Improved sorafenib activity on hepatocellular carcinoma in Notch3 silenced in vivo and in vitro models.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3061-3061
Author(s):  
Michele Baglioni ◽  
Catia Giovannini ◽  
Laura Gramantieri ◽  
Marco Baron Toaldo ◽  
Cristiano Ventrucci ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Fate ◽  
Cell Lines ◽  
Molecular Mechanisms ◽  
Randomized Clinical Trials ◽  
Advanced Stage ◽  
Sorafenib Treatment ◽  
Cellular Models

3061 Background: Sorafenib is the only approved drug for the treatment of the advanced stage of HCC. Although its efficacy has been proven with randomized clinical trials, the clinical benefit seen in overall survival for advanced HCC patients treated with sorafenib could be improved. New molecules or combination of novel targeted agents to improve sorafenib efficacy for advanced stage HCC patients are needed. Notch genes are a family of receptors involved in many cell fate regulations, their expression has been found altered in many tumors, including HCC. The aim of this study was to study the combination of sorafenib and Notch3 signaling inhibition to improve sorafenib’s therapeutic effect. Methods: HepG2 and Huh7 cellular models were used for Notch3 stable silencing by retroviral introduction of specific interfering RNAs Xenograft models in both Notch3 stable shRNA cell lines have been developed using NOD/SCID mice. Animals bearing tumors were treated with 60 mg/kg of sorafenib for 21 consecutive days. Notch3, p21 and pGSK3βSer9 protein expression were also analyzed in 20 human HCCs. Results: Notch3 silencing (shN3) in HuH7 and HepG2 cell lines treated with sorafenib showed an increase in cell death (3.8 to 5 fold increase) when shN3 cell lines were compared with their relative controls (GL2). A difference in tumor growth was observed between GL2 negative control vs shN3 xenografts in both HepG2 and Huh7 after 21 days of sorafenib treatment. Two tailed student’s t test (shN3 vs GL2) P=0,04 and P=0,01 for Huh7 and HepG2 respectively. Molecular investigations have shown the involvement of p21 and GSK3β in the enhanced response to sorafenib in Notch 3 silenced models. A significant inverse correlation between Notch3 and pGSK3βSer9 proteins accumulation (Spearman ρ= -0.666) (p < 0.01) and a direct correlation between Notch3 and p21 proteins expression (Spearman ρ= 0.681) (p < 0.01) was found in HCC samples obtained from patients. Conclusion: Our preclincal findings outline the effect of combined Notch3 inhibition and sorafenib. The molecular mechanisms responsible for sorafenib induced cell death associated with Notch3 silencing relays on inhibition of p21/CDKN1A and GSK3βSer9. This study is supported by a grant from Bayer Healthcare, Italy.

scholarly journals CASK Silence Enhances Chemosensitivity of Hepatocellular Carcinoma Through activating Apoptosis, Inducing JNK/c-Jun-Mediated Autophagic Cell Death and Decreasing ABCG2

2021 ◽  
Author(s):  
BiSha Ding ◽  
Chang Bao ◽  
Luqi Jin ◽  
Liang Xu ◽  
Zhijun Dai ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Drug Resistance ◽  
Cell Death ◽  
Molecular Mechanisms ◽  
Autophagic Cell Death ◽  
Cell Counting ◽  
Advanced Hepatocellular Carcinoma ◽  
Sorafenib Treatment

