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Hair loss, or alopecia, is associated with several psychosocial and medical comorbidities, and it remains an economic burden to individuals and the society. Alopecia is attributable to varied mechanisms and features a multifactorial predisposition, and the available conventional medical interventions have several limitations. Thus, several therapeutic strategies for alopecia in regenerative medicine are currently being explored, with increasing evidence suggesting that mesenchymal stem cell (MSC) implantation, MSC-derived secretome treatment, and blood-derived platelet-rich plasma therapies are potential treatment options. In this review, we searched the Cochrane Library, MEDLINE (PubMed), EMBASE, and Scopus using various combinations of terms, such as "stem cell," "alopecia," "hair loss," "Androgenetic alopecia," "male-pattern hair loss," "female-pattern hair loss," "regenerative hair growth," "cell therapy," "mesenchymal stem cells," "MSC-derived extracellular vesicles," "MSC-derived exosomes," and "platelet-rich plasma" and summarized the most promising regenerative treatments for alopecia. Moreover, further opportunities of improving efficacy and innovative strategies for promoting clinical application were discussed.
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Hepatopulmonary syndrome (HPS) is a pulmonary vascular complication of liver disease, which adversely affects prognosis. The disease is characterised by intrapulmonary vascular dilatations and shunts, resulting in impaired gas exchange. A complex interaction between the liver, the gut and the lungs, predominately impacting pulmonary endothelial cells, immune cells and respiratory epithelial cells, is responsible for the development of typical pulmonary alterations seen in HPS. Liver transplantation is the only therapeutic option and generally reverses HPS. Since the implementation of the model for end-stage liver disease (MELD) standard exception policy, outcomes in patients with HPS have been significantly better than they were in the pre-MELD era. This review summarises current knowledge and highlights what's new regarding the diagnosis and management of HPS, and our understanding of pathogenesis based on experimental models and translational studies.
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Objective: The pedicled greater omentum, when applied onto stressed hearts using omentopexy, has been shown to be protective in humans and animals. The mechanisms underlying cardioprotection using omentopexy remain elusive. This study examined whether macrophage-mediated angiogenesis accounts for the cardioprotective effect of omentopexy in mice. Methods: C57BL/6 mice were subjected to minimally invasive transverse aortic constriction for 6 weeks and subsequent cardio-omentopexy for 8 weeks. Control mice underwent the same surgical procedures without aortic constriction or cardio-omentopexy. Results: Transverse aortic constriction led to left ventricular concentric hypertrophy, reduced mitral E/A ratio, increased cardiomyocyte size, and myocardial fibrosis in the mice that underwent sham cardio-omentopexy surgery. The negative effects of transverse aortic constriction were prevented by cardio-omentopexy. Myocardial microvessel density was elevated in the mice that underwent aortic constriction and sham cardio-omentopexy surgery, and cardio-omentopexy further enhanced angiogenesis. Nanostring gene array analysis uncovered the activation of angiogenesis gene networks by cardio-omentopexy. Flow cytometric analysis revealed that cardio-omentopexy triggered the accumulation of cardiac MHCIIloLyve1+TimD4+ (Major histocompatibility complex class IIlow lymphatic vessel endothelial hyaluronan receptor 1+ T cell immunoglobulin and mucin domain conataining 4+) resident macrophages at the omental-cardiac interface. Intriguingly, the depletion of macrophages with clodronate-liposome resulted in the failure of cardio-omentopexy to protect the heart and promote angiogenesis. Conclusions: Cardio-omentopexy protects the heart from pressure overload-elicited left ventricular hypertrophy and dysfunction by promoting myocardial angiogenesis. Cardiac MHCIIloLyve1+TimD4+ resident macrophages play a critical role in the cardioprotective effect and angiogenesis of cardio-omentopexy.
