Inter-organ communication during tissue regeneration.

Tissue regeneration is not simply a local repair event occurring in isolation from the distant, uninjured parts of the body. Rather, evidence indicates that regeneration is a whole-animal process involving coordinated interactions between different organ systems. Here, we review recent studies that reveal how remote uninjured tissues and organ systems respond to and engage in regeneration. We also discuss the need for toolkits and technological advancements to uncover and dissect organ communication during regeneration.

Current Role and Future Perspectives of Immunotherapy and Circulating Factors in Treatment of Biliary Tract Cancers.

Biliary tract cancers (BTCs) are a heterogenous group of malignancies arising from the epithelial cells of the biliary tree and the gallbladder. They are often locally advanced or already metastatic at the time of the diagnosis and therefore prognosis remains dismal. Unfortunately, the management of BTCs has been limited by resistance and consequent low response rate to cytotoxic systemic therapy. New therapeutic approaches are needed to improve the survival outcomes for these patients. Immunotherapy, one of the newest therapeutic options, is changing the approach to the oncological treatment. Immune checkpoint inhibitors are by far the most promising group of immunotherapeutic agents: they work by blocking the tumor-induced inhibition of the immune cellular response. Immunotherapy in BTCs is currently approved as second-line treatment for patients whose tumors have a peculiar molecular profile, such as high levels of microsatellites instability, PD-L1 overexpression, or high levels of tumor mutational burden. However, emerging data from ongoing clinical trials seem to suggest that durable responses can be achieved in other subsets of patients. The BTCs are characterized by a highly desmoplastic microenvironment that fuels the growth of cancer tissue, but tissue biopsies are often difficult to obtain or not feasible in BTCs. Recent studies have hence proposed to use liquid biopsy approaches to search the blood circulating tumor cells (CTCs) or circulating tumor DNA (ctDNA) to use as biomarkers in BTCs. So far studies are insufficient to promote their use in clinical management, however trials are still in progress with promising preliminary results. Analysis of blood samples for ctDNA to research possible tumor-specific genetic or epigenetic alterations that could be linked to treatment response or prognosis was already feasible. Although there are still few data available, ctDNA analysis in BTC is fast, non-invasive, and could also represent a way to diagnose BTC earlier and monitor tumor response to chemotherapy. The prognostic capabilities of soluble factors in BTC are not yet precisely determined and more studies are needed. In this review, we will discuss the different approaches to immunotherapy and tumor circulating factors, the progress that has been made so far, and the possible future developments.

Enhancement of myogenic potential of muscle progenitor cells and muscle healing during pregnancy.

The decline of muscle regenerative potential with age has been attributed to a diminished responsiveness of muscle progenitor cells (MPCs). Heterochronic parabiosis has been used as a model to study the effects of aging on stem cells and their niches. These studies have demonstrated that, by exposing old mice to a young systemic environment, aged progenitor cells can be rejuvenated. One interesting idea is that pregnancy represents a unique biological model of a naturally shared circulatory system between developing and mature organisms. To test this hypothesis, we evaluated the muscle regeneration potential of pregnant mice using a cardiotoxin (CTX) injury mouse model. Our results indicate that the pregnant mice demonstrate accelerated muscle healing compared to nonpregnant control mice following muscle injury based on improved muscle histology, superior muscle regeneration, and a reduction in inflammation and necrosis. Additionally, we found that MPCs isolated from pregnant mice display a significant improvement of myogenic differentiation capacity in vitro and muscle regeneration in vivo when compared to the MPCs from nonpregnant mice. Furthermore, MPCs from nonpregnant mice display enhanced myogenic capacity when cultured in the presence of serum obtained from pregnant mice. Our proteomics data from these studies provides potential therapeutic targets to enhance the myogenic potential of progenitor cells and muscle repair.

Gadd45 in Preeclampsia.

