Tissue Renewal Research Articles

Activation of innate immunity during development induces unresolved dysbiotic inflammatory gut and shortens lifespan.

ABSTRACTAn early-life inflammatory response is associated with risks of age-related pathologies. How transient immune signalling activity during animal development influences life-long fitness is not well understood. Using Drosophila as a model, we find that activation of innate immune pathway Immune deficiency (Imd) signalling in the developing larvae increases adult starvation resistance, decreases food intake and shortens organismal lifespan. Interestingly, lifespan is shortened by Imd activation in the larval gut and fat body, whereas starvation resistance and food intake are altered by that in neurons. The adult flies that developed with Imd activation show sustained Imd activity in the gut, despite complete tissue renewal during metamorphosis. The larval Imd activation increases an immunostimulative bacterial species, Gluconobacter sp., in the gut microbiome, and this dysbiosis is persistent to adulthood. Removal of gut microbiota by antibiotics in the adult fly mitigates intestinal immune activation and rescues the shortened lifespan. This study demonstrates that early-life immune activation triggers long-term physiological changes, highlighted as an irreversible alteration in gut microbiota, prolonged inflammatory intestine and concomitant shortening of the organismal lifespan.

Roles of mitochondrial unfolded protein response in mammalian stem cells.

The mitochondrial unfolded protein response (UPRmt) is an evolutionarily conserved adaptive mechanism for improving cell survival under mitochondrial stress. Under physiological and pathological conditions, the UPRmt is the key to maintaining intracellular homeostasis and proteostasis. Important roles of the UPRmt have been demonstrated in a variety of cell types and in cell development, metabolism, and immune processes. UPRmt dysfunction leads to a variety of pathologies, including cancer, inflammation, neurodegenerative disease, metabolic disease, and immune disease. Stem cells have a special ability to self-renew and differentiate into a variety of somatic cells and have been shown to exist in a variety of tissues. These cells are involved in development, tissue renewal, and some disease processes. Although the roles and regulatory mechanisms of the UPRmt in somatic cells have been widely reported, the roles of the UPRmt in stem cells are not fully understood. The roles and functions of the UPRmt depend on stem cell type. Therefore, this paper summarizes the potential significance of the UPRmt in embryonic stem cells, tissue stem cells, tumor stem cells, and induced pluripotent stem cells. The purpose of this review is to provide new insights into stem cell differentiation and tumor pathogenesis.

A Scarless Healing Tale: Comparing Homeostasis and Wound Healing of Oral Mucosa With Skin and Oesophagus.

Epithelial tissues are the most rapidly dividing tissues in the body, holding a natural ability for renewal and regeneration. This ability is crucial for survival as epithelia are essential to provide the ultimate barrier against the external environment, protecting the underlying tissues. Tissue stem and progenitor cells are responsible for self-renewal and repair during homeostasis and following injury. Upon wounding, epithelial tissues undergo different phases of haemostasis, inflammation, proliferation and remodelling, often resulting in fibrosis and scarring. In this review, we explore the phenotypic differences between the skin, the oesophagus and the oral mucosa. We discuss the plasticity of these epithelial stem cells and contribution of different fibroblast subpopulations for tissue regeneration and wound healing. While these epithelial tissues share global mechanisms of stem cell behaviour for tissue renewal and regeneration, the oral mucosa is known for its outstanding healing potential with minimal scarring. We aim to provide an updated review of recent studies that combined cell therapy with bioengineering exporting the unique scarless properties of the oral mucosa to improve skin and oesophageal wound healing and to reduce fibrotic tissue formation. These advances open new avenues toward the ultimate goal of achieving scarless wound healing.