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Vasculitis is a heterogeneous group of disorders characterized by multifocal segmental inflammation of the small and medium vessels of the central nervous system. The predominant symptoms of cerebral vasculitis are stroke, headache, and encephalopathy. Additional symptoms include seizures, cranial nerve palsies, and myelopathy. Imaging techniques play a crucial role in identifying the diagnosis of vasculitis and demonstrating brain involvement. An 89-year-old woman with permanent atrial fibrillation developed an embolic stroke. In treatment, intravenous thrombolysis and thrombectomy with complete antegrade reperfusion of the left middle cerebral artery was used, without the clinical effectiveness. Brain MRI revealed bilateral oval lesions in medial parts of the orbits, which were initially misinterpreted as orbital tumors. Final diagnosis confirmed thickened arterial walls as orbital changes due to inflammatory arteritis. Ten days later, follow-up MRI was performed and showed complete regression of the orbital masses. Primary central nervous system vasculitis, manifesting as acute ischemic stroke, may be reversible with early systemic thrombolytic treatment.
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Non-alcoholic fatty liver disease (NAFLD) is reaching epidemic proportions, with a global prevalence of 25% in the adult population. Non-alcoholic steatohepatitis (NASH), which can lead to cirrhosis, has become the leading indication for liver transplantation in both Europe and the USA. Liver fibrosis is the consequence of sustained, iterative liver injury, and the main determinant of outcomes in NASH. The liver possesses remarkable inherent plasticity, and liver fibrosis can regress when the injurious agent is removed, thus providing opportunities to alter long-term outcomes through therapeutic interventions. Although hepatocyte injury is a key driver of NASH, multiple other cell lineages within the hepatic fibrotic niche play major roles in the perpetuation of inflammation, mesenchymal cell activation, extracellular matrix accumulation as well as fibrosis resolution. The constituents of this cellular interactome, and how the various subpopulations within the fibrotic niche interact to drive fibrogenesis is an area of active research. Important cellular components of the fibrotic niche include endothelial cells, macrophages, passaging immune cell populations and myofibroblasts. In this review, we will describe how rapidly evolving technologies such as single-cell genomics, spatial transcriptomics and single-cell ligand-receptor analyses are transforming our understanding of the cellular interactome in NAFLD/NASH, and how this new, high-resolution information is being leveraged to develop rational new therapies for patients with NASH.
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Heart failure (HF) is characterized by progressive fibrosis. Both fibroblasts and mesenchymal stem cells (MSCs) can differentiate into pro-fibrotic myofibroblasts. MSCs secrete and express platelet-derived growth factor (PDGF) and its receptors. We hypothesized that PDGF signaling in cardiac MSCs (cMSCs) promotes their myofibroblast differentiation and aggravates post-myocardial infarction left ventricular remodeling and fibrosis. We show that cMSCs from failing hearts post-myocardial infarction exhibit an altered phenotype. Inhibition of PDGF signaling in vitro inhibited cMSC-myofibroblast differentiation, whereas in vivo inhibition during established ischemic HF alleviated left ventricular remodeling and function, and decreased myocardial fibrosis, hypertrophy, and inflammation. Modulating cMSC PDGF receptor expression may thus represent a novel approach to limit pathologic cardiac fibrosis in HF.
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Platelet-rich plasma (PRP) is a widely accepted treatment approach and has heightened the quality of care among physicians. PRP has been used over the last decade to boost clinical results of plastic therapies, periodontal surgery and intra-bony defects. According to certain research, elevated levels of PRP growth factors that could promote tissue repair and have the potential for PRP to be beneficial in regenerating processes that Maxillofacial and Oral Surgeons, Veterinary Officers, Athletic medicine specialists and Dermatologists have long admired. PRP is an autologous whole blood fraction that has a heavy amount of a variety of growth factors such as epidermal growth factor (EGF), Vascular Endothelial Growth Factor (VEGF), hepatocyte growth factor (HGF), fibroblast growth factors (FGFs), transforming growth factor beta-1 (TGF-b), insulin-like growth factor-I (IGF-I) and platelet-derived growth factor (PDGF) which can facilitate repair and regeneration. Moreover, a clinical trial of PRP in severe angina patients has shown its excellent safety profile. However, PRP is a very complex biological substance with an array of active biomolecules, its functions are yet to be fully clarified. In-addition, there was insufficient work assessing possible cardiovascular tissue benefits from PRP. Thus, it still remains necessary to identify the most clinically important cardiovascular applications and further research in clinical scenario need to be validated.