Preeclampsia is a pregnancy-induced complex of multiple pathological changes. Numerous stresses during pregnancy, including hypoxia, immune activation, inflammatory cytokines, and oxidative stress were reported as contributing factors to the preeclamptic pathology. Seeking common sensors of various stressors in preeclampsia is of new interest and can potentially benefit in disease prevention and treatment. Recent studies have highlighted the role of the Gadd45a protein as a stress sensor in preeclampsia. In response to various pathophysiological stressors, notably hypoxia, oxidative stress, inflammatory cytokines, and AT1-AAs, Gadd45a activates Mkk3-p38 and or JNK signaling. This, in turn, results in immunological and inflammatory changes as well as triggering the production of circulating factors such as sFlt-1, which are believed to account for many of the pathophysiological-related symptoms of preeclampsia. Activation of inflammatory/immune responses in preeclampsia may function in a feedback loop to maintain elevated expression of Gadd45a protein.

Mass cytometry identifies a distinct monocyte cytokine signature shared by clinically heterogeneous pediatric SLE patients.

Systemic Lupus Erythematosus (SLE) is a heterogeneous autoimmune disease with heightened disease severity in children. The incomplete understanding of the precise cellular and molecular events that drive disease activity pose a significant hurdle to the development of targeted therapeutic agents. Here, we performed single-cell phenotypic and functional characterization of pediatric SLE patients and healthy controls blood via mass cytometry. We identified a distinct CD14hi monocyte cytokine signature, with increased levels of monocyte chemoattractant protein-1 (MCP1), macrophage inflammatory protein-1ß (Mip1ß), and interleukin-1 receptor antagonist (IL-1RA). This signature was shared by every clinically heterogeneous patient, and reproduced in healthy donors' blood upon ex-vivo exposure to plasma from clinically active patients only. This SLE-plasma induced signature was abrogated by JAK1/JAK2 selective inhibition. This study demonstrates the utility of mass cytometry to evaluate immune dysregulation in pediatric autoimmunity, by identification of a multi-parametric immune signature that can be further dissected to delineate the events that drive disease pathogenesis.

Metabolic Changes During Cancer Cachexia Pathogenesis.

Wasting of adipose tissue and skeletal muscle is a hallmark of metastatic cancer and a major cause of death. Like patients with cachexia caused by other chronic infections or inflammatory diseases, the cancer subject manifests both malnutrition and metabolic stress. Both carbohydrate utilization and amino acid incorporation are decreased in the muscles of cancer cachexia patients. Cancer cells affect host metabolism in two ways: (a) their own metabolism of nutrients into other metabolites and (b) circulating factors they secrete or induce the host to secrete. Accelerated glycolysis and lactate production, i.e., the Warburg effect and the resultant increase in Cori cycle activity, are the most widely discussed metabolic effects. Meanwhile, although a large number of pro-cachexia circulating factors have been found, such as TNFa, IL-6, myostatin, and PTHrp, none have been shown to be a dominant factor that can be targeted singly to treat cancer cachexia in humans. It is possible that given the complex multifactorial nature of the cachexia secretome, and the personalized differences between cancer patients, targeting any single circulating factor would always be insufficient to treat cachexia for all patients. Here we review the metabolic changes that occur in response to tumor growth and tumor-secreted factors during cachexia.

Mechanism of vascular dysfunction due to circulating factors in women with pre-eclampsia.

