Biology subjects

Noble, T.

Publications and source records attributed to Noble, T..

6 recordsLinked to original sources

bioRxiv2025

Klf4-dependent pivotal role of smooth muscle-derived Gli1+ lineage progenitor cells in lung cancer progression

Lung cancer remains the leading cause of cancer-related deaths worldwide. Despite the remarkable efficacy of immune checkpoint inhibitors, only a subset of lung adenocarcinoma (LUAD) patients respond and many eventually progress, underscoring the need to develop novel combination therapies. The interaction between cancer cells and the tumor microenvironment (TME), a complex niche including cells of the innate and adaptive immune system, cancer-associated fibroblasts (CAFs), vascular cells, and extracellular matrix (ECM) plays a vital role in tumorigenesis and cancer progression. Using fate mapping, we previously identified a novel subpopulation of resident vascular stem cells derived from vascular smooth muscle cells, designated AdvSca1-SM (vascular Adventitial location, Stem cell antigen-1 expression, SMooth muscle origin) cells. AdvSca1-SM cells are the predominant cell type responding to vessel wall dysfunction and their selective differentiation to myofibroblasts promotes vascular fibrosis. SMC-to-AdvSca1-SM cell reprogramming is dependent on SMC induction of the transcription factor KLF4, and KLF4 is essential for maintenance of the stem cell phenotype. The function of AdvSca1-SM cells in LUAD tumorigenesis has not been explored. Using an orthotopic immunocompetent mouse model of LUAD, we demonstrate that AdvSca1-SM cells are a major component of lung tumors, significantly contributing to cancer associated fibroblasts (CAFs). Compared to AdvSca1-SM cells, CAFs have altered ECM gene expression with a reduction of a stemness signature. AdvSca1-SM-specific genetic ablation of Klf4 altered their phenotype resulting in inhibition of communication between cancer cells and CAFs, decreases in innate immunosuppressive populations, and increased T cell infiltration into the tumor. Targeting this population may represent a novel strategy to improve the response to immunotherapy.

cancer biology↗

bioRxiv2024

KLF4 in smooth muscle cell-derived progenitor cells is essential for angiotensin II-induced cardiac inflammation and fibrosis

Cardiac fibrosis is defined by the excessive accumulation of extracellular matrix (ECM) material resulting in cardiac tissue scarring and dysfunction. While it is commonly accepted that myofibroblasts are the major contributors to ECM deposition in cardiac fibrosis, their origin remains debated. By combining lineage tracing and RNA sequencing, our group made the paradigm-shifting discovery that a subpopulation of resident vascular stem cells residing within the aortic, carotid artery, and femoral aartery adventitia (termed AdvSca1-SM cells) originate from mature vascular smooth muscle cells (SMCs) through an in situ reprogramming process. SMC-to-AdvSca1-SM reprogramming and AdvSca1-SM cell maintenance is dependent on induction and activity of the transcription factor, KLF4. However, the molecular mechanism whereby KLF4 regulates AdvSca1-SM phenotype remains unclear. In the current study, leveraging a highly specific AdvSca1-SM cell reporter system, single-cell RNA-sequencing (scRNA-seq), and spatial transcriptomic approaches, we demonstrate the profibrotic differentiation trajectory of coronary artery-associated AdvSca1-SM cells in the setting of Angiotensin II (AngII)-induced cardiac fibrosis. Differentiation was characterized by loss of stemness-related genes, including Klf4, but gain of expression of a profibrotic phenotype. Importantly, these changes were recapitulated in human cardiac hypertrophic tissue, supporting the translational significance of profibrotic transition of AdvSca1-SM-like cells in human cardiomyopathy. Surprisingly and paradoxically, AdvSca1-SM-specific genetic knockout of Klf4 prior to AngII treatment protected against cardiac inflammation and fibrosis, indicating that Klf4 is essential for the profibrotic response of AdvSca1-SM cells. Overall, our data reveal the contribution of AdvSca1-SM cells to myofibroblasts in the setting of AngII-induced cardiac fibrosis. KLF4 not only maintains the stemness of AdvSca1-SM cells, but also orchestrates their response to profibrotic stimuli, and may serve as a therapeutic target in cardiac fibrosis.

cell biology↗

bioRxiv2023

Smooth muscle-derived adventitial progenitor cells promote key cell type transitions controlling plaque stability in atherosclerosis in a Klf4-dependent manner

