Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality globally. HCC is highly heterogenous with diverse etiologies leading to different driver mutations potentiating unique tumor immune microenvironments. Current therapeutic options, including immune checkpoint inhibitors and combinations, have achieved limited objective response rates for the majority of patients. Thus, a precision medicine approach is needed to tailor specific treatment options for molecular subsets of HCC patients. Lipid nanovesicle platforms, either liposome- (synthetic) or extracellular vesicle (natural)-derived present are improved drug delivery vehicles which may be modified to contain specific cargos for targeting specific tumor sites, with a natural affinity for liver with limited toxicity. This mini-review provides updates on the applications of novel lipid nanovesicle-based therapeutics for HCC precision medicine and the challenges associated with translating this therapeutic subclass from preclinical models to the clinic.

Post-reperfusion syndrome (PRS) is a severe and highly lethal syndrome that occurs after declamping the portal vein forceps during liver transplantation. It is marked by severe hemodynamic disturbances manifested by decreased mean arterial pressure, increased heart rate and elevated pulmonary artery pressure. The complex pathogenesis of PRS remains understudied. It is generally believed to be related to the large amount of acidic, cold blood that enters the circulation after release of the portal clamp. This blood is rich in oxygen-free radicals and metabolic toxins, which not only aggravate the ischemia-reperfusion injury of the liver but also further attack the systemic organs indiscriminately. Considering the range of possible adverse prognoses including acute kidney injury, delirium and graft nonfunction, it is imperative that clinicians increase their awareness and prevention of PRS. The aim of this article is to review the current risk factors, pathophysiological mechanisms and prevention strategies for PRS.

Exosomes derived from bone marrow mesenchymal stem cells (BMSCs) exhibit considerable therapeutic potential for myocardial regeneration. In our investigation, we delved into their impact on various aspects of myocardial infarction (MI), including cardiac function, tissue damage, inflammation, and macrophage polarization in a murine model. We meticulously isolated the exosomes from TNF-α-treated BMSCs and evaluated their therapeutic efficacy in a mouse MI model induced by coronary artery ligation surgery. Our comprehensive analysis, incorporating ultrasound, serum assessment, Western blot, and qRT-PCR, revealed that exosomes from TNF-α-treated BMSCs demonstrated significant therapeutic potential in reducing MI-induced injury. Treatment with these exosomes resulted in improved cardiac function, reduced infarct area, and increased left ventricular wall thickness in MI mice. On a mechanistic level, exosome treatment fostered M2 macrophage polarization while concurrently suppressing M1 polarization. Hence, exosomes derived from TNF-α-treated BMSCs emerge as a promising therapeutic strategy for alleviating MI injury in a mouse model.

This study is to investigate the therapeutical effect and mechanisms of human-derived adipose mesenchymal stem cells (ADSC) in relieving adriamycin (ADR)-induced nephropathy (AN). SD rats were separated into normal group, ADR group, ADR+Losartan group (20 mg/kg), and ADR + ADSC group. AN rats were induced by intravenous injection with adriamycin (8 mg/kg), and 4 d later, ADSC (2 × 10 cells/mouse) were administrated twice with 2 weeks interval time (i.v.). The rats were euthanized after the 6 weeks' treatment. Biochemical indicators reflecting renal injury, such as blood urea nitrogen (BUN), neutrophil gelatinase alpha (NGAL), serum creatinine (Scr), inflammation, oxidative stress, and pro-fibrosis molecules, were evaluated. Results demonstrated that we obtained high qualified ADSCs for treatment determined by flow cytometry, and ADSCs treatment significantly ameliorated renal injuries in DN rats by decreasing BUN, Scr and NGAL in peripheral blood, as well as renal histopathological injuries, especially protecting the integrity of podocytes by immunofluorescence. Furthermore, ADSCs treatment also remarkably reduced the renal inflammation, oxidative stress, and fibrosis in DN rats. Preliminary mechanism study suggested that the ADSCs treatment significantly increased renal neovascularization via enhancing proangiogenic VEGF production. Pharmacodynamics study using in vivo imaging confirmed that ADSCs via intravenous injection could accumulate into the kidneys and be alive at least 2 weeks. In a conclusion, ADSC can significantly alleviate ADR-induced nephropathy, and mainly through reducing oxidative stress, inflammation and fibrosis, as well as enhancing VEGF production.