Circulating factors have been proposed to play a major role in the pathophysiology of endothelial dysfunction in pre-eclampsia (PE), which is defined as new-onset hypertension with proteinuria after 20 weeks of gestation. However, the mechanisms leading to altered vascular reactivity remain unclear. We hypothesized that circulating factors lead to endothelial dysfunction by increasing oxidative stress and reducing nitric oxide (NO) and prostaglandin (PG) bioavailability. Pregnant rat uterine and mesenteric arteries were incubated overnight with 3% normotensive (NP) or PE plasma collected from women upon admission to hospital. Responses to methacholine (MCh) were obtained using wire myography to assess endothelial function pathways. Vascular superoxide level was measured via dihydroethidium staining and nitric oxide synthase (NOS) expression via Western blots. PE plasma significantly increased superoxide levels and impaired endothelial dysfunction in uterine arteries (Emax 79.9±5.6% compared with 44.9±6.3%, P=0.0004), which was restored in the presence of oxidant scavengers or PG synthesis inhibition. Uterine artery vasodilation was abolished in the presence of pan-NOS inhibitor (P<0.0001) in both NP- and PE-treated vessels, but inducible nitric oxide synthase (iNOS)-dependent vasodilation was present only in NP-treated arteries. Uterine arteries exposed to PE plasma exhibit an increased endothelial NOS expression and a decreased iNOS expression. PE plasma did not alter endothelial function in mesenteric arteries, suggesting that the effect of circulating factors was vascular-bed-specific. We have shown that circulating factors lead to endothelial dysfunction via altered oxidative stress and vasodilator pathways. The present study contributes to our understanding of the pathophysiology and finding a potential target for intervention in PE.

The glomerular permeability factors in idiopathic nephrotic syndrome.

It is currently postulated that steroid-sensitive idiopathic nephrotic syndrome (SSNS) and steroid-resistant idiopathic nephrotic syndrome (SRNS), which are not related to the mutation of a gene coding for podocyte structures or for glomerular basement membrane proteins, result from a circulating factor affecting podocyte shape and function. T lymphocytes have for a long time been suspected to be involved in the pathophysiology of these diseases. The successful treatment of steroid-dependant nephrotic syndrome with rituximab suggests a potential role for B lymphocytes. Clinical and experimental data indicate roles for cytokines IL-13, TNFα, circulating cardiotrophin-like cytokine factor 1 (member of the IL-6 family), circulating hemopexin, radical oxygen species, and the soluble urokinase-type plasminogen activator receptor (suPAR) in the development of nephrotic syndrome. Podocyte metabolism modifications-leading to the overexpression of the podocyte B7-1antigen (CD 80), hypoactivity of the podocyte enzyme sphingomyelin phosphodiesterase acid-like 3 b (SMPDL3b), and to the podocyte production of a hyposialylated form of the angiopoietin-like 4 (Angptl4)-are mechanisms possibly involved in the changes in the podocyte cytoskeleton leading to SSNS and or SRNS. Different multifactorial pathophysiological mechanisms can be advocated for SSNS and SRNS. The present paper reviews the experimental and clinical data upon which the different hypotheses are based and reports their possible clinical applications.

Vascular dysfunction in preeclampsia.

Preeclampsia is a complex disorder which affects an estimated 5% of all pregnancies worldwide. It is diagnosed by hypertension in the presence of proteinuria after the 20th week of pregnancy and is a prominent cause of maternal morbidity and mortality. As delivery is currently the only known treatment, preeclampsia is also a leading cause of preterm delivery. Preeclampsia is associated with maternal vascular dysfunction, leading to serious cardiovascular risk both during and following pregnancy. Endothelial dysfunction, resulting in increased peripheral resistance, is an integral part of the maternal syndrome. While the cause of preeclampsia remains unknown, placental ischemia resulting from aberrant placentation is a fundamental characteristic of the disorder. Poor placentation is believed to stimulate the release of a number of factors including pro- and antiangiogenic factors and inflammatory activators into the maternal systemic circulation. These factors are critical mediators of vascular function and impact the endothelium in distinctive ways, including enhanced endothelial oxidative stress. The mechanisms of action and the consequences on the maternal vasculature will be discussed in this review.

Rejuvenation of young blood on aging organs: Effects, circulating factors, and mechanisms.