Abstract Background: Advanced hepatocellular carcinoma (HCC) patients usually fail to be treated because of drug resistance, including sorafenib. Methods: The expression and prognostic role of calcium/calmodulin-dependent serine protein kinase (CASK) in HCC were assessed by combination of bioinformatic analysis and experimental validation. The effects of CASK in regulating proliferation, apoptosis and drug resistance of HCC cells in vitro and in vivo were investigated using gain- or loss-of-function strategies by performing lots of specific methods including Cell Counting kit-8 (CCK8), colony formation assay, flow cytometry, transmission electron microscopy, immunofluorescent confocal laser microscopy and tumor xenograft experiments, immunohistochemistry staining. Moreover, the underlying molecular mechanisms responsible for CASK’s functions in HCC were also explored. Results: Currently, we discovered that CASK was positively associated with sorafenib resistance of HCC in vitro and in vivo, and was significantly related with poor prognosis in HCC. Moreover, inhibition of CASK can increase the effect of sorafenib partially by promoting apoptosis and autophagy, while CASK overexpression presented the opposite results. Besides, all the pan-caspase inhibitor Z-VAD-FMK, autophagy inhibitor 3-Methyladenine (3-MA) and small interfering RNA (siRNA) of LC3B reversed CASK knockout-induced effects with sorafenib treatment, suggesting that both apoptosis and autophagy were involved in CASK-mediated above functions and autophagy played a pro-death role in this research. Intriguingly, similar results were observed in vivo. In molecular level, CASK knockout activated the c-Jun N-terminal kinase (JNK) pathway, and treatment with JNK inhibitor SP600125 or transiently transfected with si-JNK significantly attenuated CASK knockout-mediated autophagic cell death. Besides, knockout of CASK dramatically inhibited the expression of ATP binding cassette subfamily G member 2 (ABCG2) and reversed of multidrug-resistance (MDR) of HCC. Conclusions: Collectively, all these results together indicated that CASK might be a promising biomarker for HCC patients and a potential therapeutic target for relieving drug resistance of HCC.

Efficacy of Panobinostat (LBH589) in CTCL Cell Lines and a Murine Xenograft Model: Defining Molecular Pathways of Panobinostat Activity in CTCL.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1375-1375 ◽  
Author(s):  
Wenlin Shao ◽  
Joseph D. Growney ◽  
Yun Feng ◽  
Gregory O’Connor ◽  
Minying Pu ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Lines ◽  
Molecular Mechanisms ◽  
Tumor Regression ◽  
Single Agent ◽  
Xenograft Model ◽  
Stat Proteins ◽  
Murine Xenograft Model

Abstract Panobinostat (LBH589) is a highly potent oral pan-deacetylase (DAC) inhibitor currently undergoing clinical development in hematologic and solid malignancies. Panobinostat demonstrated preliminary clinical efficacy in cutaneous T-cell lymphoma (CTCL) patients in a phase I trial, with 6 responders out of 10 patients. Here we report the characterization of the effects of panobinostat on CTCL cells in vitro and in a murine xenograft model of CTCL. Panobinostat was found to potently induce growth inhibition of all CTCL cell lines tested (HuT78, HuT102, MJ, and HH) and exhibited significant cytotoxic activity against two CTCL cell lines (HuT78 and HH). Panobinostat was found to induce activation of caspases 3 and 7 in HuT78 and HH cell lines, consistent with its effects on cell viability in these cells. To investigate the effect of panobinostat in vivo, an HH CTCL xenograft mouse model was treated with vehicle or different doses of panobinostat by iv administration qd×5 for 2 weeks. Treatment with panobinostat at 10 mg/kg resulted in complete tumor regression relative to vehicle-treated animals. To gain a better understanding of panobinostat activity in CTCL, molecular mechanisms underlying cell sensitivity or lack thereof were investigated. Inhibition of DAC activity as measured by hyperacetylation of histones H3, H4, and tubulin was observed equally in all four cell lines. Interestingly, CTCL cells insensitive to panobinostat cytotoxicity (HuT102 and MJ) were found to express significantly higher levels of IL-2 receptor and to secrete high levels of select cytokines, including IFN-α, IFN-γ, and TNF-α, as compared with CTCL cells sensitive to panobinostat-induced cytotoxicity. Contrary to panobinostat-sensitive CTCL cells, cells insensitive to panobinostat-induced cell death were found to contain constitutively active NF-κB signaling and elevated activation of STAT proteins. Panobinostat-insensitive HuT102 and MJ cell lines were also found to express high levels of the pro-survival protein Bcl-2, an anti-apoptotic target whose transcription can be activated by NF-κB signaling. Although inhibition of STAT5 activation using a JAK inhibitor did not confer panobinostat sensitivity in the HuT102 and MJ CTCL cell lines, combination of a Bcl-2 inhibitor with panobinostat revealed a synergistic effect on cytotoxicity in these CTCL cells. Such results suggest that blocking anti-apoptotic signaling in combination with panobinostat treatment is effective in conferring panobinostat sensitivity to CTCL cells refractory to panobinostat-induced cell death. These data demonstrate that panobinostat exhibits significant anti-cancer effects on CTCL cells both in vitro and in vivo at clinically attainable concentrations. In addition, we have identified a cellular mechanism of insensitivity to panobinostat and furthermore provided a potential approach for sensitizing cells to panobinostat treatment in combination with a Bcl-2 inhibitor. Panobinostat, as a single agent or in combination, is a promising therapy for CTCL and these studies support continued clinical evaluation of panobinostat in the treatment of CTCL.