We previously established that vascular smooth muscle-derived adventitial progenitor cells (AdvSca1-SM) preferentially differentiate into myofibroblasts and contribute to fibrosis in response to acute vascular injury. However, the role of these progenitor cells in chronic atherosclerosis has not been defined. Using an AdvSca1-SM lineage tracing model, scRNA-Seq, flow cytometry, and histological approaches, we confirmed that AdvSca1-SM cells localize throughout the vessel wall and atherosclerotic plaques, where they primarily differentiate into fibroblasts, SMCs, or remain in a stem-like state. Klf4 knockout specifically in AdvSca1-SM cells induced transition to a more collagen-enriched myofibroblast phenotype compared to WT mice. Additionally, Klf4 depletion drastically modified the phenotypes of non-AdvSca1-SM-derived cells, resulting in more contractile SMCs and atheroprotective macrophages. Functionally, overall plaque burden was not altered with Klf4 depletion, but multiple indices of plaque vulnerability were reduced. Collectively, these data support that modulating the AdvSca1-SM population confers increased protection from the development of unstable atherosclerotic plaques.

pathology↗

bioRxiv2022

Distinct selection signatures during domestication and improvement in crops: a tale of two genes in mungbean

Domestication and improvement are two crucial processes underlying the evolution of crops. Domestication transformed wild plants into a utilizable form for humans; improvement refined cultivars adapting to distinct environments and local preferences. Using whole-genome re-sequencing of Vigna radiata, we investigated the demographic history and compared the genetic footprints of domestication and improvement. The Asian wild population migrated to Australia at about 50 kya, and domestication happened in Asia about 9 kya selecting for non-shattering pods. The key candidate gene for this trait, VrMYB26a, has lower expression in cultivars, consistent with the reduced polymorphism in the promoter region reflecting hard selective sweep. The determinate stems were later selected as an improvement phenotype and associated with the gene VrDet1. Two ancient haplotypes reducing gene expression exhibit intermediate frequencies in cultivars, consistent with selection favoring independent haplotypes in soft selective sweep. Our results suggest domestication and improvement may leave different genomic signatures of selection, reflecting the fundamental differences in the two processes and highlighting the limitations of genome-scan methods relying on hard selective sweep.

plant biology↗

bioRxiv2022

The climatic constrains of the historical global spread of mungbean

While the domestication history has been investigated in many crops, the process of cultivation range expansion and factors governing this process received relatively little attention. Here using mungbean (Vigna radiata var. radiata) as a test case, we investigated the genomes of more than one thousand accessions to illustrate climatic adaptations role in dictating the unique routes of cultivation range expansion. Despite the geographical proximity between South and Central Asia, genetic evidence suggests mungbean cultivation first spread from South Asia to Southeast, East, and finally reached Central Asia. Combining evidence from demographic inference, climatic niche modeling, plant morphology, and records from ancient Chinese sources, we showed that the specific route was shaped by the unique combinations of climatic constraints and farmer practices across Asia, which imposed divergent selection favoring higher yield in the south but short-season and more drought-tolerant accessions in the north. Our results suggest that mungbean did not radiate from the domestication center as expected purely under human activity, but instead the spread of mungbean cultivation is highly constrained by climatic adaptation, echoing the idea that human commensals are more difficult to spread through the south-north axis of continents.

evolutionary biology↗

bioRxiv2019

Mapping biology from mouse to man using transfer learning

Biomedical research often involves conducting experiments on model organisms in the anticipation that the biology learnt from these experiments will transfer to the human. Yet, it is commonly the case that biology does not transfer effectively, often for unknown reasons. Despite its importance to translational research this transfer process is not currently rigorously quantified. Here, we show that transfer learning - the branch of machine learning that concerns passing information from one domain to another - can be used to efficiently map biology from mouse to man, using the bone marrow (BM) as a representative example of a complex tissue. We first trained an artificial neural network (ANN) to accurately recognize various different cell types in mouse BM using data obtained from single-cell RNA-sequencing (scRNA-Seq) experiments. We found that this ANN, trained exclusively on mouse data, was able to identify individual human cells obtained from comparable scRNA-Seq experiments of human BM with 83% overall accuracy. However, while some human cell types were easily identified, others were not, indicating important differences in biology. To obtain a more accurate map of the human BM we then retrained the mouse ANN using scRNA-Seq data from a limited sample of human BM cells. Typically, less than 10 human cells of a given type were needed to accurately learn its representation in the updated model. In some cases, human cell identities could be inferred directly from the mouse ANN without retraining, via a process of biologically-guided zero-shot learning. These results show how machine learning can be used to reconstruct complex biology from limited data and have broad implications for biomedical research.

systems biology↗