Aging causes degenerative changes in organs, leading to a decline in physical function. Over the past two decades, researchers have made significant progress in understanding the rejuvenating effects of young blood on aging organs, benefiting from heterochronic parabiosis models that connect the blood circulation of aged and young rodents. It has been discovered that young blood can partially rejuvenate organs in old animals by regulating important aging-related signaling pathways. Clinical trials have also shown the effectiveness of young blood in treating aging-related diseases. However, the limited availability of young blood poses a challenge to implementing anti-aging therapies on a large scale for older individuals. As a promising alternative, scientists have identified some specific anti-aging circulating factors in young blood that have been shown to promote organ regeneration, reduce inflammation, and alleviate fibrosis associated with aging in animal experiments. While previous reviews have focused primarily on the effects and mechanisms of circulating factors on aging, it is important to acknowledge that studying the rejuvenating effects and mechanisms of young blood has been a significant source of inspiration in this field, and it will continue to be in the future. In recent years, new findings have emerged, further expanding our knowledge in this area. This review aims to summarize the rejuvenating effects and mechanisms of young blood and circulating factors, discussing their similarities and connections, addressing discrepancies in previous studies, outlining future research directions, and highlighting the potential for clinical translation in anti-aging interventions.

Mechanism and prevention strategy of a bidirectional relationship between heart failure and cancer (Review).

The relationship between cancer and heart failure has been extensively studied in the last decade. These studies have focused on describing heart injury caused by certain cancer treatments, including radiotherapy, chemotherapy and targeted therapy. Previous studies have demonstrated a higher incidence of cancer in patients with heart failure. Heart failure enhances an over-activation of the sympathetic nervous system and the renin-angiotensin-aldosterone system, and subsequently promotes cancer development. Other studies have found that heart failure and cancer both have a common pathological origin, flanked by chronic inflammation in certain organs. The present review aims to summarize and describe the recent discoveries, suggested mechanisms and relationships between heart failure and cancer. The current review provides more ideas on clinical prevention strategies according to the pathological mechanism involved.

Parabiosis: Assessing the Effects of Circulating Cells and Factors on the Skeleton.

The circulatory system carries within it numerous types of cells, proteins, and other factors that are able to influence the local biology of tissues. Within this chapter, we present a protocol for parabiosis, a surgical model which results in shared circulation between two mice. Such chimeras have recently been used to probe the impact of age-associated changes in the circulation on skeletal, muscular, and neural biology. In conjunction with transgenic mouse models, parabiosis can be used as a tool to investigate the effects of specific factors on local tissues. Here we discuss our adaptation of this surgical procedure including technique details, pitfalls, and suggestions for optimization.

Improved Bone Quality and Bone Healing of Dystrophic Mice by Parabiosis.

Duchenne muscular dystrophy (DMD) is a degenerative muscle disorder characterized by a lack of dystrophin expression in the sarcolemma of muscle fibers. DMD patients acquire bone abnormalities including osteopenia, fragility fractures, and scoliosis indicating a deficiency in skeletal homeostasis. The dKO (dystrophin/Utrophin double knockout) is a more severe mouse model of DMD than the mdx mouse (dystrophin deficient), and display numerous clinically-relevant manifestations, including a spectrum of degenerative changes outside skeletal muscle including bone, articular cartilage, and intervertebral discs. To examine the influence of systemic factors on the bone abnormalities and healing in DMD, parabiotic pairing between dKO mice and mdx mice was established. Notably, heterochronic parabiosis with young mdx mice significantly increased bone mass and improved bone micro-structure in old dKO-hetero mice, which showed progressive bone deterioration. Furthermore, heterochronic parabiosis with WT C56/10J mice significantly improved tibia bone defect healing in dKO-homo mice. These results suggest that systemic blood-borne factor(s) and/or progenitors from WT and young mdx mice can influence the bone deficiencies in dKO mice. Understanding these circulating factors or progenitor cells that are responsible to alleviate the bone abnormalities in dKO mice after heterochronic parabiosis might be useful for the management of poor bone health in DMD.

Intercellular and inter-organ crosstalk in browning of white adipose tissue: molecular mechanism and therapeutic complications.