Forage productivity and chemical composition of Panicum maximum cv. Mombaça under defoliations intensities and frequencies

The effects of defoliation frequency (28, 35, 42 and 49 days) and defoliation intensity (30, 40 and 50 cm above the ground) on green dry matter (GDM) yield, and chemical composition of Panicum maximum cv. Mombaça were evaluated under natural field conditions at the Roraima´s savannas. Defoliation regimes affect productivity and chemical composition of grass forage. The decrease in the pasture defoliation frequency and intensity improved the accumulation of forage, however it reduces the tissue concentrations of N, P, Ca, Mg and K. Irrespective of defoliation frequencies, the highest levels of N (23.99 g kg-1), P (2.12 g kg-1), Ca (4.22 g kg-1), Mg (2.87 g kg-1) and K (21.45 g kg-1) were recorded for the defoliation intensity at 40 cm above the ground. The use of defoliation frequency around 42 days and defoliation intensity of 42,9 cm above the ground can be considered adequate for the management of pastures of P. maximum cv. Mombaça, in order to provides higher forage productivity and quality, regrowth vigor, larger efficiency of forage utilization, greater tissue renewal and canopy structure more favorable to grazing.

An isoform of Dicer protects mammalian stem cells against multiple RNA viruses.

In mammals, early resistance to viruses relies on interferons, which protect differentiated cells but not stem cells from viral replication. Many other organisms rely instead on RNA interference (RNAi) mediated by a specialized Dicer protein that cleaves viral double-stranded RNA. Whether RNAi also contributes to mammalian antiviral immunity remains controversial. We identified an isoform of Dicer, named antiviral Dicer (aviD), that protects tissue stem cells from RNA viruses-including Zika virus and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-by dicing viral double-stranded RNA to orchestrate antiviral RNAi. Our work sheds light on the molecular regulation of antiviral RNAi in mammalian innate immunity, in which different cell-intrinsic antiviral pathways can be tailored to the differentiation status of cells.

An antiviral Dicer defends stem cells

Antiviral Defense Stem cells have a pivotal role in maintaining tissue architecture, integrity, and renewal. Poirier et al. demonstrate that mammalian stem cells can protect themselves from some RNA viruses by expressing an alternatively spliced isoform of the enzyme Dicer called aviD, which potentiates antiviral RNA interference (see the Perspective by Shahrudin and Ding). aviD acts by cleaving long, base-paired viral RNAs to generate small interfering RNAs that direct the sequence-specific cleavage of homologous viral RNAs. This process is reminiscent of that in insects and worms, which also use Dicer-dependent RNA interference in antiviral defense, and contrasts with mammalian differentiated cells, which generally rely on the interferon system to combat virus infection. Science , abg2264, this issue p. [231][1]; see also abj5673, p. [160][2] [1]: /lookup/doi/10.1126/science.abg2264 [2]: /lookup/doi/10.1126/science.abj5673

Factors affecting postpartum ovarian activity of goats in tropical semi-arid region


 There have been few studies on the use of diets and strategies to reduce the length of postpartum anoestrus in dairy goats, especially in tropical semi-arid regions. This review discusses the factors influencing the return of postpartum ovarian activity in goats. During the postpartum period, goats are in puerperal anoestrus and their reproductive tract is being prepared for a new conception. Anoestrus is necessary for tissue renewal in the uterus (uterine involution) associated with the return of cyclic ovarian activity, and is influenced by factors such as suckling of the offspring, social interactions, body condition score (BCS) before and after birth, intensity of negative energy balance (NEB) and stress from adverse climatic conditions. The anoestrus period can be extended by delays in the resumption of reproductive activity of females in puerperium. The duration of puerperal anoestrus in goats directly affects the productivity of the herd and is mainly influenced by nutrition, lactation period and heat stress. To minimize the negative effects of postpartum anoestrus on productivity, we recommend a mating season and a plan for the kidding period, as well as a program to monitor the body condition score during pregnancy so that the animals will have a better BCS at parturition. To minimize the effects of a negative energy balance, we suggest nutritional supplementation with levels of energy above the requirements for maintenance.
 Highlights
 
 The duration of postpartum anoestrus in goats is influenced by nutrition and body condition score.
 Heat stress can intensify the negative energy balance, consequently increased the period of anoestrus.
 Puerperal anoestrus occurs as a result of tissue renewal in the uterus.
 Suckling of the offspring associated with the period of lactation and social interactions can modified the puerperal anoestrus period.
 Use of diets and strategies to reduce the postpartum anoestrus in goats.