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The process of restenosis is based on the interplay of various mechanical and biological processes triggered by angioplasty-induced vascular trauma. Early arterial recoil, negative vascular remodeling, and neointimal formation therefore limit the long-term patency of interventional recanalization procedures. The most serious of these processes is neointimal hyperplasia, which can be traced back to 4 main mechanisms: endothelial damage and activation; monocyte accumulation in the subintimal space; fibroblast migration; and the transformation of vascular smooth muscle cells. A wide variety of animal models exists to investigate the underlying pathophysiology. Although mouse models, with their ease of genetic manipulation, enable cell- and molecular-focused fundamental research, and rats provide the opportunity to use stent and balloon models with high throughput, both rodents lack a lipid metabolism comparable to humans. Rabbits instead build a bridge to close the gap between basic and clinical research due to their human-like lipid metabolism, as well as their size being accessible for clinical angioplasty procedures. Every different combination of animal, dietary, and injury model has various advantages and disadvantages, and the decision for a proper model requires awareness of species-specific biological properties reaching from vessel morphology to distinct cellular and molecular features.
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Tumor angiogenesis is vital for the growth and development of various solid cancers and as such is a valid and promising therapeutic target. Unfortunately, the use of the currently available anti-angiogenic drugs increases the progression-free survival by only a few months. Conversely, targeting angiogenesis to prompt both vessel reduction and normalization, has been recently viewed as a promising approach to improve therapeutic efficacy. As a double-edged sword, this line of attack may on one side halt tumor growth as a consequence of the reduction of nutrients and oxygen supplied to the tumor cells, and on the other side improve drug delivery and, hence, efficacy. Thus, it is of upmost importance to better characterize the mechanisms regulating vascular stability. In this context, recruitment of pericytes along the blood vessels is crucial to their maturation and stabilization. As the extracellular matrix molecule Multimerin-2 is secreted by endothelial cells and deposited also in juxtaposition between endothelial cells and pericytes, we explored Multimerin-2 role in the cross-talk between the two cell types. We discovered that Multimerin-2 is an adhesion substrate for pericytes. Interestingly, and consistent with the notion that Multimerin-2 is a homeostatic molecule deposited in the later stages of vessel formation, we found that the interaction between endothelial cells and pericytes promoted the expression of Multimerin-2. Furthermore, we found that Multimerin-2 modulated the expression of key cytokines both in endothelial cells and pericytes. Collectively, our findings posit Multimerin-2 as a key molecule in the cross-talk between endothelial cells and pericytes and suggest that the expression of this glycoprotein is required to maintain vascular stability.
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Pulmonary tumor thrombotic microangiopathy (PTTM) is a rare but fatal cancer-related disease. Owing to its non-specific findings, aggressive course, and lack of established treatment guidelines, only a few cases of antemortem diagnosis in long-term survivors have been reported. We aimed to report a case of uterine cervical cancer induced PTTM that was suspected based on pulmonary hypertension and successfully treated using combination chemotherapy despite of delayed diagnose. It is important to be aware that PTTM should be suspected when respiratory failure occurs in patients with unexplained pulmonary hypertension. Multidisciplinary treatments including molecular targeted therapies might be effective treatment options.
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Portal hypertension, defined as increased pressure in the portal vein, develops as a consequence of increased intrahepatic vascular resistance due to the dysregulation of liver sinusoidal endothelial cells (LSECs) and hepatic stellate cells (HSCs), frequently arising from chronic liver diseases. Extrahepatic haemodynamic changes contribute to the aggravation of portal hypertension. The pathogenic complexity of portal hypertension and the unsuccessful translation of preclinical studies have impeded the development of effective therapeutics for patients with cirrhosis, while counteracting hepatic and extrahepatic mechanisms also pose a major obstacle to effective treatment. In this review article, we will discuss the following topics: i) cellular and molecular mechanisms of portal hypertension, focusing on dysregulation of LSECs, HSCs and hepatic microvascular thrombosis, as well as changes in the extrahepatic vasculature, since these are the major contributors to portal hypertension; ii) translational/clinical advances in our knowledge of portal hypertension; and iii) future directions.
