Ordono, J. | Search bioRxiv

bioRxiv2022

Yersinia pestis genomes reveal plague in Britain 4,000 years ago

Extinct lineages of Yersinia pestis, the causative agent of the plague, have been identified in several individuals from Central Europe and Asia between 5,000 and 3,500 years before present (BP). One of these, the LNBA lineage (Late Neolithic and Bronze Age), has been suggested to have spread into Central Europe with human groups expanding from the Eurasian steppes. Here, we show that LNBA plague was spread to Europes northwestern periphery by sequencing Yersinia pestis genomes from two individuals dating to ~4,000 cal BP from an unusual mass burial context in Somerset, England, UK. This represents the earliest evidence of plague in Britain documented to date. These British Yersinia pestis genomes belong to a sublineage previously observed in two Bronze Age individuals from Central Europe that had lost the putative virulence factor yapC. This sublineage is later found in Central Asia ~3,600 BP. While the severity of disease is currently unclear, the wide geographic distribution within a few centuries suggests substantial transmissibility.

evolutionary biology↗

bioRxiv2020

Lactate promotes cardiomyocyte dedifferentiation through metabolic reprogramming

Cardiomyocytes undergo different metabolic changes during development and differentiation crucial for their maturation and adult function, such as contraction, growth and survival. Alterations of cardiac metabolism have been associated with multiple disease states and pathological hypertrophy. The shift in substrate preference can impair the stress response, but it may also have a role in cell growth and survival. Here, we evaluated the response of cardiomyocytes to the presence of exogenous lactate, an important metabolite for the fetal heart and cardiogenesis. Lactate-exposed mouse primary cardiomyocytes and human iPSC-derived cardiomyocytes quickly acquired a characteristic dedifferentiated phenotype, with enhanced proliferative capacity as determined by an increased expression of cell cycle (Ki67) and cytokinesis (Aurora-B) effectors. This effect was specific to cardiomyocytes and did not affect other heart cell populations (e.g. cardiac fibroblasts). Nevertheless, cardiac fibroblasts exposed to lactate promoted a pro-regenerative environment through the modulation of the release of cytokines (such as Fas, IL-13 or SDF1a). We characterized lactate-induced cardiomyocyte dedifferentiation through RNA-sequencing and gene expression analysis and identified increased expression of BMP10 (a TGF{beta} family protein involved in embryonic cardiomyocyte proliferation and stemness) and proteins associated to cell fate regulation (LIN28, TCIM) together with downregulation of cardiac maturation genes (GRIK1, DGKK). Bottom-up analysis suggested the phenotype promoted by lactate could be related to the activation of hypoxia signaling pathways. This finding indicated that, indeed, lactate may be a key player of hypoxic regenerative responses in the heart, as it usually accumulates as a result of glycolysis. In addition, ex vivo neonatal heart culture showed prolonged beating function and cardiac tissue integrity when culture media was supplemented with lactate. Thus, we conclude that lactate enhances cardiac proliferation by reprogramming cardiomyocytes towards a dedifferentiated stem cell-like state, supporting the notion that modulation of the metabolic microenvironment might be a powerful novel approach for promoting cardiac regeneration and tissue engineering applications.

bioengineering↗