Gene therapy knockdown of Hippo signaling induces cardiomyocyte renewal in pigs after myocardial infarction.

Human heart failure, a leading cause of death worldwide, is a prominent example of a chronic disease that may result from poor cell renewal. The Hippo signaling pathway is an inhibitory kinase cascade that represses adult heart muscle cell (cardiomyocyte) proliferation and renewal after myocardial infarction in genetically modified mice. Here, we investigated an adeno-associated virus 9 (AAV9)-based gene therapy to locally knock down the Hippo pathway gene Salvador (Sav) in border zone cardiomyocytes in a pig model of ischemia/reperfusion-induced myocardial infarction. Two weeks after myocardial infarction, when pigs had left ventricular systolic dysfunction, we administered AAV9-Sav-short hairpin RNA (shRNA) or a control AAV9 viral vector carrying green fluorescent protein (GFP) directly into border zone cardiomyocytes via catheter-mediated subendocardial injection. Three months after injection, pig hearts treated with a high dose of AAV9-Sav-shRNA exhibited a 14.3% improvement in ejection fraction (a measure of left ventricular systolic function), evidence of cardiomyocyte division, and reduced scar sizes compared to pigs receiving AAV9-GFP. AAV9-Sav-shRNA-treated pig hearts also displayed increased capillary density and reduced cardiomyocyte ploidy. AAV9-Sav-shRNA gene therapy was well tolerated and did not induce mortality. In addition, liver and lung pathology revealed no tumor formation. Local delivery of AAV9-Sav-shRNA gene therapy to border zone cardiomyocytes in pig hearts after myocardial infarction resulted in tissue renewal and improved function and may have utility in treating heart failure.

Telocytes: An Emerging Component of Stem Cell Niche Microenvironment.

Telocytes (TCs) are newly identified interstitial cells characterized by thin and long cytoplasmic processes, called telopodes, which exhibit a distinctive moniliform shape and, often, a sinuous trajectory. Telopodes typically organize in intricate networks within the stromal space of most organs, where they communicate with neighboring cells by means of specialized cell-to-cell junctions or shedding extracellular vesicles. Hence, TCs are generally regarded as supporting cells that help in the maintenance of local tissue homeostasis, with an ever-increasing number of studies trying to explore their functions both in physiological and pathological conditions. Notably, TCs appear to be part of stem cell (SC) niches in different organs, including the intestine, skeletal muscle, heart, lung, and skin. Indeed, growing evidence points toward a possible implication of TCs in the regulation of the activity of tissue-resident SCs and in shaping the SC niche microenvironment, thus contributing to tissue renewal and repair. Here, we review how the introduction of TCs into the scientific literature has deepened our knowledge of the stromal architecture focusing on the intestine and skeletal muscle, two organs in which the recently unveiled unique relationship between TCs and SCs is currently in the spotlight as potential target for tissue regenerative purposes.

374-P: Oleate Prevents Palmitate-Induced Abnormalities in Insulin Signaling in Human Cardiac Progenitor Cells

