Parabiosis and single-cell RNA sequencing reveal a limited contribution of monocytes to myofibroblasts in kidney fibrosis

Fibrosis is the common final pathway of virtually all chronic injury to the kidney. While it is well accepted that myofibroblasts are the scar-producing cells in the kidney, their cellular origin is still hotly debated. The relative contribution of proximal tubular epithelium and circulating cells, including mesenchymal stem cells, macrophages, and fibrocytes, to the myofibroblast pool remains highly controversial. Using inducible genetic fate tracing of proximal tubular epithelium, we confirm that the proximal tubule does not contribute to the myofibroblast pool. However, in parabiosis models in which one parabiont is genetically labeled and the other is unlabeled and undergoes kidney fibrosis, we demonstrate that a small fraction of genetically labeled renal myofibroblasts derive from the circulation. Single-cell RNA sequencing confirms this finding but indicates that these cells are circulating monocytes, express few extracellular matrix or other myofibroblast genes, and express many proinflammatory cytokines. We conclude that this small circulating myofibroblast progenitor population contributes to renal fibrosis by paracrine rather than direct mechanisms

Understanding deregulated cellular and molecular dynamics in the haematopoietic stem cell niche to develop novel therapeutics for bone marrow fibrosis

Bone marrow fibrosis is the continuous replacement of blood-forming cells in the bone marrow with excessive scar tissue, leading to failure of the body to produce blood cells and ultimately to death. Myofibroblasts are fibrosis-driving cells and are well characterized in solid organ fibrosis, but their role and cellular origin in bone marrow fibrosis have remained obscure. Recent work has demonstrated that Gli1+ and leptin receptor+ mesenchymal stromal cells are progenitors of fibrosis-causing myofibroblasts in the bone marrow. Genetic ablation or pharmacological inhibition of Gli1+ mesenchymal stromal cells ameliorated fibrosis in mouse models of myelofibrosis. Conditional deletion of the platelet-derived growth factor (PDGF) receptor-α (PDGFRA) gene (Pdgfra) and inhibition of PDGFRA by imatinib in leptin receptor+ stromal cells suppressed their expansion and ameliorated bone marrow fibrosis. Understanding the cellular and molecular mechanisms in the haematopoietic stem cell niche that govern the mesenchymal stromal cell-to-myofibroblast transition and myofibroblast expansion will be critical to understand the pathogenesis of bone marrow fibrosis in both malignant and non-malignant conditions, and will guide the development of novel therapeutics. In this review, we summarize recent discoveries of mesenchymal stromal cells as part of the haematopoietic niche and as myofibroblast precursors, and discuss potential therapeutic strategies in the specific targeting of fibrotic transformation in bone marrow fibrosis

Untangling cellular and molecular mechanisms of fibrotic disease

Tissue fibrosis, or scar formation, is the common final pathway of virtually all chronic diseases and affects nearly every organ, including kidney, heart, lung, bone marrow and liver, among others. Myofibroblasts are the cells that cause fibrosis but their cellular origin has been controversial and their mechanism of activation has been unclear. We have identified Gli1+ cells as a major source of fibrosis driving myofibroblasts and demonstrated that GLi2 protein is a major driver of their expansion. Genetic ablation of these cells ameliorates fibrosis and rescues organ function. Pharmacologic inhibition of Gli proteins halts myofibroblast cell-cycle progression and ameliorates fibrosis. In conclusion our data indicates that Gli1+ perivascular cells are a promising therapeutic target in fibrosis

Petrophysical zoning elements of Chertovo Koryto gold-ore deposit (Patom Upland, Eastern Siberia)

The paper considers magnetic susceptibility (chi) and electrode potentials (EP) of rocks in the Chertovo Koryto deposit. Carbon-bearing substance is found in all the studied samples, but in some cases, this substance supplies EP (-150 ± -400 mV). In these samples [chi] rarely exceeds 40·10{-5} SI units, while, in other samples [chi] is 8-10 (up to 30) times higher. Less intensive EP (-20 ± -240 mV) is furnished due to the sulfides in this deposit. Rocks with polarized carbon-bearing substance do not contain magnetic pyrrhotine and are negative linear EP anomalies. Rocks in which carbon-bearing substance is associated with pyrrhotine are revealed as magnetic anomalies. The adjacent rocks determine petrophysical zoning of the Chertovo Koryto deposit. The combination of negative linear EP anomalies and magnetic anomalies is a potential indicator and can define the multi-stage formation of the deposit itself