With the rapid development of the field of life sciences, traditional 2D cell culture and animal models have long been unable to meet the urgent needs of modern biomedical research and new drug development. Establishing a new generation of experimental models and research models is of great significance for deeply understanding human health and disease processes, and developing effective treatment measures. As is well known, long research and development cycles, high risks, and high costs are the "three mountains" facing the development of new drugs today. Organoids and organ-on-chips technology can highly simulate and reproduce the human physiological environment and complex reactions in , greatly improving the accuracy of drug clinical efficacy prediction, reducing drug development costs, and avoiding the defects of drug testing animal models. Therefore, organ-on-chips have enormous potential in medical diagnosis and treatment.

Gasdermin-D (GSDMD) belongs to the Gasdermin family (GSDM), which are pore-forming effector proteins that facilitate inflammatory cell death, also known as pyroptosis. This type of programmed cell death is dependent on inflammatory caspase activation, which cleaves gasdermin-D (GSDMD) to form membrane pores and initiates the release of pro-inflammatory cytokines. Pyroptosis plays an important role in achieving immune regulation and homeostasis within various organ systems. The role of GSDMD in pyroptosis has been extensively studied in recent years. In this review, we summarize the role of GSDMD in cellular and organ injury mediated by pyroptosis. We will also provide an outlook on GSDMD therapeutic targets in various organ systems.

Decellularized scaffolds are promising biomaterials for tissue and organ reconstruction; however, strategies to effectively suppress the host immune responses toward these implants, particularly those without chemical crosslinking, remain warranted. Administration of mesenchymal stem cells is effective against immune-mediated inflammatory disorders. Herein, we investigated the effect of isogeneic abdominal adipose-derived mesenchymal stem/stromal cells (ADMSCs) on xenogeneic biomaterial-induced immunoreactions. Peripheral bronchi from pigs, decellularized using a detergent enzymatic method, were engrafted onto tracheal defects of Brown Norway (BN) rats. BN rats were implanted with native pig bronchi (Xenograft group), decellularized pig bronchi (Decellularized Xenograft), or Decellularized Xenograft and ADMSCs (Decellularized Xenograft+ADMSC group). In the latter group, ADMSCs were injected intravenously immediately post implantation. Harvested graft implants were assessed histologically and immunohistochemically. We found that acute rejections were milder in the Decellularized Xenograft and Decellularized Xenograft+ADMSC groups than in the Xenograft group. Mild inflammatory cell infiltration and reduced collagen deposition were observed in the Decellularized Xenograft+ADMSC group. Additionally, ADMSC administration decreased CD8+ lymphocyte counts but increased CD163+ cell counts. In the Decellularized Xenograft+ADMSC group, serum levels of vascular endothelial growth factor and IL-10 were elevated and tissue deposition of IgM and IgG was low. The significant immunosuppressive effects of ADMSCs illustrate their potential use as immunosuppressive agents for xenogeneic biomaterial-based implants.

It is known to all that Wnt signaling pathway plays an important role in the early development of tooth. Our previous research found that Wnt signaling pathway played crucial roles in dental development, and mutations in antagonist of Wnt signaling pathway may lead to the formation of supernumerary teeth. However, the expression pattern of Wnt signaling molecules in early development of tooth, especially genes with stage specificity, remains unclear. Hence, we applied RNA-seq analysis to determine the expression levels of wnt signal molecules at five different stages of rat first molar tooth germ. In addition, after literature review we summarized the function of Wnt signaling molecules during tooth development and the relationship between Wnt signaling molecules variation and tooth agenesis. Our research may have implications for exploring the role of Wnt signaling molecules in different stages of tooth development.

Oral leukoplakia (OLK) and oral lichen planus (OLP) are common precancerous lesions of the oral mucosa. The role of circular RNAs (circRNAs) in OLK and OLP is unclear. The aim of this study was to evaluate the circRNA expression profiles of OLK and OLP, and further explore the potential role of circRNAs in the pathogenesis of these two diseases.

Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), the most common types of cholestatic liver disease (CLD), result in enterohepatic obstruction, bile acid accumulation, and hepatotoxicity. The mechanisms by which hepatocytes respond to and cope with CLD remain largely unexplored. This study includes the characterization of hepatocytes isolated from explanted livers of patients with PBC and PSC. We examined the expression of hepatocyte-specific genes, intracellular bile acid (BA) levels, and oxidative stress in primary-human-hepatocytes (PHHs) isolated from explanted livers of patients with PBC and PSC and compared them with control normal human hepatocytes. Our findings provide valuable initial insights into the hepatocellular response to cholestasis in CLD and help support the use of PHHs as an experimental tool for these diseases.

Articular cartilage is a common cartilage type found in a multitude of joints throughout the human body. However, cartilage is limited in its regenerative capacity. A range of methods have been employed to aid adults under the age of 45 with cartilage defects, but other cartilage pathologies such as osteoarthritis are limited to non-steroidal anti-inflammatory drugs and total joint arthroplasty. Cell therapies and synthetic biology can be utilized to assist not only cartilage defects but have the potential as a therapeutic approach for osteoarthritis as well. In this review, we will cover current cell therapy approaches for cartilage defect regeneration with a focus on autologous chondrocyte implantation and matrix autologous chondrocyte implantation. We will then discuss the potential of stem cells for cartilage repair in osteoarthritis and the use of synthetic biology to genetically engineer cells to promote cartilage regeneration and potentially reverse osteoarthritis.

In drug development, conventional preclinical and clinical testing stages rely on cell cultures and animal experiments, but these methods may fall short of fully representing human biology. To overcome this limitation, the emergence of organ-on-a-chip (OOC) technology has sparked interest as a transformative approach in drug testing research. By closely replicating human organ responses to external signals, OOC devices hold immense potential in revolutionizing drug efficacy and safety predictions. This review focuses on the advancements, applications, and prospects of OOC devices in drug testing. Based on the latest advances in the field of OOC systems and their clinical applications, this review reflects the effectiveness of OOC devices in replacing human volunteers in certain clinical studies. This review underscores the critical role of OOC technology in transforming drug testing methodologies.

Prostate cancer (PCa) poses a serious burden to men. Interferon-β (IFN-β) is implicated in cancer cell growth. This study hence explored the regulation of IFN-β-modified human umbilical cord mesenchymal stem cell-derived exosomes (hUCMSC-Exos) in PCa cells. cultured hUCMSCs were transfected with pcDNA3.1-IFN-β plasmid or IFN-β siRNA. hUCMSC-Exos were extracted by ultracentrifugation and identified. PCa cells (PC3 and LNCap) were treated with Exos. Cellular internalization of Exos by cells was detected by uptake assay. Cell proliferation, cycle, and apoptosis were evaluated by CCK-8, EdU staining, and flow cytometry. Levels of cell cycle-related proteins (cyclin D/cyclin E) were determined by Western blot. The effect of IFN-β-modified hUCMSC-Exos was analyzed. IFN-β-modified hUCMSC-Exos (Exo or Exo) were successfully isolated. IFN-β was encapsulated in Exos, and PCa cells could uptake Exos. After treating with Exo, PCa cell proliferation was impeded, the percentage of cells in the G0/G1 phase, cyclin D/cyclin E levels, and cell apoptotic rate were elevated, while cells treated with Exo exhibited contrary trends. IFN-β-modified hUCMSC-Exos reduced PCa tumor size and weight . Conjointly, IFN-β-modified hUCMSC-Exos suppress PCa cell proliferation and facilitate apoptosis.

Based on successes in preclinical animal transplant models, adoptive cell therapy (ACT) with regulatory T cells (Tregs) is a promising modality to induce allograft tolerance or reduce the use of immunosuppressive drugs to prevent rejection. Extensive work has been done in optimizing the best approach to manufacture Treg cell products for testing in transplant recipients. Collectively, clinical evaluations have demonstrated that large numbers of Tregs can be expanded and infused safely. However, these trials have failed to induce robust drug-free tolerance and/or significantly reduce the level of immunosuppression needed to prevent solid organ transplant (SOTx) rejection. Improving Treg therapy effectiveness may require increasing Treg persistence or orchestrating Treg migration to secondary lymphatic tissues or places of inflammation. In this review, we describe current clinical Treg manufacturing methods used for clinical trials. We also highlight current strategies being implemented to improve delivered Treg ACT persistence and migration in preclinical studies.

