Organ Remodeling Research Articles

Immunosenescence and Aging: Neuroinflammation Is a Prominent Feature of Alzheimer's Disease and Is a Likely Contributor to Neurodegenerative Disease Pathogenesis.

Alzheimer's disease (AD) is a chronic multifactorial and complex neuro-degenerative disorder characterized by memory impairment and the loss of cognitive ability, which is a problem affecting the elderly. The pathological intracellular accumulation of abnormally phosphorylated Tau proteins, forming neurofibrillary tangles, and extracellular amyloid-beta (Aβ) deposition, forming senile plaques, as well as neural disconnection, neural death and synaptic dysfunction in the brain, are hallmark pathologies that characterize AD. The prevalence of the disease continues to increase globally due to the increase in longevity, quality of life, and medical treatment for chronic diseases that decreases the mortality and enhance the survival of elderly. Medical awareness and the accurate diagnosis of the disease also contribute to the high prevalence observed globally. Unfortunately, no definitive treatment exists that can be used to modify the course of AD, and no available treatment is capable of mitigating the cognitive decline or reversing the pathology of the disease as of yet. A plethora of hypotheses, ranging from the cholinergic theory and dominant Aβ cascade hypothesis to the abnormally excessive phosphorylated Tau protein hypothesis, have been reported. Various explanations for the pathogenesis of AD, such as the abnormal excitation of the glutamate system and mitochondrial dysfunction, have also been suggested. Despite the continuous efforts to deliver significant benefits and an effective treatment for this distressing, globally attested aging illness, multipronged approaches and strategies for ameliorating the disease course based on knowledge of the underpinnings of the pathogenesis of AD are urgently needed. Immunosenescence is an immune deficit process that appears with age (inflammaging process) and encompasses the remodeling of the lymphoid organs, leading to alterations in the immune function and neuroinflammation during advanced aging, which is closely linked to the outgrowth of infections, autoimmune diseases, and malignant cancers. It is well known that long-standing inflammation negatively influences the brain over the course of a lifetime due to the senescence of the immune system. Herein, we aim to trace the role of the immune system in the pathogenesis of AD. Thus, we explore alternative avenues, such as neuroimmune involvement in the pathogenesis of AD. We determine the initial triggers of neuroinflammation, which is an early episode in the pre-symptomatic stages of AD and contributes to the advancement of the disease, and the underlying key mechanisms of brain damage that might aid in the development of therapeutic strategies that can be used to combat this devastating disease. In addition, we aim to outline the ways in which different aspects of the immune system, both in the brain and peripherally, behave and thus to contribute to AD.

E74 knockdown represses larval development and chitin synthesis in Hyphantria cunea

E74 is a key transcription factor induced by 20E, which plays a broad role in many physiological events during insect growth and development, including vitellogenesis, organ remodeling and new tissue formation, programmed cell death and metamorphosis. However, whether it is involved in regulating insect chitin biosynthesis remains largely unclear. Here, the E74 gene was identified for the first time from Hyphantria cunea, a notorious defoliator of forestry. Thereafter, the role of HcE74 in regulating growth, development and chitin synthesis in H. cunea larvae was evaluated. Bioinformatics analysis showed that HcE74 shared the highest identity (95.53%) with E74A of Spodoptera litura, which belonged to Ets superfamily. The results of RNAi bioassay showed that the larval mortality on 6 d after HcE74 knockdown was up to 51.11 ± 6.94%. Meanwhile, a distinct developmental deformity phenotype was found when HcE74 was silenced. These results indicated that HcE74 plays an important role in the development and molting of H. cunea larvae. Moreover, HcE74 knockdown also significantly decreased the expression of four key genes related to chitin synthesis, including glucose-6-phosphate isomerase (HcG6PI), UDP-N-acetylglucosamine pyrophosphorylase (HcUAP), chitin synthetase A (HcCHSA), and chitin synthetase B (HcCHSB). As a result, the content of chitin in midgut and epidermis decreased by 0.54- and 0.08-fold, respectively. Taken together, these results demonstrated that HcE74 not only plays a critical role in the growth and molting of H. cunea larvae, but also probably participates in the transcriptional regulation of genes involved in chitin biosynthesis.