Myocardial ectopic lipid deposition has been associated with insulin resistance and cardiovascular risk. Palmitate, one of the most abundant saturated fatty acids, has been shown to impair insulin signaling in multiple cell types. Human cardiac progenitor cells (CPC) represent a compartment of multipotent stem cells essential for constant tissue repair and renewal in the adult heart. In this study, the ability of palmitate to impair insulin signaling, and the modulatory effects of oleate, a mono-unsaturated fatty acid, on palmitate-induced abnormalities were investigated in human CPC isolated from control subjects undergoing cardiac surgery. Human CPC express insulin receptor (IR), as assessed by quantitative RT-PCR and immunoblotting. Specifically, in human CPC both IR isoforms, A (IR-A) and B (IR-B), were identified, and IR-A was more expressed than IR-B. Exposure of human CPC to 100 nM insulin for 15 minutes resulted in increased Akt and p44/p42 MAPK phosphorylation (p<0.05), evidenced by immunoblotting. Treatment of human CPC with 0.25 mM palmitate for 24 h impaired the ability of insulin, added for the last 15 minutes, to phosphorylate both Akt and p44/p42 MAPK (p<0.05), without no effect on total Akt and p44/p42 MAPK protein levels. Interestingly, palmitate was able to increase both IR-A and IR-B mRNA levels (p<0.05), and to reduce IR protein expression (p<0.05). Co-incubation of palmitate with 0.1 mM oleate prevented the ability of palmitate to reduce insulin-induced Akt phosphorylation (p<0.05), but did not rescue the impaired p44/p42 MAPK phosphorylation. In addition, co-treatment with oleate also prevented both palmitate-induced upregulation of IR-A and IR-B mRNA (p<0.05), and downregulation of IR protein levels (p<0.05). In conclusion, oleate prevents some of the palmitate-induced impairments in insulin signaling in human CPC, thus contributing to cardiac protection from lipotoxicity-induced metabolic alterations. Disclosure R. Doria: None. F. Giorgino: Consultant; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Novo Nordisk, Roche Diabetes Care, Sanofi, Research Support; Self; Lilly Diabetes, Roche Diabetes Care. C. Caccioppoli: None. R. Schipani: None. V. Genchi: None. A. Leonardini: None. A. Natalicchio: Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Sanofi. S. Perrini: None. A. Cignarelli: None. L. Laviola: Advisory Panel; Self; A. Menarini Diagnostics, Abbott, AstraZeneca, Lilly Diabetes, Novo Nordisk Inc., Roche Diabetes Care, Sanofi-Aventis, Speaker’s Bureau; Self; Boehringer Ingelheim International GmbH, Medtronic.

Adrenal cortex renewal in health and disease.

Resident progenitor and/or stem cell populations in the adult adrenal cortex enable cortical cells to undergo homeostatic renewal and regeneration after injury. Renewal occurs predominantly in the outer layers of the adrenal gland but newly formed cells undergo centripetal migration, differentiation and lineage conversion in the process of forming the different functional steroidogenic zones. Over the past 10 years, advances in the genetic characterization of adrenal diseases and studies of mouse models with altered adrenal phenotypes have helped to elucidate the molecular pathways that regulate adrenal tissue renewal, several of which are fine-tuned via complex paracrine and endocrine influences. Moreover, the adrenal gland is a sexually dimorphic organ, and testicular androgens have inhibitory effects on cell proliferation and progenitor cell recruitment in the adrenal cortex. This Review integrates these advances, including the emerging role of sex hormones, into existing knowledge on adrenocortical cell renewal. An in-depth understanding of these mechanisms is expected to contribute to the development of novel therapies for severe endocrine diseases, for which current treatments are unsatisfactory.

Anatomical adaptations in aquatic and wetland dicot plants: Disentangling the environmental, morphological and evolutionary signals

Understanding how plants adjust their internal structures to withstand adverse environmental conditions is vital for predicting their responses to ongoing environmental change. Plants have repeatedly evolved small water transporting conduits and large storage parenchyma tissues to cope with anoxia, freezing- or drought‐induced damages. However, how these adaptations evolved in unrelated taxa across hydrological and thermal gradients, remains unclear. Here we show that stem anatomical variations in 212 European aquatic and wetland dicots are driven by thermal and hydrological constraints via control over plant size, growth form, and leaf traits, while phylogenetic constraints have only a weak effect. Phylogenetic comparative analyses controlling for confounding factors showed that both waterlogging (anoxia) and low-temperature promote smaller plants with reduced vessel conduits and limited lignification, but extended parenchyma and hence storage and tissue renewal capacity to secure resilience to biomass loss induced by running water or frost disturbances. Decreasing water depth and anoxia promote larger wetland plants with thick-walled libriform fibers, large vessels with simple perforation plates securing high hydraulic efficiency, and semi-ring porous xylem with wide earlywood vessels in spring and narrow latewood vessels in summer, providing both efficiency and safety in water transport. The aquatic environment promotes plants with a large cortex zone with photosynthetic chlorenchyma and starch-storing parenchyma cells along with extensive air spaces that provide aeration and buoyancy. Low temperatures promote short-stature forbs with smaller vessels, scalariform perforation plate, extended parenchyma, resulting in reduced embolism risk. Although most anatomical variation was explained by differences between aquatic and wet terrestrial growth forms, environmental gradients, plant size, and leaf properties exerted a significant control on plant tissue structures not confounded by phylogenetic inertia. Distinct habitats, spread across broad thermal and hydrological gradients, harbor unrelated species with different evolutionary histories that have converged to similar anatomical and hence morphological structures.