scholarly journals miR-182-5p and miR-378a-3p regulate ferroptosis in I/R-induced renal injury

2020 ◽  
Vol 11 (10) ◽  
Author(s):  
Chenguang Ding ◽  
Xiaoming Ding ◽  
Jin Zheng ◽  
Bo Wang ◽  
Yang Li ◽  
...  
Keyword(s):  
Cell Death ◽  
Renal Injury ◽  
Molecular Mechanisms ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Luciferase Reporter ◽  
Renal Tubular Cell ◽  
In Cells

Abstract Renal tubular cell death is the key factor of the pathogenesis of ischemia/reperfusion (I/R) kidney injury. Ferroptosis is a type of regulated cell death (RCD) found in various diseases. However, the underlying molecular mechanisms related to ferroptosis in renal I/R injury remain unclear. In the present study, we investigated the regulatory role of microRNAs on ferroptosis in I/R-induced renal injury. We established the I/R-induced renal injury model in rats, and H/R induced HK-2 cells injury in vitro. CCK-8 was used to measure cell viability. Fe2+ and ROS levels were assayed to evaluate the activation of ferroptosis. We performed RNA sequencing to profile the miRNAs expression in H/R-induced injury and ferroptosis. Western blot analysis was used to detect the protein expression. qRT-PCR was used to detect the mRNA and miRNA levels in cells and tissues. We further used luciferase reporter assay to verify the direct targeting effect of miRNA. We found that ischemia/reperfusion-induced ferroptosis in rat’s kidney. We identified that miR-182-5p and miR-378a-3p were upregulated in the ferroptosis and H/R-induced injury, and correlates reversely with glutathione peroxidases 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11) expression in renal I/R injury tissues, respectively. In vitro studies showed that miR-182-5p and miR-378a-3p induced ferroptosis in cells. We further found that miR-182-5p and miR-378a-3p regulated the expression of GPX4 and SLC7A11 negatively by directly binding to the 3′UTR of GPX4 and SLC7A11 mRNA. In vivo study showed that silencing miR-182-5p and miR-378a-3p alleviated the I/R-induced renal injury in rats. In conclusion, we demonstrated that I/R induced upregulation of miR-182-5p and miR-378a-3p, leading to activation of ferroptosis in renal injury through downregulation of GPX4 and SLC7A11.

scholarly journals Therapeutic evaluation of palbociclib and its compatibility with other chemotherapies for primary and recurrent nasopharyngeal carcinoma

2020 ◽  
Author(s):  
zhichao xue ◽  
Vivian Wai Yan Lui ◽  
Yongshu Li ◽  
Jia Lin ◽  
Chanping You ◽  
...  
Keyword(s):  
Cell Death ◽  
Nasopharyngeal Carcinoma ◽  
Cell Lines ◽  
Chemotherapeutic Drugs ◽  
Induce Cell Cycle Arrest ◽  
Ki 67 ◽  
Concurrent Treatment ◽  
Xenograft Models