In mouse chronic pancreatitis CD25+FOXP3+ regulatory T cells control pancreatic fibrosis by suppression of the type 2 immune response

Chronic pancreatitis (CP) is characterized by chronic inflammation and the progressive fibrotic replacement of exocrine and endocrine pancreatic tissue. We identify Treg cells as central regulators of the fibroinflammatory reaction by a selective depletion of FOXP3-positive cells in a transgenic mouse model (DEREG-mice) of experimental CP. In Treg-depleted DEREG-mice, the induction of CP results in a significantly increased stroma deposition, the development of exocrine insufficiency and significant weight loss starting from day 14 after disease onset. In CP, FOXP3+CD25+ Treg cells suppress the type-2 immune response by a repression of GATA3+ T helper cells (Th2), GATA3+ innate lymphoid cells type 2 (ILC2) and CD206+ M2-macrophages. A suspected pathomechanism behind the fibrotic tissue replacement may involve an observed dysbalance of Activin A expression in macrophages and of its counter regulator follistatin. Our study identified Treg cells as key regulators of the type-2 immune response and of organ remodeling during CP. The Treg/Th2 axis could be a therapeutic target to prevent fibrosis and preserve functional pancreatic tissue.

743 Hair follicles can “taste”: Stevioside stimulation of the bitter taste receptor, TAS2R4, inhibits human hair growth ex vivo

Besides taste buds, many other tissues express taste receptors (TR), where they exert various, often ill-explored non-gustatory functions, e.g. in immunity and metabolism. These evolutionary ancient functions of human TRs can be optimally interrogated in human skin, whose keratinocytes express selected TRs, and its dominant appendage, the hair follicle (HF). However, the role of TRs in human skin physiology is unknown. Therefore, we have asked whether TRs are expressed in human scalp HFs and if their specific stimulation or silencing affects hair growth. Here, we show that human scalp HF keratinocytes prominently and hair cycle-dependently express the bitter taste receptor, TAS2R4 (mRNA, protein). When TAS2R4 was stimulated in organ-cultured anagen scalp HFs by the sweet-tasting steviol-glycoside TAS2R4 agonist, rebaudioside A (Reb A), this significantly inhibited hair matrix keratinocyte proliferation and induced premature catagen development ex vivo. These RebA effects could be reversed by TAS2R4 knockdown ex vivo. Mechanistically, these HF effects are mainly caused by TAS2R4-mediated enhanced expression/ secretion of the key catagen-promoting growth factor, TGFβ2, since TGFß-neutralization counteracted RebA-induced catagen induction and since RNAseq analysis showed upregulation of TGFß-related signaling pathways. Thus, we introduce here TRs as important, ancestral chemosensory regulators of human skin physiology, human (mini-)organ remodeling (=HF cycling), and growth factor production (TGFß). We also identify a novel, drug-free, “gustatory” strategy for the therapeutic inhibition of unwanted hair growth (hirsutism, hypertrichosis) with a natural sweetener.

The role of circRNAs in the regulation of myocardial angiogenesis in coronary heart disease.

During myocardial ischemia, timely reperfusion is critical to limit infarct area and the overall loss of cardiac contractile function. New treatment strategies need to be developed for patients who are neither able to receive interventional treatment nor suitable for surgical blood transport reconstruction surgery. Therapeutic angiogenesis is a promising approach that can be used to guide new treatment strategies. The goal of these therapies is to form new blood vessels or promote the maturation of existing vasculature systems, bypassing blocked arteries to maintain organ perfusion, thereby relieving symptoms and preventing the remodeling of bad organs. Non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs), have been attracted much attention for their roles in various physiological and pathological processes. There is growing evidence that ncRNAs, especially circRNAs, play an important role in the regulation of cardiomyopathy angiogenesis due to its diversity of functions. Therefore, this article reviews the role and mechanisms of circRNA in myocardial angiogenesis to better understand the role of circRNA in myocardial angiogenesis, which may provide useful insights and new revelations for the research field of identifying diagnostic markers and therapeutic approaches for the treatment of coronary artery disease.

MiR-204-5p in vivo inhibition cause diminished CD45RO cells rate in lungs of melanoma B16-bearing mice.