HISTOLOGICAL STUDY OF THE ROOT AND LEAF OF WITHANIA FRUTESCENS (SOLANACEAE) IN THE REGION OF TLEMCEN (WESTERN ALGERIA)

Histology (from the ancient Greek hystos = tissue and logos = study) is the branch of biology and medicine that studies biological tissue. We used to talk about microscopic anatomies. It aims to explore the structure of living organisms, the constitutive and functional relationships between their functional elements, as well as tissue renewal. The methodology of plant histology is not fundamentally different from that of animal histology. The basic technique generally involves fixing the samples followed by hardening or inclusion in paraffin or plastics, sections by microtomy and then either topographic staining when looking for an overview, or specific when looking for an overview, or specific when wants to electively characterize certain structures. In this summary, we will present a study of the internal structure of the stem and leaf of Withania frutescens (Solanaceae) at the microscopic scale. The histological study carried out at the root and leaf level of Withania frutescens (Solanaceae) allows us to analyze the different structures well and with precision and to draw the general characteristics concerning the arrangement of tissues in plant organs.

Can neural signals override cellular decisions in the presence of DNA damage?

Cells within an organism are in constant crosstalk with their surrounding environment. Short and long-range signals influence cellular behavior associated with division, differentiation, and death. This crosstalk among cells underlies tissue renewal to guarantee faithful replacement of old or damaged cells over many years. Renewing tissues also offer recurrent opportunities for DNA damage and cellular transformation that tend to occur with aging. Most cells with extensive DNA damage have limited options such as halting cell cycle to repair DNA, undergo senescence, or programmed cell death. However, in some cases cells carrying toxic forms of DNA damage survive and proliferate. The underlying factors driving survival and proliferation of cells with DNA damage remain unknown. Here we discuss potential roles the nervous system may play in influencing the fate of cells with DNA damage. We present a brief survey highlighting the implications the nervous system has in regeneration, regulation of stem cells, modulation of the immune system, and its contribution to cancer progression. Finally, we propose the use of planarian flatworms as a convenient model organism to molecularly dissect the influence of neural signals over cellular fate regulation in the presence of DNA damage.

COMPARISON OF ADHESION AND PROLIFERATION OF MESENCHYMAL STEM CELLS ON AMNIOTIC MEMBRANE AND COLLAGEN PORCINE-DERIVED SCAFFOLD