Abstract Background: Recent genomic analyses revealed that druggable molecule targets were detectable in approximately 6% of patients with nasopharyngeal carcinoma (NPC). However, a dependency on dysregulated CDK4/6–cyclinD1 pathway signaling is an essential event in the pathogenesis of NPC. In this study, we aimed to evaluate the therapeutic efficacy of a specific CDK4/6 inhibitor, palbociclib, and its compatibility with other chemotherapeutic drugs for the treatment of NPC by using newly established xenograft models and cell lines derived from primary, recurrent, and metastatic NPC. Methods: We evaluated the efficacies of palbociclib monotherapy and concurrent treatment with palbociclib and cisplatin or suberanilohydroxamic acid (SAHA) in NPC cell lines and xenograft models. RNA sequencing was then used to profile the drug response–related pathways. Palbociclib-resistant NPC cell lines were established to determine the potential use of cisplatin as a second-line treatment after the development of palbociclib resistance. We further examined the efficacy of palbociclib treatment against cisplatin-resistant NPC cells. Results: In NPC cells, palbociclib monotherapy was confirmed to induce cell cycle arrest in the G1 phase in vitro . Palbociclib monotherapy also had significant inhibitory effects in all six tested NPC tumor models in vivo , as indicated by substantial reductions in the total tumor volumes and in Ki-67 proliferation marker expression. In NPC cells, concurrent palbociclib treatment mitigated the cytotoxic effect of cisplatin in vitro . Notably, concurrent treatment with palbociclib and SAHA synergistically promoted NPC cell death both in vitro and in vivo . This combination also further inhibited tumor growth by inducing autophagy-associated cell death. NPC cell lines with induced palbociclib or cisplatin resistance remained sensitive to treatment with cisplatin or palbociclib, respectively. Conclusions: Our study findings provide essential support for the use of palbociclib as an alternative therapy for NPC and increase awareness of the effective timing of palbociclib administration with other chemotherapeutic drugs. Our results provide a foundation for the design of first-in-human clinical trials of palbociclib regimens in patients with NPC.

scholarly journals Ivermectin induces autophagy-mediated cell death through the AKT/mTOR signaling pathway in glioma cells

2019 ◽  
Vol 39 (12) ◽  
Author(s):  
Jingjing Liu ◽  
Hongsheng Liang ◽  
Chen Chen ◽  
Xiaoxing Wang ◽  
Faling Qu ◽  
...  
Keyword(s):  
Cell Death ◽  
Molecular Mechanisms ◽  
Anticancer Agent ◽  
Glioma Cells ◽  
Mtor Signaling ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Transmission Electron ◽  
Diphenyltetrazolium Bromide

Abstract Glioma is one of the most common types of primary brain tumors. Ivermectin (IVM), a broad-spectrum antiparasitic drug, has been identified as a novel anticancer agent due to its inhibitory effects on the proliferation of glioma cells in vitro and in vivo. However, the ability of IVM to induce autophagy and its role in glioma cell death remains unclear. The main objective of the present study was to explore autophagy induced by IVM in glioma U251 and C6 cells, and the deep underlying molecular mechanisms. In addition, we examined the effects of autophagy on apoptosis in glioma cells. In the present study, transmission electron microscopy (TEM), immunofluorescence, Western blot and immunohistochemistry were used to evaluate autophagy activated by IVM. Cell viability was measured by 3-(4,5-dimethylthiazol2-yl)-2, 5-diphenyltetrazolium bromide (MTT) and colony formation assay. The apoptosis rate was detected by flow cytometry and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL). Meanwhile, autophagy inhibition was achieved by using chloroquine (CQ). U251-derived xenografts were established for examination of IVM-induced autophagy on glioma in vivo. Taken together, the results of the present study showed that autophagy induced by IVM has a protective effect on cell apoptosis in vitro and in vivo. Mechanistically, IVM induced autophagy through AKT/mTOR signaling and induced energy impairment. Our findings show that IVM is a promising anticancer agent and may be a potential effective treatment for glioma cancers.

Advances and Challenges in Kidney Organoids

2021 ◽  
Vol 16 ◽  
Author(s):  
Vikram Sabapathy ◽  
Gabrielle Costlow ◽  
Rajkumar Venkatadri ◽  
Murat Dogan ◽  
Sanjay Kumar ◽  
...  
Keyword(s):  
Cell Fate ◽  
Pluripotent Stem Cells ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Complex Structures ◽  
Cell Culture Systems ◽  
Epigenetic Signatures ◽  
Kidney Organoids

: The advent of organoids has renewed researcher's interest in in vitro cell culture systems. A wide variety of protocols, primarily utilizing pluripotent stem cells, are under development to improve organoid generation to mimic organ development. The complexity of organoids generated is greatly influenced based on the method used. Understanding the process of kidney organoid formation gives developmental insights into how renal cells form, mature, and interact with the adjacent cells to form specific spatiotemporal structural patterns. This knowledge can bridge the gaps in understanding in vivo renal developmental processes. Evaluating genetic and epigenetic signatures in specialized cell types can help interpret the molecular mechanisms governing cell fate. In addition, development in single-cell RNA sequencing and 3D bioprinting and microfluidic technologies has led to better identification and understanding of a variety of cell types during differentiation and designing of complex structures to mimic the conditions in vivo. While several reviews have highlighted the application of kidney organoids, there is no comprehensive review of various methodologies specifically focusing on the kidney organoids. This review summarizes the updated differentiation methodologies, applications, and challenges associated with kidney organoids. Here we have comprehensively collated all the different variables influencing the organoid generation.