Adipose tissue (AT) is highly plastic and heterogeneous in response to environmental and nutritional changes. The development of heat-dissipating beige adipocytes in white AT (WAT) through a process known as browning (or beiging) has garnered much attention as a promising therapeutic strategy for obesity and its related metabolic complications. This is due to its inducibility in response to thermogenic stimulation and its association with improved metabolic health. WAT consists of adipocytes, nerves, vascular endothelial cells, various types of immune cells, adipocyte progenitor cells, and fibroblasts. These cells contribute to the formation of beige adipocytes through the release of protein factors that significantly influence browning capacity. In addition, inter-organ crosstalk is also important for beige adipocyte biogenesis. Here, we summarize recent findings on fat depot-specific differences, secretory factors participating in intercellular and inter-organ communications that regulate the recruitment of thermogenic beige adipocytes, as well as challenges in targeting beige adipocytes as a potential anti-obese therapy.

Cancer and heart disease: associations and relations.

Emerging evidence supports that cancer incidence is increased in patients with cardiovascular (CV) disease and heart failure (HF), and patients with HF frequently die from cancer. Recently, data have been generated showing that circulating factors in relation to HF promote tumour growth and development in murine models, providing proof that a causal relationship exists between both diseases. Several common pathophysiological mechanisms linking HF to cancer exist, and include inflammation, neuro-hormonal activation, oxidative stress and a dysfunctional immune system. These shared mechanisms, in combination with risk factors, in concert may explain why patients with HF are prone to develop cancer. Investigating the new insights linking HF with cancer is rapidly becoming an exciting new field of research, and we herein review the most recent data. Besides insights in mechanisms, we call for clinical awareness, that is essential to optimize treatment strategies of patients having developed cancer with a history of HF. Finally, ongoing and future trials should strive for comprehensive phenotyping of both CV and cancer end points, to allow optimal usefulness of data, and to better describe and understand common characteristics of these two lethal diseases.

Circulating Factors and Ultrasono-findings are Linked to Previous Atherosclerotic Burden and Recurrent Risk.

BACKGROUND: In the progression of atherosclerosis, platelet activation and the interaction of platelets with leukocytes play a crucial role in arterial thrombus formation and are associated with the pathophysiology of carotid and cerebrovascular disease (CVD), including ischemic stroke. With aged participants, we evaluated and followed up the change in circulating factor and platelet-leukocyte aggregate levels in participants with or without CVD history. This study investigated whether circulating factor changes and ultrasonographic characteristics link to CVD risk and other relating long-term outcomes. MATERIALS AND METHODS: Two hundred fifteen participants who enrolled in the study were divided into two groups with CVD and without CVD history. We evaluated and analyzed the correlation between ultrasonography-based morphological characteristics and circulating factor-based functional changes in both groups. RESULTS: There was no difference in p-selectin level between both groups. However, activated monocyte and platelet-monocyte aggregate levels were higher in patients with previous CVD than without previous CVD. Circulating factor and ultrasonographical characteristics were correlated in the group with CVD, whereas these factors were not correlated in the group without CVD. CONCLUSION: We found that circulating blood factor levels showed a different tendency in participants with and without CVD history. The results depict that atherosclerotic severity might depend on the history of CVD and progression of atherosclerosis. We suggest that the circulating factor levels, atherosclerotic severity, and history of CVD are considered in the observation of pathologic progression to manage the development of CVD risks and CVD relating outcomes.

Autophagy Is Required for Memory Formation and Reverses Age-Related Memory Decline.

Age-related declines in cognitive fitness are associated with a reduction in autophagy, an intracellular lysosomal catabolic process that regulates protein homeostasis and organelle turnover. However, the functional significance of autophagy in regulating cognitive function and its decline during aging remains largely elusive. Here, we show that stimulating memory upregulates autophagy in the hippocampus. Using hippocampal injections of genetic and pharmacological modulators of autophagy, we find that inducing autophagy in hippocampal neurons is required to form novel memory by promoting activity-dependent structural and functional synaptic plasticity, including dendritic spine formation, neuronal facilitation, and long-term potentiation. We show that hippocampal autophagy activity is reduced during aging and that restoring its levels is sufficient to reverse age-related memory deficits. Moreover, we demonstrate that systemic administration of young plasma into aged mice rejuvenates memory in an autophagy-dependent manner, suggesting a prominent role for autophagy to favor the communication between systemic factors and neurons in fostering cognition. Among these youthful factors, we identify osteocalcin, a bone-derived molecule, as a direct hormonal inducer of hippocampal autophagy. Our results reveal that inducing autophagy in hippocampal neurons is a necessary mechanism to enhance the integration of novel stimulations of memory and to promote the influence of systemic factors on cognitive fitness. We also demonstrate the potential therapeutic benefits of modulating autophagy in the aged brain to counteract age-related cognitive impairments.