<h3>Background</h3> Cellular scaffolds are 3D structures that support cell adhesion and proliferation, promoting an environment favorable to cell culture. The amniotic membrane (AM) is a scaffold that has suitable mechanical properties, low immune rejection and low cost of obtaining and processing. The mesenchymal stem cells (MSC) are known for their immunomodulatory capacity, maintenance and renewal of cells and tissues, and its association with AM may have a great potential in tissue engineering. The aim of this study was to compare the capacity of adhesion and proliferation of dental pulp-derived MSC (DPSC) after cultivation on decellularized AM with the commercial porcine collagen membrane (CPCM) already used clinically. <h3>Methods</h3> The AM was collected, isolated and decellularized. The DPSC were obtained from permanent tooth pulp by mechanical dissociation followed by enzymatic digestion and expanded in vitro. The DPSC were genetically modified to express the luciferase enzyme. These transfected cells were plated at different concentrations: 10,000, 30,000, 50,000 and 100,000 per cm² on AM and CPCM, and used in bioluminescence analysis to assess adherence and proliferation capacity on both scaffolds over 24 hours, 7 days, 14 days, 21 days and 28 days. <h3>Results</h3> The concentration of 100,000 cells per cm² showed better adhesion in all tested samples. There was a significant difference (<i>p</i> = 0.004) 24 hours after cell culture, with CPCM presenting five times more cells than AM. The difference was also observed on the 7th day (<i>p</i> = 0.011), with CPCM presenting eight times more cells than AM. On the 14th and 21st days (<i>p</i> = 0.006 and p = 0.004, respectively), CPCM showed a considerable decrease in cell proliferation. At the same time, AM presented an increase in cell proliferation, with two times more cells than CPCM. Finally, there was a significant difference on the 28th day (<i>p</i> = 0.010), where AM presented three times more cells than CPCM. <h3>Conclusion</h3> The results showed AM is a viable source to be used as a scaffold for cell adhesion and proliferation. When extrapolated to an in vivo environment, it is possible that CPCM's showed more difficulty in maintaining cell adhesion for more than a week which could affect clinical outcomes. In this scenario, AM it seems to be a more stable scaffold, enabling cell adhesion for up to three weeks. The presented technology proved to be accessible, reproducible, and can be an alternative to commercial membranes.

Human skin aging is associated with increased expression of the histone variant H2A.J in the epidermis

Cellular senescence is an irreversible growth arrest that occurs as a result of damaging stimuli, including DNA damage and/or telomere shortening. Here, we investigate histone variant H2A.J as a new biomarker to detect senescent cells during human skin aging. Skin biopsies from healthy volunteers of different ages (18–90 years) were analyzed for H2A.J expression and other parameters involved in triggering and/or maintaining cellular senescence. In the epidermis, the proportions of H2A.J-expressing keratinocytes increased from ≈20% in young to ≈60% in aged skin. Inverse correlations between Ki67- and H2A.J staining in germinative layers may reflect that H2A.J-expressing cells having lost their capacity to divide. As cellular senescence is triggered by DNA-damage signals, persistent 53BP1-foci, telomere lengths, and telomere-associated damage foci were analyzed in epidermal keratinocytes. Only slight age-related telomere attrition and few persistent nuclear 53BP1-foci, occasionally colocalizing with telomeres, suggest that unprotected telomeres are not a significant cause of senescence during skin aging. Quantification of integrin-α6+ basal cells suggests that the number and function of stem/progenitor cells decreased during aging and their altered proliferation capacities resulted in diminished tissue renewal with epidermal thinning. Collectively, our findings suggest that H2A.J is a sensitive marker of epidermal aging in human skin.

Evaluation of Ehretia Laevis Roxb. (Khandu Chakka/Ajan Vruksha) in the Wound Healing Adjudged by Histological Examination of the Tissue

Many herbal plants are mentioned in Ayurveda for wound healing. Folklore medicine for various ailmentsincluding wound healing is being practiced in India. Ehretia Laevis Roxb. contains many such chemicalcompounds useful for promotion of healing &amp; repair. Tissue renewal goes hand in hand with inflammationinfluenced by multiple processes. Ehretia Laevis Roxb. called Khandu Chakka &amp; Ajan Vruksha andtraditionally being used for wound healing, body pain &amp; minor fractures in the form of local application byfolklore in the state of Maharashtra India. Objectives of the present study is to know the effect of EhretiaLaevis Roxb. in the wound healing on the histological parameters in animal model. Phenytoin ointmentas a control was used. The present study has found put that leaf extract paste of Ehretia Laevis Roxb.has enhanced the process of wound healing ascertained on histological parameters as compared to topicalphenytoin application. Ehretia Laevis Roxb. paste is found to be immensely useful at wound healing ascompared to Phenytoin. Ehretia Laevis Roxb. is concluded to promote the healing significantly as observedby feature of granulation, collagenisation &amp; re epithelisation of the wounds suggesting early healing byprimary intension

Oxygen regulates epithelial stem cell proliferation via RhoA-actomyosin-YAP/TAZ signal in mouse incisor.