The treatment of melanoma remains a challenge, despite novel approaches recently becoming available for disseminated tumors. RNA targeting is being intensively studied in various types of disease. The aim of the present study was to explore whether the in vivo use of a microRNA (miR)-204-5p inhibitor affected melanoma progression, and whether its metastasis affects target organ remodeling. CD45RO+, CD3+, CD8+, forkhead box P3+, smooth muscle α-actin+ cells in the lungs of B16 melanoma-bearing mice were evaluated using immunohistochemistry following miR-204-5p inhibitor transfection. Next, CD45RO expression in peripheral blood mononuclear cells (PBMCs), as well as the apoptosis of these cells, were measured by flow cytometry. The results revealed that the number of CD45RO+ cells was decreased in the lungs of B16 melanoma-bearing mice and CD45RO+ PBMCs following the use of an miR-204-5p inhibitor, which was associated with increased levels of PBMC apoptosis. In conclusion, the findings of the present study suggested that targeting miR-204-5p in melanoma metastasis target organs could be used to develop novel approaches for the treatment of disseminated forms of the disease.

Derivation of extra-embryonic and intra-embryonic macrophage lineages from human pluripotent stem cells.

Tissue-resident macrophages are increasingly recognized as important determinants of organ homeostasis, tissue repair, remodeling and regeneration. Although the ontogeny and function of tissue-resident macrophages has been identified as distinct from postnatal hematopoiesis, the inability to specify, in vitro, similar populations that recapitulate these developmental waves has limited our ability to study their function and potential for regenerative applications. We took advantage of the concept that tissue-resident macrophages and monocyte-derived macrophages originate from distinct extra-embryonic and definitive hematopoietic lineages to devise a system to generate pure cultures of macrophages that resemble tissue-resident or monocyte-derived subsets. We demonstrate that human pluripotent stem cell-derived extra-embryonic-like and intra-embryonic-like hematopoietic progenitors differentiate into morphologically, transcriptionally and functionally distinct macrophage populations. Single-cell RNA sequencing of developing and mature cultures uncovered distinct developmental trajectories and gene expression programs of macrophages derived from extra-embryonic-like and intra-embryonic-like hematopoietic progenitors. These findings establish a resource for the generation of human tissue resident-like macrophages to study their specification and function under defined conditions and to explore their potential use in tissue engineering and regenerative medicine applications.

Smad on X is vital for larval-pupal transition in a herbivorous ladybird beetle

Insect development is regulated by a combination of juvenile hormone (JH) and 20-hydroxyecdysone (20E). Production of both JH and 20E is regulated by transforming growth factor-β (TGFβ) signaling. TGFβ can be classified into two branches, the Activin and Bone Morphogenetic Protein (BMP) pathways. In Drosophila melanogaster, BMP signaling is critical for JH synthesis, whereas Activin signal is required to generate the large pulse of 20E necessary for entering metamorphosis. However, to which extent the roles of these signals are conserved remains unknown. Here we studied the role of an Activin component Smad on X (Smox) in post-embryonic development in a defoliating ladybird Henosepilachna vigintioctopunctata. RNA interference (RNAi)-aided knockdown of Hvsmox inhibited larval growth, and impaired larval development. All Hvmyo RNAi larvae arrested at the fourth-instar larval stage. Moreover, knockdown of Hvsmox delayed gut and Malpighian tubules remodeling. Furthermore, the expression of a JH biosynthesis gene (Hvjhamt), a JH receptor gene HvMet and a JH response gene HvKr-h1 was greatly enhanced. Conversely, the expression levels of an ecdysteroidogenesis gene (Hvspo), a 20E receptor gene (HvEcR) and six 20E response genes (HvBrC, HvE74, HvE75, HvE93, HvHR3 and HvHR4) were significantly lowered. Knockdown of HvMet partially restored the negative phenotypes in the Hvsmox RNAi beetles. Our results suggest that Smox exerts regulative roles in JH production, ecdysteroidogenesis and organ remodeling, thus contributing to modulate the larva-pupa-adult transformation in H. vigintioctopunctata.

The Role of Matrix Proteins in Cardiac Pathology.