Hard-to-heal wounds can be detrimental to patients' quality of life. Currently, there is scarcity of therapeutic alternatives to mainstay surgical treatment, which uses the principles of tissue debridement, temporary wound coverage, and subsequent tissue reconstruction. Here, a new approach is proposed that harnesses the regenerative power of autologous peripheral blood, through a process termed hypoxia-adjusted preconditioning. The effectiveness of this method is demonstrated with six cases of surgical wounds, including two cases of large full-thickness dermal wounds that developed as a result of skin necrosis following abdominoplasty and buttock-lift procedures in heavy smokers, as well as a case of extensive inflammatory tissue damage that occurred following breast surgery. While these wounds differed in size (4-160 cm), geometry and location, all of them could be managed conservatively with topical application of growth factor-enriched hypoxia preconditioned serum derived from the patient's own peripheral blood. This treatment led to complete wound closure by latest 135 days. The finding of complete skin regeneration even in large (>10 cm), full-thickness wounds, where initially no dermal tissue was available in the wound bed, strongly suggests that the treatment targeted key cellular regenerative mechanisms, including differentiation, angiogenesis, granulation tissue induction, contraction and epithelialization. The method is readily clinically applicable, cost effective, and overcomes limitations of the classic reconstructive approach.

Encephalitis, the most significant of the central nervous system (CNS) diseases caused by Herpes simplex virus 1 (HSV-1), may have long-term sequelae in survivors treated with acyclovir, the cause of which is unclear. HSV-1 exhibits a tropism toward neurogenic niches in CNS enriched with neural precursor cells (NPCs), which play a pivotal role in neurogenesis. NPCs are susceptible to HSV-1. There is a paucity of information regarding the influence of HSV-1 on neurogenesis in humans. We investigated HSV-1 infection of NPCs from two individuals. Our results show (i) HSV-1 impairs, to different extents, the proliferation, self-renewing, and, to an even greater extent, migration of NPCs from these two subjects; (ii) The protective effect of the gold-standard antiherpetic drug acyclovir (ACV) varies with viral dose and is incomplete. It is also subject to differences in terms of efficacy of the NPCs derived from these two individuals. These results suggest that the effects of HSV-1 may have on aspects of NPC neurogenesis may vary among individuals, even in the presence of acyclovir, and this may contribute to the heterogeneity of cognitive sequelae across encephalitis survivors. Further analysis of NPC cell lines from a larger number of individuals is warranted.

Mesenchymal stem cells (MSC) and induced pluripotent stem cells (iPSC) have been reported to be able to differentiate to hepatocyte in vitro with varying degree of hepatocyte maturation. A simple method to decellularize liver scaffold has been established by the Department of Histology, Faculty of Medicine, Universitas Indonesia, in SCTE IMERI lab. This study aims to evaluate hepatocyte differentiation from iPSCs compared to MSCs derived in our decellularized liver scaffold. The research stages started with iPSC culture, decellularization, seeding cell culture into the scaffold, and differentiation into hepatocytes for 21 days. Hepatocyte differentiation from iPSCs and MSCs in the scaffolds was characterized using hematoxylin-eosin, Masson Trichrome, and immunohistochemistry staining to determine the fraction of the differentiation area. RNA samples were isolated on days 7 and 21. Expression of albumin, CYP450, and CK-19 genes were analyzed using the qRT-PCR method. Electron microscopy images were obtained by SEM. Immunofluorescence examination was done using HNF4-α and CEBPA markers. The results of this study in hepatocyte-differentiated iPSCs compared with hepatocyte-differentiated MSCs in decellularized liver scaffold showed lower adhesion capacity, single-cell-formation and adhered less abundant, decreased trends of albumin, and lower CYP450 expression. Several factors contribute to this result: lower initial seeding number, which causes only a few iPSCs to attach to certain parts of decellularized liver scaffold, and manual syringe injection for recellularization, which abruptly and unevenly creates pattern of single-cell-formation by hepatocyte-differentiated iPSC in the scaffold. Hepatocyte-differentiated MSCs have the advantage of higher adhesion capacity to collagen fiber decellularized liver scaffold. This leads to positive result: increase trends of albumin and higher CYP450 expression. Hepatocyte maturation is shown by diminishing CK-19, which is more prominent in hepatocyte-differentiated iPSCs in decellularized liver scaffold. Confirmation of mature hepatocyte-differentiated iPSCs in decellularized liver scaffold maturation is positive for HNF4-a and CEBPA. The conclusion of this study is hepatocyte-differentiated iPSCs in decellularized liver scaffold is mature with lower cell-ECM adhesion, spatial cell distribution, albumin, and CYP450 expression than hepatocyte-differentiated MSCs in decellularized liver scaffold.