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BACKGROUND: Abdominal adhesions are common and often develop after abdominal surgery. There are currently no useful targeted pharmacotherapies for adhesive disease. Saffron and its active constituents, Crocin and Crocetin, are wildly used in traditional medicine for alleviating the severity of inflammatory or malignant disease. PURPOSE: The aim of this study was to investigate the therapeutic potential of the pharmacological active component of saffron in attenuating the formation of post-operative adhesion bands using different administration methods in a murine model. MATERIAL METHOD: saffron extract (100 mg/kg), Crocin (100 mg/kg), and Crocetin (100 mg/kg) were administered intraperitoneally and by gavage in various groups of male Wistar rat post-surgery. Also three groups were first treated intra-peritoneally by saffron extract, Crocin, and Crocetin (100 mg/kg) for 10 days and then had surgery. At the end of the experiments, animals sacrificed for biological assessment. RESULT: A hydro-alcoholic extract of saffron and crocin but not crocetin potently reduced the adhesion band frequency in treatment and pre-treatment groups in the mice given intra-peritoneal (i.p) injections. Following the saffron or crocin administration, histological evaluation and quantitative analysis represented less inflammatory cell infiltration and less collagen composition, compared to control group. Moreover, the oxidative stress was significantly reduced in treatment groups. CONCLUSION: These findings suggest that a hydro-alcoholic extract of saffron or its active compound, crocin, is a potentially novel therapeutic strategy for the prevention of adhesions formation and might be used as beneficial anti-inflammatory or anti-fibrosis agents in clinical trials. TAXONOMY: Abdominal surgeries/post-surgical adhesions.
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The prevalence of hepatocellular carcinoma (HCC) is increasing worldwide, whereas that of most other cancers is decreasing. Non-alcoholic fatty liver disease (NAFLD), which has increased with the epidemics of obesity and type 2 diabetes, increases the risk of HCC. Interestingly, NAFLD-associated HCC can develop in patients with or without cirrhosis. A lack of awareness about NAFLD-related HCC has led to delays in diagnosis. Therefore, a large number of patients with HCC are diagnosed with advanced-stage HCC with low 5-year survival. In this context, increasing awareness of NAFLD and NAFLD-related HCC may lead to earlier diagnosis and more effective interventions.
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The family of vascular endothelial growth factors (VEGFs) includes 5 members (VEGF-A to -D, and placenta growth factor), which regulate several critical biological processes. VEGF-A exerts a variety of biological effects through high-affinity binding to tyrosine kinase receptors (VEGFR-1, -2 and -3), co-receptors and accessory proteins. In addition to its fundamental function in angiogenesis and endothelial cell biology, VEGF/VEGFR signalling also plays a role in other cell types including epithelial cells. This review provides an overview of VEGF signalling in biliary epithelial cell biology in both normal and pathologic conditions. VEGF/VEGFR-2 signalling stimulates bile duct proliferation in an autocrine and paracrine fashion. VEGF/VEGFR-1/VEGFR-2 and angiopoietins are involved at different stages of biliary development. In certain conditions, cholangiocytes maintain the ability to secrete VEGF-A, and to express a functional VEGFR-2 receptor. For example, in polycystic liver disease, VEGF secreted by cystic cells stimulates cyst growth and vascular remodelling through a PKA/RAS/ERK/HIF1α-dependent mechanism, unveiling a new level of complexity in VEFG/VEGFR-2 regulation in epithelial cells. VEGF/VEGFR-2 signalling is also reactivated during the liver repair process. In this context, pro-angiogenic factors mediate the interactions between epithelial, mesenchymal and inflammatory cells. This process takes place during the wound healing response, however, in chronic biliary diseases, it may lead to pathological neo-angiogenesis, a condition strictly linked with fibrosis progression, the development of cirrhosis and related complications, and cholangiocarcinoma. Novel observations indicate that in cholangiocarcinoma, VEGF is a determinant of lymphangiogenesis and of the immune response to the tumour. Better insights into the role of VEGF signalling in biliary pathophysiology might help in the search for effective therapeutic strategies.