The extracellular matrix (ECM) and ECM-regulatory proteins mediate structural and cell-cell interactions that are crucial for embryonic cardiac development and postnatal homeostasis, as well as organ remodeling and repair in response to injury. These proteins possess a broad functionality that is regulated by multiple structural domains and dependent on their ability to interact with extracellular substrates and/or cell surface receptors. Several different cell types (cardiomyocytes, fibroblasts, endothelial and inflammatory cells) within the myocardium elaborate ECM proteins, and their role in cardiovascular (patho)physiology has been increasingly recognized. This has stimulated robust research dissecting the ECM protein function in human health and disease and replicating the genetic proof-of-principle. This review summarizes recent developments regarding the contribution of ECM to cardiovascular disease. The clear importance of this heterogeneous group of proteins in attenuating maladaptive repair responses provides an impetus for further investigation into these proteins as potential pharmacological targets in cardiac diseases and beyond.

The effect of coal-derived humic substances and their silver-containing bionanocomposites on arginine balance in peritoneal macrophages of intact mice

Background. Antigen-presenting cells (APCs), especially macrophages, play an important role in the body defense against various pathogens. Their dysfunction and polarization are associated with most inflammatory and autoimmune diseases. The inflammatory process is regulated by activation and / or inhibition of genes differentially expressed by macrophages. Successful correction of inflammation leads firstly to elimination of inflammatory stimuli and then to remodeling and restoration of tissues and organs. It was experimentally confirmed that silvercontaining bionanocomposites based on natural humic substances (HS) obtained from coal of different origin, as well as initial matrices of these HS, are capable of activating pro- and anti-inflammatory properties of macrophages.Aim. To study cytotoxic, pyrogenic, and immunomodulatory properties (arginine balance) of initial HS samples and samples of silver nanoparticles ultradispersed in these HS matrices (HS-AgNPs) in the cell culture of peritoneal macrophages, as well as their effect on pro- and anti-inflammatory properties of APCs.Materials and methods. Cultural and biochemical methods were used in the study.Results. The study showed that the samples CHE-K, CHE-AgNPs, CHS-K, and CHP-K increased M1 macrophage polarization due to stimulation of the NO-synthase activity and inhibition of arginase. The samples CHI-K, CHIAgNPs, CHP-AgNPs, and CHS-AgNPs modulated an alternative M2 or M2-like state of macrophage activation. At the same time, HS are not cytotoxic at effective concentrations, and three out of four studied samples did not contain pyrogenic impurities.Conclusion. The use of HS and their silver-containing bionanocomposites, which have the ability to greatly affect the polarization of antigen-presenting cells, is a promising research area in correction of the inflammatory response for solving an important social and medical problem of treating chronic wounds.

Stress-induced premature senescence is associated with a prolonged QT interval and recapitulates features of cardiac aging.

Rationale: Aging in the heart is a gradual process, involving continuous changes in cardiovascular cells, including cardiomyocytes (CMs), namely cellular senescence. These changes finally lead to adverse organ remodeling and resulting in heart failure. This study exploits CMs from human induced pluripotent stem cells (iCMs) as a tool to model and characterize mechanisms involved in aging.Methods and Results: Human somatic cells were reprogrammed into human induced pluripotent stem cells and subsequently differentiated in iCMs. A senescent-like phenotype (SenCMs) was induced by short exposure (3 hours) to doxorubicin (Dox) at the sub-lethal concentration of 0.2 µM. Dox treatment induced expression of cyclin-dependent kinase inhibitors p21 and p16, and increased positivity to senescence-associated beta-galactosidase when compared to untreated iCMs. SenCMs showed increased oxidative stress, alteration in mitochondrial morphology and depolarized mitochondrial membrane potential, which resulted in decreased ATP production. Functionally, when compared to iCMs, SenCMs showed, prolonged multicellular QTc and single cell APD, with increased APD variability and delayed afterdepolarizations (DADs) incidence, two well-known arrhythmogenic indexes. These effects were largely ascribable to augmented late sodium current (INaL) and reduced delayed rectifier potassium current (Ikr). Moreover sarcoplasmic reticulum (SR) Ca2+ content was reduced because of downregulated SERCA2 and increased RyR2-mediated Ca2+ leak. Electrical and intracellular Ca2+ alterations were mostly justified by increased CaMKII activity in SenCMs. Finally, SenCMs phenotype was furtherly confirmed by analyzing physiological aging in CMs isolated from old mice in comparison to young ones.Conclusions: Overall, we showed that SenCMs recapitulate the phenotype of aged primary CMs in terms of senescence markers, electrical and Ca2+ handling properties and metabolic features. Thus, Dox-induced SenCMs can be considered a novel in vitro platform to study aging mechanisms and to envision cardiac specific anti-aging approach in humans.