The human eyelid embodies a vast diversity of functions. Acting as a protective shield for the ocular apparatus and as a light regulator in the sight process, eyelids stand a fascinating - yet omitted - role in facial aesthetics, serving as a racial trait by which humankind succeeded to manifest heterogeneity as a species. These assumptions are precisely forecasted right from in-utero life through intricate processes of growth and cell differentiation. In the Department of Anatomy of "Carol Davila" University of Medicine and Pharmacy, we performed morphological assessments on 41 embryos and fetuses with gestational ages ranging from 6 to 29 weeks. This study aims to illustrate the morphogenesis of eyelids in human embryos and fetuses and highlight macroscopic features which could potentially have significant clinical implications in ophthalmic pathology.

Hippo pathway is a cellular regulatory pathway composed of core molecules such as MST1/2, LATS1/2, SAV1, MOB1A/B and downstream YAP/TAZ. Fully involved in regulating cell proliferation, differentiation, migration and apoptosis, the Hippo pathway is critical in regulating stem cells of oral origin, for instance, DPSCs and PDLSCs, enamel formation and periodontium regeneration. Here, we summarized the Hippo pathway involved in these progresses and concluded crosstalks of the Hippo pathway with BCL-2, ERK1/2, ROCK, TGF-β/BMP and Wnt/β-catenin pathways, hoping to provide foundation for further clinical therapy.

Antibody-mediated rejection (ABMR) is the major cause of chronic allograft dysfunction and loss in kidney transplantation. The immunological mechanisms of ABMR that have been featured in the latest studies indicate a highly complex interplay between various immune and nonimmune cell types. Clinical diagnostic standards have long been criticized for being arbitrary and the lack of accuracy. Transcriptomic approaches, including microarray and RNA sequencing of allograft biopsies, enable the identification of differential gene expression and the continuous improvement of diagnostics. Given that conventional bulk transcriptomic approaches only reflect the average gene expression but not the status at the single-cell level, thereby ignoring the heterogeneity of the transcriptome across individual cells, single-cell RNA sequencing is rising as a powerful tool to provide a high-resolution transcriptome map of immune cells, which allows the elucidation of the pathogenesis and may facilitate the development of novel strategies for clinical treatment of ABMR.

The prevalence of end-stage liver disease (ESLD) in the US is increasing at an alarming rate. It can be caused by several factors; however, one of the most common routes begins with nonalcoholic fatty liver disease (NAFLD). ESLD is diagnosed by the presence of irreversible damage to the liver. Currently, the only definitive treatment for ESLD is orthotopic liver transplantation (OLT). Nevertheless, OLT is limited due to a shortage of donor livers. Several promising alternative treatment options are under investigation. Researchers have focused on the effect of liver-enriched transcription factors (LETFs) on disease progression. Specifically, hepatocyte nuclear factor 4-alpha (HNF4α) has been reported to reset the liver transcription network and possibly play a role in the regression of fibrosis and cirrhosis. In this review, we describe the function of HNF4α, along with its regulation at various levels. In addition, we summarize the role of HNF4α in ESLD and its potential as a therapeutic target in the treatment of ESLD.