scholarly journals Current translational potential and underlying molecular mechanisms of necroptosis

2019 ◽  
Vol 10 (11) ◽  
Author(s):  
Tamás Molnár ◽  
Anett Mázló ◽  
Vera Tslaf ◽  
Attila Gábor Szöllősi ◽  
Gabriella Emri ◽  
...  
Keyword(s):  
Cell Death ◽  
Protein Kinase ◽  
Posttranslational Modifications ◽  
Molecular Mechanisms ◽  
Inflammatory Diseases ◽  
Immune Surveillance ◽  
Kinase Domain ◽  
Tumor Formation

Abstract Cell death has a fundamental impact on the evolution of degenerative disorders, autoimmune processes, inflammatory diseases, tumor formation and immune surveillance. Over the past couple of decades extensive studies have uncovered novel cell death pathways, which are independent of apoptosis. Among these is necroptosis, a tightly regulated, inflammatory form of cell death. Necroptosis contribute to the pathogenesis of many diseases and in this review, we will focus exclusively on necroptosis in humans. Necroptosis is considered a backup mechanism of apoptosis, but the in vivo appearance of necroptosis indicates that both caspase-mediated and caspase-independent mechanisms control necroptosis. Necroptosis is regulated on multiple levels, from the transcription, to the stability and posttranslational modifications of the necrosome components, to the availability of molecular interaction partners and the localization of receptor-interacting serine/threonine-protein kinase 1 (RIPK1), receptor-interacting serine/threonine-protein kinase 3 (RIPK3) and mixed lineage kinase domain-like protein (MLKL). Accordingly, we classified the role of more than seventy molecules in necroptotic signaling based on consistent in vitro or in vivo evidence to understand the molecular background of necroptosis and to find opportunities where regulating the intensity and the modality of cell death could be exploited in clinical interventions. Necroptosis specific inhibitors are under development, but >20 drugs, already used in the treatment of various diseases, have the potential to regulate necroptosis. By listing necroptosis-modulated human diseases and cataloging the currently available drug-repertoire to modify necroptosis intensity, we hope to kick-start approaches with immediate translational potential. We also indicate where necroptosis regulating capacity should be considered in the current applications of these drugs.

scholarly journals Anticancer Activity of Cynomorium coccineum

Cancers ◽  
2018 ◽  
Vol 10 (10) ◽  
pp. 354 ◽  
Author(s):  
Mouna Sdiri ◽  
Xiangmin Li ◽  
William Du ◽  
Safia El-Bok ◽  
Yi-Zhen Xie ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Death ◽  
Anticancer Activity ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cell Cycle Progression ◽  
Cycle Progression

The extensive applications of Cynomorium species and their rich bioactive secondary metabolites have inspired many pharmacological investigations. Previous research has been conducted to examine the biological activities and numerous interesting pharmaceutical activities have been reported. However, the antitumor activities of these species are unclear. To understand the potential anticancer activity, we screened Cynomorium coccineum and Cynomorium songaricum using three different extracts of each species. In this study, the selected extracts were evaluated for their ability to decrease survival rates of five different cancer cell lines. We compared the cytotoxicity of the three different extracts to the anticancer drug vinblastine and one of the most well-known medicinal mushrooms Amaurederma rude. We found that the water and alcohol extracts of C. coccineum at the very low concentrations possessed very high capacity in decreasing the cancer cells viability with a potential inhibition of tumorigenesis. Based on these primitive data, we subsequently tested the ethanol and the water extracts of C. coccineum, respectively in in vitro and in vivo assays. Cell cycle progression and induction of programmed cell death were investigated at both biological and molecular levels to understand the mechanism of the antitumor inhibitory action of the C. coccineum. The in vitro experiments showed that the treated cancer cells formed fewer and smaller colonies than the untreated cells. Cell cycle progression was inhibited, and the ethanol extract of C. coccineum at a low concentration induced accumulation of cells in the G1 phase. We also found that the C. coccineum’s extracts suppressed viability of two murine cancer cell lines. In the in vivo experiments, we injected mice with murine cancer cell line B16, followed by peritoneal injection of the water extract. The treatment prolonged mouse survival significantly. The tumors grew at a slower rate than the control. Down-regulation of c-myc expression appeared to be associated with these effects. Further investigation showed that treatment with C. coccineum induced the overexpression of the tumor suppressor Foxo3 and other molecules involved in inducing autophagy. These results showed that the C. coccineum extract exerts its antiproliferative activity through the induction of cell death pathway. Thus, the Cynomorium plants appear to be a promising source of new antineoplastic compounds.

