Biology subjects

Steinhauser, M. L.

Publications and source records attributed to Steinhauser, M. L..

4 recordsLinked to original sources

bioRxiv2024

Lactate transport inhibition therapeutically reprograms fibroblast metabolism in experimental pulmonary fibrosis

Myofibroblast differentiation, essential for driving extracellular matrix synthesis in pulmonary fibrosis, requires increased glycolysis. While glycolytic cells must export lactate, the contributions of lactate transporters to myofibroblast differentiation are unknown. In this study, we investigated how MCT1 and MCT4, key lactate transporters, influence myofibroblast differentiation and experimental pulmonary fibrosis. Our findings reveal that inhibiting MCT1 or MCT4 reduces TGF{beta}-stimulated pulmonary myofibroblast differentiation in vitro and decreases bleomycin-induced pulmonary fibrosis in vivo. Through comprehensive metabolic analyses, including bioenergetics, stable isotope tracing, metabolomics, and imaging mass spectrometry in both cells and mice, we demonstrate that inhibiting lactate transport enhances oxidative phosphorylation, reduces reactive oxygen species production, and diminishes glucose metabolite incorporation into fibrotic lung regions. Furthermore, we introduce VB253, a novel MCT4 inhibitor, which ameliorates pulmonary fibrosis in both young and aged mice, with comparable efficacy to established antifibrotic therapies. These results underscore the necessity of lactate transport for myofibroblast differentiation, identify MCT1 and MCT4 as promising pharmacologic targets in pulmonary fibrosis, and support further evaluation of lactate transport inhibitors for patients for whom limited therapeutic options currently exist. SUMMARYSmall molecule inhibitors of lactate transporters, including the novel MCT4 inhibitor VB253, reprogram fibroblast metabolism to prevent myofibroblast differentiation and decrease bleomycin-induced pulmonary fibrosis.

cell biology↗

bioRxiv2023

Evidence for conservation of a primordial 12-hour ultradian gene program in humans

While circadian rhythms are entrained to the once daily light-dark cycle of the sun, many marine organisms exhibit [~]12h ultradian rhythms corresponding to the twice daily movement of the tides. Although human ancestors emerged from circatidal environment millions of years ago, direct evidence of [~]12h ultradian rhythms in humans is lacking. Here, we performed prospective, temporal transcriptome profiling of peripheral white blood cells and identified robust [~]12h transcriptional rhythms from three healthy participants. Pathway analysis implicated [~]12h rhythms in RNA and protein metabolism, with strong homology to the circatidal gene programs previously identified in Cnidarian marine species. We further observed [~]12h rhythms of intron retention events of genes involved in MHC class I antigen presentation, synchronized to expression of mRNA splicing genes in all three participants. Gene regulatory network inference revealed XBP1, and GABP and KLF transcription factor family members as potential transcriptional regulators of human [~]12h rhythms. These results suggest that human [~]12h biological rhythms have a primordial evolutionary origin with important implications for human health and disease.

systems biology↗

bioRxiv2019

Control of cytokinesis by β-adrenergic receptors indicates an approach for regulating cardiomyocyte endowment

ABSTRACT/SUMMARYOne million patients with congenital heart disease (CHD) live in the US. They have a lifelong risk of developing heart failure. Current concepts do not sufficiently address mechanisms of heart failure development specifically for these patients. We show that cardiomyocyte cytokinesis failure is increased in tetralogy of Fallot with pulmonary stenosis (ToF/PS), a common form of CHD. Labeling of a ToF/PS baby with isotope-tagged thymidine showed cytokinesis failure after birth. We used single-cell transcriptional profiling to discover that the underlying mechanism is repression of the cytokinesis gene ECT2, and show that this is downstream of {beta}-adrenergic receptors ({beta}-AR). Inactivation of the {beta}-AR genes and administration of the {beta}-blocker propranolol increased cardiomyocyte division in neonatal mice, which increased the endowment and conferred benefit after myocardial infarction in adults. Propranolol enabled the division of ToF/PS cardiomyocytes. These results suggest that {beta}-blockers should be evaluated for increasing cardiomyocyte division in patients with ToF/PS and other types of CHD.

cell biology↗

bioRxiv2019

Transduction of gluconeogenic enzymes prolongs cone photoreceptor survival and function in models of retinitis pigmentosa

The hereditary nature of many retinal degenerative disorders makes them potentially amenable to corrective gene therapies. Numerous clinical trials are ongoing with the goal to rectify the genetic defect in the afflicted cell types. However, the personalized nature of these approaches excludes many patients for whom the underlying mutation is not mapped, or the number of affected individuals is too few to develop a commercially viable therapy (vide infra). Thus, a therapy that can delay visual impairment irrespective of the underlying genetic etiology can satisfy this unmet medical need. Here, we demonstrate the utility of such an approach in retinitis pigmentosa (RP) by promoting survival of cone photoreceptors by targeting metabolic stress. These cells are not primarily affected by the inherited mutation, but their non-autonomous demise leads to a decline in daylight vision, greatly reducing the quality of life. We designed adeno-associated virus (AAV) vectors that promote gluconeogenesis- a pathway found in the liver which produces glucose in response to hypoglycemia. Retinal transduction with these vectors resulted in improved cone survival and delayed a decline in visual acuity in three different RP mouse models. Because this approach extended visual function independent of the primary mutation, therapies emanating from this approach could be used as a treatment option for a genetically heterogenous cohort of patients.

neuroscience↗