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BACKGROUND: Achilles tendon rupture is one of the most common serious injuries in athletes. Various studies to accelerate the healing process of the Achilles tendon have been performed as it takes a longer time to repair the tissue compared to other tendons. Here, we report a case of an acute Achilles tendon rupture in a male basketball player treated by a combination of an intra-tissue injection of freeze-dried platelet-derived factor concentrate, which included a platelet-derived growth factor with an early rehabilitation protocol after the operative treatment to facilitate the biological healing of the injured tendon tissue. To the best of our knowledge, this case is the first instance that enabled the athlete to return to original sport activity at only 3-months after the injury. CASE REPORT: A 23-year-old male basketball player who belonged to a university basketball team sustained an Achilles tendon rupture during running in a training match. The remaining time period until the final tournament of the university league as a senior player was only 3 months. The patient received a combination of an intra-tissue injection of freeze-dried platelet-derived factor concentrate and early rehabilitation protocol after operative treatment. Surgery was performed 4 days after the injury and the early rehabilitation protocols were applied postoperatively. A freeze-dried platelet-derived factor concentrate was injected into the ruptured site of the Achilles tendon under ultrasound guide at 4 weeks postoperatively. The patient could return to play at the pre-injury level without any symptoms and disfunctions at 3 months after surgery. At two years postoperatively, the patient could play basketball without symptoms or rerupture. CONCLUSIONS: We reported a case of an Achilles tendon rupture which was treated by a combination of intra-tissue injection of freeze-dried platelet-derived factor concentrate and an early rehabilitation protocol after the operative treatment. The patient could return to play basketball at the pre-injury activity level at only 3-months after the injury, suggesting that the role of applying excessively early rehabilitation of mechanical loading could facilitate tendon tissue healing when combined with an intra-tissue injection of freeze-dried platelet-derived factor concentrate.
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Neointimal hyperplasia after vascular injury is a representative complication of restenosis. Endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR) is involved in the pathogenesis of vascular intimal hyperplasia. PARP16, a member of the poly(ADP-ribose) polymerases family, is correlated with the nuclear envelope and the ER. Here, we found that PERK and IRE1α are ADP-ribosylated by PARP16, and this might promote proliferation and migration of smooth muscle cells (SMCs) during the platelet-derived growth factor (PDGF)-BB stimulating. Using chromatin immunoprecipitation coupled with deep sequencing (ChIP-seq) analysis, PARP16 was identified as a novel target gene for histone H3 lysine 4 (H3K4) methyltransferase SMYD3, and SMYD3 could bind to the promoter of Parp16 and increased H3K4me3 level to activate its host gene's transcription, which causes UPR activation and SMC proliferation. Moreover, knockdown either of PARP16 or SMYD3 impeded the ER stress and SMC proliferation. On the contrary, overexpression of PARP16 induced ER stress and SMC proliferation and migration. In vivo depletion of PARP16 attenuated injury-induced neointimal hyperplasia by mediating UPR activation and neointimal SMC proliferation. This study identified SMYD3-PARP16 is a novel signal axis in regulating UPR and neointimal hyperplasia, and targeting this axis has implications in preventing neointimal hyperplasia related diseases.
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As one of the most important components of caveolae, caveolin-1 is involved in caveolae-mediated endocytosis and transcytosis pathways, and also plays a role in regulating the cell membrane cholesterol homeostasis and mediating signal transduction. In recent years, the relationship between the expression level of caveolin-1 in the tumor microenvironment and the prognostic effect of tumor treatment and drug treatment resistance has also been widely explored. In addition, the interplay between caveolin-1 and nano-drugs is bidirectional. Caveolin-1 could determine the intracellular biofate of specific nano-drugs, preventing from lysosomal degradation, and facilitate them penetrate into deeper site of tumors by transcytosis; while some nanocarriers could also affect caveolin-1 levels in tumor cells, thereby changing certain biophysical function of cells. This article reviews the role of caveolin-1 in tumor prognosis, chemotherapeutic drug resistance, antibody drug sensitivity, and nano-drug delivery, providing a reference for the further application of caveolin-1 in nano-drug delivery systems.