scholarly journals IMMU-14. ONCOLYTIC VIRUS EXPRESSING A POSITIVE IMMUNE CHECKPOINT MODULATOR AS A THERAPEUTIC APPROACH FOR DIPG

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi122-vi122
Author(s):  
Virginia Laspidea ◽  
Montse Puigdelloses ◽  
Ignacio Iñigo-Marco ◽  
Marc Garcia-Moure ◽  
Iker Ausejo ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Cell Death ◽  
Cell Lines ◽  
Oncolytic Virus ◽  
Murine Models ◽  
Antitumoral Effect ◽  
Infected Cells

Abstract Diffuse intrinsic pontine glioma (DIPG) is an aggressive brain tumor, being the leading cause of pediatric death caused by cancer. We previously showed that administration of the oncolytic virus Delta-24-RGD to DIPG murine models was safe and led to an increase in the median survival of these animals. However, not all the animals responded, underscoring the need to improve this therapy. In order to increase the antitumoral effect of the virus, we have engineered Delta-24-RGD with the costimulatory ligand 4-1BBL (Delta24-ACT). 4-1BB is a costimulatory receptor that promotes the survival and expansion of activated T cells, and the generation and maintenance of memory CD8+ T cells. In this project, we evaluated the oncolytic effect of Delta24-ACT and the antitumor immune response in DIPG murine models. In vitro, Delta24-ACT was able to infect and induce cell death in a dose-dependent manner in murine DIPG cell lines. In addition, Delta24-ACT was able to replicate in these tumor cells and to express viral proteins. Moreover, infected cells expressed 41BBL in their membranes. Delta24-ACT could induce immunogenic cell death due to an increased secretion of ATP and calreticulin translocation to the membrane of infected cells (in no-infected cells it located in the ER), DAMPs that can trigger the immune response activation. In vivo, Delta24-ACT demonstrated to be safe in all the tested doses and was able to induce a significant increase in the median survival of the treated animals. Moreover, long-term survivors display immunological memory. Delta24-ACT treatment led to antitumoral effect in DIPG murine cell lines in vitro. Of significance, we have demonstrated that in vivo administration of Delta24-ACT is safe and results in an enhanced antitumor effect. Future in vivo studies will explore the underlying immune mechanism of the virus.

scholarly journals The Role of Prep1 in the Regulation of Mesenchymal Stromal Cells

2019 ◽  
Vol 20 (15) ◽  
pp. 3639 ◽  
Author(s):  
Giorgia Maroni ◽  
Daniele Panetta ◽  
Raffaele Luongo ◽  
Indira Krishnan ◽  
Federica La Rosa ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Fate ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Molecular Mechanisms ◽  
Gene Dosage ◽  
Homeobox Gene ◽  
Fate Decision

Molecular mechanisms governing cell fate decision events in bone marrow mesenchymal stromal cells (MSC) are still poorly understood. Herein, we investigated the homeobox gene Prep1 as a candidate regulatory molecule, by adopting Prep1 hypomorphic mice as a model to investigate the effects of Prep1 downregulation, using in vitro and in vivo assays, including the innovative single cell RNA sequencing technology. Taken together, our findings indicate that low levels of Prep1 are associated to enhanced adipogenesis and a concomitant reduced osteogenesis in the bone marrow, suggesting Prep1 as a potential regulator of the adipo-osteogenic differentiation of mesenchymal stromal cells. Furthermore, our data suggest that in vivo decreased Prep1 gene dosage favors a pro-adipogenic phenotype and induces a “browning” effect in all fat tissues.

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