Magnetic Resonance Imaging Evaluation of Hemangioma Resection for Encephalofacial Angiomatosis (Sturge-Weber Syndrome) in Children under Intelligent Algorithm.

This study was aimed to evaluate the clinical efficacy of hemangioma resection in the treatment of infantile encephalofacial angiomatosis (Sturge–Weber syndrome, SWS) through magnetic resonance imaging (MRI) images, and intelligent algorithms were employed to process MRI images. A retrospective study of 45 children diagnosed with facial hemangioma admitted to hospital was conducted. Then, MRS images were acquired, and a mathematical model for MRI image denoising and reconstruction was constructed based on nonlocal similar block low-rank prior algorithms. The processing effect was assessed regarding the peak signal-to-noise ratio (PSNR) and structural similarity (SSIM). Finally, MRI images were collected to analyze the difference between the metabolites of N-acetylaspartic acid (NAA), creatine (Cr), choline (Cho), and their ratios in the lesions of the children before and after treatment. The improvement rate was analyzed through a twelve-month follow-up. The algorithm test results showed that compared with the classic K-singular value decomposition (K-SVD) denoising algorithm and the Sparse MRI reconstruction algorithm, the proposed algorithm processed MRI images more clearly and had more detailed information. The quantitative results showed that the PSNR and SSIM in the image processed by the algorithm proposed were remarkably large. The clinical treatment results showed that compared with those before treatment, the nCho level after treatment, the ratio of Cho/Cr and Cho/NAA were remarkably reduced, and the difference was remarkable (P < 0.05). The follow-up results showed that the considerable improvement rate was 88.89%, the postoperative organ remodeling rate was 17.78%, and the probability of reoperation was only 6.67%. In summary, the introduction of intelligent algorithms for denoising and reconstruction of MRI images can remarkably improve image quality and help doctors use image information to diagnose diseases and evaluate treatment effects. The hemangioma resection for the treatment of pediatric SWS had a high treatment improvement rate and was worthy of clinical adoption.

Влияние преждевременного рождения на васкуляризацию миокарда левого желудочка крыс в постнатальном периоде онтогенеза

Introduction. Preterm birth disrupts important processes of fetal growth and development and can serve as a trigger for maladaptive organ remodeling in the postnatal ontogenesis. The aim of the study was to evaluate the effect of preterm birth on the angiogenesis of the left ventricular myocardium of rats from days 1 to 21 of the postnatal ontogenesis. Materials and methods. We performed immunohistochemical (CD31) and morphometric (specific volume of blood capillaries, specific volume of cardiomyocytes, diameter of blood capillaries, trophic index and pericapillary diffusion zone) study of the left ventricular myocardium of full-term and prematurely born (12 and 24 hours preterm) Wistar rats (n=88) of both sexes on days 1, 7, 14, and 21 of the postnatal ontogenesis. Results. The birth of rats 12 and 24 hours preterm does not result in change in the specific volume of blood capillaries and the trophic index in the left ventricular myocardium on days 1, 7, 14, and 21 of the postnatal period. Preterm birth leads to a decrease in the specific volume of cardiomyocytes of the left ventricular myocardium of rats, compared to the parameters of animals in the control group, on days 7–21 of the postnatal period. Preterm birth results in a decrease in the diameter of the blood capillaries of the left ventricular myocardium in female rats on day 21 of the postnatal period. Preterm birth (24 hours preterm) is accompanied by an increase in the size of the zone of pericapillary diffusion in the left ventricular myocardium of rats on day 14 of the postnatal ontogenesis, in comparison with that of animals in the control group. Conclusion. The shorter the duration of the intrauterine period of development of rats, the greater the severity of the observed changes in the left ventricular myocardium are. It seems promising to study the functional state of endotheliocytes of myocardial blood vessels in preterm animals in the postnatal period. Keywords: preterm birth, prematurity, myocardium, angiogenesis, vascular indexes