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Polo-like kinase 4 (PLK4) is canonically known for its cytoplasmic function in centriole duplication. Here we show a noncanonical PLK4 function of regulating the transcription factor SRF's nuclear activity and associated myofibroblast-like cell-type transition. In this context, we have further found that PLK4's phosphorylation and transcription are respectively regulated by PDGF receptor and epigenetic factor BRD4. Furthermore, in vivo experiments suggest PLK4 inhibition as a potential approach to mitigating vascular fibrosis.
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INTRODUCTION: The p75 neurotrophin receptor (p75NTR) is known as an efficient marker for the prospective isolation of mesenchymal stem cells (MSCs) and neural crest-derived stem cells (NCSCs). To date, there is quite limited information concerning p75NTR-expressing cells in umbilical cord (UC), although UC is known as a rich source of MSCs. We show for the first time the localization, phenotype, and functional properties of p75NTR+ cells in UC. METHODS: Human UC tissue sections were subjected to immunohistochemistry for MSC markers including p75NTR. Enzymatically isolated umbilical artery (UA) cells containing p75NTR+ cells were assessed for immunophenotype, clonogenic capacity, and differentiation potential. To identify the presence of neural crest-derived cells in the UA, P0-Cre/Floxed-EGFP reporter mouse embryos were used, and immunohistochemical analysis of UC tissue was performed. RESULTS: Immunohistochemical analysis revealed that p75NTR+ cells were specifically localized to the subendothelial area of the UA and umbilical vein. The p75NTR+ cells co-expressed PDGFRß, CD90, CD146, and NG2, phenotypic markers of MSCs and pericytes. Isolated UA cells possessed the potential to form neurospheres that further differentiated into neuronal and glial cell lineages. Genetic lineage tracing analysis showed that EGFP+ neural crest-derived cells were detected in the subendothelial area of UA with p75NTR immunoreactivity. CONCLUSIONS: These results show that UA tissue harbors p75NTR+ pericyte-like cells in the subendothelial area that have the capacity to form neurospheres and the potential for neurogenic differentiation. The lineage tracing data suggests the p75NTR+ cells are putatively derived from the neural crest.
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BACKGROUND & AIMS: Increasing evidence highlights dietary fructose as a major driver of non-alcoholic fatty liver disease (NAFLD) pathogenesis, the majority of which is cleared on first pass through the hepatic circulation by enzymatic phosphorylation to fructose-1-phosphate via the ketohexokinase (KHK) enzyme. Without a current approved therapy, disease management emphasises lifestyle interventions, but few patients adhere to such strategies. New targeted therapies are urgently required. METHODS: We have used a unique combination of human liver specimens, a murine dietary model of NAFLD and human multicellular co-culture systems to understand the hepatocellular consequences of fructose administration. We have also performed a detailed nuclear magnetic resonance-based metabolic tracing of the fate of isotopically labelled fructose upon administration to the human liver. RESULTS: Expression of KHK isoforms is found in multiple human hepatic cell types, although hepatocyte expression predominates. KHK knockout mice show a reduction in serum transaminase, reduced steatosis and altered fibrogenic response on an Amylin diet. Human co-cultures exposed to fructose exhibit steatosis and activation of lipogenic and fibrogenic gene expression, which were reduced by pharmacological inhibition of KHK activity. Analysis of human livers exposed to 13C-labelled fructose confirmed that steatosis, and associated effects, resulted from the accumulation of lipogenic precursors (such as glycerol) and enhanced glycolytic activity. All of these were dose-dependently reduced by administration of a KHK inhibitor. CONCLUSIONS: We have provided preclinical evidence using human livers to support the use of KHK inhibition to improve steatosis, fibrosis, and inflammation in the context of NAFLD. LAY SUMMARY: We have used a mouse model, human cells, and liver tissue to test how exposure to fructose can cause the liver to store excess fat and become damaged and scarred. We have then inhibited a key enzyme within the liver that is responsible for fructose metabolism. Our findings show that inhibition of fructose metabolism reduces liver injury and fibrosis in mouse and human livers and thus this may represent a potential route for treating patients with fatty liver disease in the future.