motor neurons, and loss of voluntary motor function in spinal cord injury (SCI) results from damage to CSN axons. For functional regeneration of specifically affected neuronal circuitry in vivo, or for optimally informative disease modeling and/or therapeutic screening in vitro, it is important to reproduce the type or subtype of neurons involved. No such appropriate in vitro models exist with which to investigate CSN selective vulnerability and degeneration in ALS, or to investigate routes to regeneration of CSN circuitry for ALS or SCI, critically limiting the relevance of much research. Here, we identify that the HMG-domain transcription factor Sox6 is expressed by a subset of NG2+ endogenous cortical progenitors in postnatal and adult cortex, and that Sox6 suppresses a latent neurogenic program by repressing proneural Neurog2 expression by progenitors. We FACS-purify these progenitors from postnatal mouse cortex and establish a culture system to investigate their potential for directed differentiation into CSN. We then employ a multi-component construct with complementary and differentiation-sharpening transcriptional controls (activating Neurog2, Fezf2, while antagonizing Olig2 with VP16:Olig2). We generate corticospinal-like neurons from SOX6+/NG2+ cortical progenitors, and find that these neurons differentiate with remarkable fidelity compared with corticospinal neurons in vivo. They possess appropriate morphological, molecular, transcriptomic, and electrophysiological characteristics, without characteristics of the alternate intracortical or other neuronal subtypes. We identify that these critical specifics of differentiation are not reproduced by commonly employed Neurog2-driven differentiation. Neurons induced by Neurog2 instead exhibit aberrant multi-axon morphology and express molecular hallmarks of alternate cortical projection subtypes, often in mixed form. Together, this developmentally-based directed differentiation from cortical progenitors sets a precedent and foundation for in vitro mechanistic and therapeutic disease modeling, and toward regenerative neuronal repopulation and circuit repair.

neuroscience↗

bioRxiv2020

Hematological parameters of high and low altitude Tibetan populations

High altitude hypoxia is believed to be experienced at elevations more than 2500 meters. A few studies have shed light on the biochemical aspects of high altitude acclimatization that profoundly included the subjects sojourning to the high altitude from low altitude and observation of the transient changes. However, information regarding the difference between the adapted people in high altitude and their counterpart, who reside in the low altitude are lacking. To address that issue, we have measured various hematological parameters and level of serum erythropoietin (EPO) in Tibetan population, who are residing in both high and low altitudes. We observed significant difference (p value < 0.0001) between high and low altitude Tibetan, in various hematological parameters, including red blood cells (RBC) count, hematocrit (HCT) or packed cell volume (PCV), and hemoglobin concentration (Hb). In case of mean corpuscular volume (MCV), significant difference was observed only in females (p value < 0.0001). Mean corpuscular hemoglobin concentration (MCHC) was significantly different between both males and females, but age was a potential confounder. There was no significant difference in serum EPO level between these two groups, either in males or females, which might be due to blunted erythropoietin response in the Tibetan population. We have also analyzed correlation between serum EPO with Hb and serum EPO with HCT and found no significant correlation. In multiple regression analysis, low altitude and male-gender showed significant impact on both Hb and HCT. In conclusion, our study suggests significant perturbation of hematological parameters, when native high altitude populations migrated to low altitude and inhabited for a long period.

physiology↗