Tempo-Express, a CBR Approach to Musical Tempo Transformations

The original publication is available at www.springerlink.comIn this paper, we describe a CBR system for applying musically acceptable tempo transformations to monophonic audio recordings of musical performances. Within the tempo transformation process, the expressivity of the performance is adjusted in such a way that the result sounds natural for the new tempo. A case base of previously performed melodies is used to infer the appropriate expressivity. Tempo transformation is one of the audio post-processing tasks manually done in audiolabs. Automatizing this process may, therefore, be of industrial interest.This research has been partially supported by the Spanish Ministry of Science and Technology under the project TIC 2003-07776-C2-02 "CBR-ProMusic: Content-based Music Processing using CBR" and EU-FEDER funds.Peer reviewe

Cardiac remodeling in chronic kidney disease

Cardiac remodeling occurs frequently in chronic kidney disease patients and affects quality of life and survival. Current treatment options are highly inadequate. As kidney function declines, numerous metabolic pathways are disturbed. Kidney and heart functions are highly connected by organ crosstalk. Among others, altered volume and pressure status, ischemia, accelerated atherosclerosis and arteriosclerosis, disturbed mineral metabolism, renal anemia, activation of the renin-angiotensin system, uremic toxins, oxidative stress and upregulation of cytokines stress the sensitive interplay between different cardiac cell types. The fatal consequences are left-ventricular hypertrophy, fibrosis and capillary rarefaction, which lead to systolic and/or diastolic left-ventricular failure. Furthermore, fibrosis triggers electric instability and sudden cardiac death. This review focuses on established and potential pathophysiological cardiorenal crosstalk mechanisms that drive uremia-induced senescence and disease progression, including potential known targets and animal models that might help us to better understand the disease and to identify novel therapeutics

Role of Genetic Haploinsufficiency in the Biology and Targeted Therapy of Del(5q) Myelodysplastic Syndrome

The studies presented in this thesis focused on the identification of genes that play a central role in the pathogenesis of myelodysplastic syndromes with a deletion of the short arm (q) of chromosome 5, the del(5q) MDS. The overall goal of the projects was to gain a better understanding of how gene haploinsufficiency in (del)5q MDS leads to a clonal advantage, ineffective hematopoiesis and how haploinsufficiency can be targeted. Heterozygous deletion of RPS14 occurs in del(5q) myelodysplastic syndrome (MDS) and has been linked to impaired erythropoiesis, characteristic of this disease subtype. So far, it was not well understood how ribosomal haploinsufficiency affects protein synthesis and if differentially translated proteins have a impact on the erythroid differentiation defect (chapter 1). We generated a murine model with conditional inactivation of Rps14 and demonstrated a p53-dependent erythroid differentiation defect with apoptosis at the transition from polychromatic to orthochromatic erythroblasts resulting in age- and erythroid stress dependent progressive anemia, megakaryocyte dysplasia, and loss of hematopoietic stem cell (HSC) quiescence (chapter 2). Protein synthesis was significantly reduced in Rps14 haploinsufficient hematopoietic stem cells and in particular in erythroid progenitor cells relative to wild-type cells. As assessed by quantitative proteomics, Rps14 haploinsufficient erythroblasts expressed higher levels of proteins involved in innate immune signaling, notably the heterodimeric S100 calcium-binding proteins S100a8 and S100a9 (alarmins). S100a8 is functionally involved in the erythroid defect caused by the Rps14 deletion, as addition of recombinant S100a8 was sufficient to induce an erythroid differentiation defect in wild-type erythroid cells (phenocopy), and genetic inactivation of S100a8 expression rescued the erythroid differentiation defect of Rps14-haploIn the current study it was our goal to focus on important design criteria including (1) the opportunity for reproducible and user-defined properties such as the choice of substrate, extracellular matrix, cell types, and degradability; (2) the ability to induce vascularisation; (3) accessibility and suitability for complementary histological/cytological analysis; and, most importantly, (4) the functional ability to capture and retrieve endogenous hematopoietic cells efficiently