Regulation of Mating-Induced Increase in Female Germline Stem Cells in the Fruit Fly Drosophila melanogaster

In many insect species, mating stimuli can lead to changes in various behavioral and physiological responses, including feeding, mating refusal, egg-laying behavior, energy demand, and organ remodeling, which are collectively known as the post-mating response. Recently, an increase in germline stem cells (GSCs) has been identified as a new post-mating response in both males and females of the fruit fly, Drosophila melanogaster. We have extensively studied mating-induced increase in female GSCs of D. melanogaster at the molecular, cellular, and systemic levels. After mating, the male seminal fluid peptide [e.g. sex peptide (SP)] is transferred to the female uterus. This is followed by binding to the sex peptide receptor (SPR), which evokes post-mating responses, including increase in number of female GSCs. Downstream of SP-SPR signaling, the following three hormones and neurotransmitters have been found to act on female GSC niche cells to regulate mating-induced increase in female GSCs: (1) neuropeptide F, a peptide hormone produced in enteroendocrine cells; (2) octopamine, a monoaminergic neurotransmitter synthesized in ovary-projecting neurons; and (3) ecdysone, a steroid hormone produced in ovarian follicular cells. These humoral factors are secreted from each organ and are received by ovarian somatic cells and regulate the strength of niche signaling in female GSCs. This review provides an overview of the latest findings on the inter-organ relationship to regulate mating-induced female GSC increase in D. melanogaster as a model. We also discuss the remaining issues that should be addressed in the future.

Organ remodeling: The molecular choreography of a dance of destruction

A new study reveals that the Drosophila tracheal system is disassembled during pupation via ecdysone-dependent remodeling of the extracellular matrix, which then signals through the Hippo-Yorkie/YAP network to induce apoptosis.

Decellularization for the Preparation of Highly Preserved Human Acellular Skin Matrix for Regenerative Medicine.

Extracellular matrix (ECM) provides biophysical and biochemical stimuli to support self-renewal, proliferation, survival, and differentiation of surrounding cells due to its content of diverse bioactive molecules. Due to these characteristics, the ECM has been recently considered a promising candidate for the creation of biological scaffolds to boost tissue regeneration. Emerging studies have demonstrated that decellularized human tissues could resemble the native ECM in their structural and biochemical profiles, preserving the three-dimensional (3D) architecture and the content of fundamental biological molecules. Hence, decellularized ECM can be employed to promote tissue remodeling, repair, and functional reconstruction of many organs. Selecting the appropriate decellularization procedure is crucial to obtain acellular tissues that retain the characteristics of the ideal microenvironment for cells. The protocol described here provides a detailed step-by-step description of the decellularization method to obtain a reproducible and effective cell-free biological ECM. Skin fragments from patients undergoing plastic surgery were scaled down and decellularized using a combination of sodium dodecylsulfate (SDS), Triton X-100, and antibiotics. To promote the regular and homogeneous transport of the solution through the samples, they were enclosed in embedding cassettes to ensure protection from mechanical insults. After the decellularization procedure, the snow-white color of skin fragments indicated complete and successful decellularization. Additionally, decellularized samples showed an intact and well-preserved architecture. The results suggest that the proposed decellularization method was effective, fast, and reproducible and protected samples from architectural damages.