Investigational drugs in development for focal segmental glomerulosclerosis.

INTRODUCTION: Focal segmental glomerulosclerosis is an important cause of end stage kidney disease and is a paradigm for the study of glomerular scarring. There are no FDA approved treatments for this condition. Current therapies, assessed based on reduction in proteinuria, are generally effective in a subset of patients which suggests that FSGS is a heterogeneous group of glomerular disorders or podocytopathies that converge on a common histopathological phenotype. Areas covered: We searched for investigational drugs agents that target different pathophysiological pathways using the key words 'FSGS' and 'podocyte' in American and European clinical trial registers (clinicaltrials.gov; clinicaltrialsregister.eu). Published articles were searched in PubMed, Medline, the Web of Science and the Cochrane Central Register of Controlled Trials Library. Expert opinion: Progress is being made in defining the mechanism of action of subtypes of FSGS. Current and investigational therapies for FSGS target these different pathways of injury. It is anticipated that advances in systems biology will further refine the classification of FSGS by subdividing the disease based on the primary mechanism of glomerular injury, identify biomarkers to discriminate between different subtypes, and enable appropriate selection of appropriate therapy for each individual in accordance with the goals of precision medicine.

Role of circulating factors in cardiac aging.

Worldwide increase in life expectancy is a major contributor to the epidemic of chronic degenerative diseases. Aging, indeed, simultaneously affects multiple organ systems, and it has been hypothesized that systemic alterations in regulators of tissue physiology may regulate this process. Cardiac aging itself is a major risk factor for cardiovascular diseases and, because of the intimate relationship with the brain, may contribute to increase the risk of neurodegenerative disorders. Blood-borne factors may play a major role in this complex and still elusive process. A number of studies, mainly based on the revival of parabiosis, a surgical technique very popular during the 70s of the 20th century to study the effect of a shared circulation in two animals, have indeed shown the potential that humoral factors can control the aging process in different tissues. In this article we review the role of circulating factors in cardiovascular aging. A better understanding of these mechanisms may provide new insights in the aging process and provide novel therapeutic opportunities for chronic age-related disorders.

Effects of Acute Stroke Serum on Non-Ischemic Cerebral and Mesenteric Vascular Function.

We investigated the effects of circulating factors in serum obtained from patients in the acute phase of different subtypes of ischemic stroke on non-ischemic cerebral and mesenteric arteries, as a potential mechanism involved in influencing regional perfusion and thus clinical evolution. Posterior cerebral arteries (PCAs) and mesentery arteries (MAs) isolated from Wistar Kyoto rats were perfused with serum from acute stroke patients with large vessel disease without (LVD) or with hypertension (LVD + HTN), cardioembolism with hypertension (CE + HTN), or physiologic saline as controls. Myogenic activity and nitric oxide-dependent vasorelaxation were assessed after 2 h of intraluminal exposure to serum. Vascular function was differentially affected by sera. Exposure to LVD serum increased myogenic tone and produced endothelial dysfunction in both PCAs and MAs. However, CE + HTN serum increased tone and decreased smooth muscle sensitivity to NO in vessels from both vascular beds. LVD + HTN serum was associated with reduced smooth muscle sensitivity to NO in vessels from both vascular beds but increased tone only in PCAs. Inflammation and oxidative stress, determined by measurement of high sensitivity C-reactive protein, uric acid, and free 8-isoprostane, were enhanced in all the serum groups. These results demonstrate vasoactive properties of acute stroke serum related to stroke subtypes that could potentially contribute to the pathogenesis of early hemodynamic-based clinical events.