Stem cells are maintained in specific niches that strictly regulate their proliferation and differentiation for proper tissue regeneration and renewal. Molecular oxygen (O2) is an important component of the niche microenvironment, but little is known about how O2 governs epithelial stem cell (ESC) behavior. Here, we demonstrate that O2 plays a crucial role in regulating the proliferation of ESCs using the continuously growing mouse incisors. We have revealed that slow-cycling cells in the niche are maintained under relatively hypoxic conditions compared with actively proliferating cells, based on the blood vessel distribution and metabolic status. Mechanistically, we have demonstrated that, during hypoxia, HIF1α upregulation activates the RhoA signal, thereby promoting cortical actomyosin and stabilizing the adherens junction complex, including merlin. This leads to the cytoplasmic retention of YAP/TAZ to attenuate cell proliferation. These results shed light on the biological significance of blood-vessel geometry and the signaling mechanism through microenvironmental O2 to orchestrate ESC behavior, providing a novel molecular basis for the microenvironmental O2-mediated stem cell regulation during tissue development and renewal.

Reactive Oxygen Species in intestinal stem cell metabolism, fate and function

Long dismissed as merely harmful respiratory by-products, Reactive Oxygen Species (ROS) have emerged as critical intracellular messengers during cell growth and differentiation. ROS's signaling roles are particularly prominent within the intestine, whose high regenerative capacity is maintained by Intestinal Stem Cells (ISCs). In this review, we outline roles for ROS in ISCs as revealed by studies using Drosophila and mouse model systems. We focus particularly on recent studies highlighting how ROS ties to metabolic adaptations, which ensure energy supply matches demand during ISC activation and differentiation. We describe how declines in these adaptive mechanisms, through aging or pathology, promote reciprocal changes in ISC metabolism and ROS signaling. These changes ultimately contribute to aberrant ISC function, a loss of tissue homeostasis, and a shortened lifespan.

Engineering Exosome-Like Nanovesicles Derived from Asparagus cochinchinensis Can Inhibit the Proliferation of Hepatocellular Carcinoma Cells with Better Safety Profile.

BackgroundExosomes are a type of membrane vesicles secreted by living cells. Recent studies suggest exosome-like nanovesicles (ELNVs) from fruits and vegetables are involved in tissue renewal process and functional regulation against inflammatory diseases or cancers. However, there are few reports on ELNVs derived from medicinal plants.MethodsELNVs derived from Asparagus cochinchinensis (Lour.) Merr. (ACNVs) were isolated and characterized. Cytotoxicity, antiproliferative and apoptosis-inducing capacity of ACNVs against hepatoma carcinoma cell were assessed. The endocytosis mechanism of ACNVs was evaluated on Hep G2 cells in the presence of different endocytosis inhibitors. In vivo distribution of ACNVs was detected in healthy and tumor-bearing mice after scavenger receptors (SRs) blockade. PEG engineering of ACNVs was achieved through optimizing the pharmacokinetic profiles. In vivo antitumor activity and toxicity were evaluated in Hep G2 cell xenograft model.ResultsACNVs were isolated and purified using a differential centrifugation method accompanied by sucrose gradient ultracentrifugation. The optimized ACNVs had an average size of about 119 nm and showed a typical cup-shaped nanostructure containing lipids, proteins, and RNAs. ACNVs were found to possess specific antitumor cell proliferation activity associated with an apoptosis-inducing pathway. ACNVs could be internalized into tumor cells mainly via phagocytosis, but they were quickly cleared once entering the blood. Blocking the SRs or PEGylation decoration prolonged the blood circulation time and increased the accumulation of ACNVs in tumor sites. In vivo antitumor results showed that PEGylated ACNVs could significantly inhibit tumor growth without side effects.ConclusionThis study provides a promising functional nano platform derived from edible Asparagus cochinchinensis that can be used in antitumor therapy with negligible side effects.