RAAV9\u2010mediated supplementation of miR-29b improve angiotensin-II induced renal fibrosis in mice

BackgroundRenin–angiotensin–aldosterone system activation is the critical factor in renal remodeling and dysfunction. Our previous study suggested that miR-29b may attenuate AngII-induced renal intestinal fibrosis in vitro. In the present study, we aimed to determine whether recombinant rAAV9-mediated miR-29b delivery protects against AngII-induced renal fibrosis and dysfunction.MethodMice were treated with AngII via osmotic mini-pumps, or phosphate-buffered saline. rAAV9 vectors were produced using the rBac-based system in SF9 cells. rAAV9-miR-29b or rAAV9-control-miR was injected into the kidneys of mice subjected to the model of AngII infusion. The role of miR-29b in renal fibrosis was assessed using quantitative polymerase chain reaction, western blot, and histology.ResultsIn AngII-induced fibrotic kidney tissue, miR-29b expression was downregulated. rAAV9-miR-29b delivery significantly reversed renal injury as indicated by decreased serum creatinine and injury related gene expression in AngII-infused mice. Regarding organ remodeling, tubulointerstitial fibrosis and deposition of extracellular matrix components such as collagen type I and type III were significantly decreased in renal tissue from mice delivered rAAV9-miR-29b.ConclusionOur results demonstrate great potential for use of rAAV9 as an applicable vector for delivery of miR-29b as an antifibrogenic factor for treatment of tubulointerstitial fibrosis-induced renal injury.

Metformin and Fibrosis: A Review of Existing Evidence and Mechanisms

Fibrosis is a physiological response to organ injury and is characterized by the excessive deposition of connective tissue components in an organ, which results in the disruption of physiological architecture and organ remodeling, ultimately leading to organ failure and death. Fibrosis in the lung, kidney, and liver accounts for a substantial proportion of the global burden of disability and mortality. To date, there are no effective therapeutic strategies for controlling fibrosis. A class of metabolically targeted chemicals, such as adenosine monophosphate-activated protein kinase (AMPK) activators and peroxisome proliferator-activated receptor (PPAR) agonists, shows strong potential in fighting fibrosis. Metformin, which is a potent AMPK activator and is the only recommended first-line drug for the treatment of type 2 diabetes, has emerged as a promising method of fibrosis reduction or reversion. In this review, we first summarize the key experimental and clinical studies that have specifically investigated the effects of metformin on organ fibrosis. Then, we discuss the mechanisms involved in mediating the antifibrotic effects of metformin in depth.

Prenatal Development and Function of Human Mononuclear Phagocytes.

The human mononuclear phagocyte (MP) system, which includes dendritic cells, monocytes, and macrophages, is a critical regulator of innate and adaptive immune responses. During embryonic development, MPs derive sequentially in yolk sac progenitors, fetal liver, and bone marrow haematopoietic stem cells. MPs maintain tissue homeostasis and confer protective immunity in post-natal life. Recent evidence – primarily in animal models – highlight their critical role in coordinating the remodeling, maturation, and repair of target organs during embryonic and fetal development. However, the molecular regulation governing chemotaxis, homeostasis, and functional diversification of resident MP cells in their respective organ systems during development remains elusive. In this review, we summarize the current understanding of the development and functional contribution of tissue MPs during human organ development and morphogenesis and its relevance to regenerative medicine. We outline how single-cell multi-omic approaches and next-generation ex-vivo organ-on-chip models provide new experimental platforms to study the role of human MPs during development and disease.

A Metabolic Reprogramming of Glycolysis and Glutamine Metabolism Is a Requisite for Renal Fibrogenesis-Why and How?

Chronic Kidney Disease (CKD) is characterized by organ remodeling and fibrosis due to failed wound repair after on-going or severe injury. Key to this process is the continued activation and presence of matrix-producing renal fibroblasts. In cancer, metabolic alterations help cells to acquire and maintain a malignant phenotype. More recent evidence suggests that something similar occurs in the fibroblast during activation. To support these functions, pro-fibrotic signals released in response to injury induce metabolic reprograming to meet the high bioenergetic and biosynthetic demands of the (myo)fibroblastic phenotype. Fibrogenic signals such as TGF-β1 trigger a rewiring of cellular metabolism with a shift toward glycolysis, uncoupling from mitochondrial oxidative phosphorylation, and enhanced glutamine metabolism. These adaptations may also have more widespread implications with redirection of acetyl-CoA directly linking changes in cellular metabolism and regulatory protein acetylation. Evidence also suggests that injury primes cells to these metabolic responses. In this review we discuss the key metabolic events that have led to a reappraisal of the regulation of fibroblast differentiation and function in CKD.