Melatonin attenuates radiation-induced cortical bone-derived stem cells injury and enhances bone repair in postradiation femoral defect model

2021 ◽  
Author(s):  
Wei Hu ◽  
Jiawu Liang ◽  
Song Liao ◽  
Zhidong Zhao ◽  
Yuxing Wang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Stem Cells ◽  
Flow Cytometry ◽  
Genomic Stability ◽  
Bone Defects ◽  
Self Renewal ◽  
Tnf Α ◽  
Radiation Induced ◽  
Γ Ray

Abstract Background Ionizing radiation poses a challenge to the healing of bone defects. Radiation therapy and accidental exposure to gamma-ray (γ-ray) radiation inhibit bone formation and increase the risk of fractures. Cortical bone-derived stem cells (CBSCs) are essential for osteogenic lineages, bone maintenance, and repair. This study aimed to investigate the effects of melatonin on postradiation CBSCs and bone defects. Methods CBSCs were extracted from C57/BL6 mice and were identified by flow cytometry. The effects of exogenous melatonin on the self-renewal and osteogenic capacity of postradiation CBSCs were detected in vitro. The underlying mechanisms in terms of genomic stability, apoptosis and oxidative stress-related signaling were further analyzed by western blotting, flow cytometry and immunofluorescence. Finally, the effects of melatonin on healing in postradiation bone defects were evaluated in vivo by micro-CT and immunohistochemical analysis. Results The radiation-induced reduced self-renewal and osteogenic capacity were partially reversed in postradiation CBSCs treated with melatonin. Melatonin maintained the genomic stability and apoptosis of postradiation CBSCs, and intracellular oxidative stress was decreased significantly while antioxidant-related enzymes were enhanced. Western blotting verified the anti-inflammatory effect of melatonin by downregulating the levels of IL-6 and TNF-α via extracellular regulated kinase (ERK)/nuclear factor erythroid 2-related factor 2 (NRF2)/heme oxygenase 1 (HO-1) signaling, distinct from its antioxidant effect via NRF2 signaling. In vivo experiments demonstrated that the newly formed bone in the melatonin plus Matrigel group had higher trabecular bone volume per tissue volume (BV/TV) and bone mineral density (BMD) values, and lower levels of IL-6 and TNF-α than those in the irradiation and the Matrigel groups. Conclusions This study suggested the potential of melatonin to protect CBSCs against γ-ray radiation and to assist the healing of postradiation bone defects.

scholarly journals Melatonin attenuates radiation-induced cortical bone-derived stem cells injury and enhances bone repair in postradiation femoral defect model

2021 ◽  
Vol 8 (1) ◽  
Author(s):  
Wei Hu ◽  
Jia-Wu Liang ◽  
Song Liao ◽  
Zhi-Dong Zhao ◽  
Yu-Xing Wang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Flow Cytometry ◽  
Genomic Stability ◽  
Bone Defects ◽  
Self Renewal ◽  
Femoral Defect ◽  
Tnf Α ◽  
Radiation Induced ◽  
Γ Ray

Abstract Background The healing of bone defects can be challenging for clinicians to manage, especially after exposure to ionizing radiation. In this regard, radiation therapy and accidental exposure to gamma (γ)-ray radiation have been shown to inhibit bone formation and increase the risk of fractures. Cortical bone-derived stem cells (CBSCs) are reportedly essential for osteogenic lineages, bone maintenance and repair. This study aimed to investigate the effects of melatonin on postradiation CBSCs and bone defect healing. Methods CBSCs were extracted from C57BL/6 mice and were identified by flow cytometry. Then CBSCs were subjected to 6 Gy γ-ray radiation followed by treatment with various concentrations of melatonin. The effects of exogenous melatonin on the self-renewal and osteogenic capacity of postradiation CBSCs in vitro were analyzed. The underlying mechanisms involved in genomic stability, apoptosis and oxidative stress-related signaling were further analyzed by Western blotting, flow cytometry and immunofluorescence assays. Moreover, postradiation femoral defect models were established and treated with Matrigel and melatonin. The effects of melatonin on postradiation bone healing in vivo were evaluated by micro-CT and pathological analysis. Results The decrease in radiation-induced self-renewal and osteogenic capacity were partially reversed in postradiation CBSCs treated with melatonin (P < 0.05). Melatonin maintained genomic stability, reduced postradiation CBSC apoptosis and intracellular oxidative stress, and enhanced expression of antioxidant-related enzymes (P < 0.05). Western blotting validated the anti-inflammatory effects of melatonin by downregulating interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) levels via the extracellular regulated kinase (ERK)/nuclear factor erythroid 2-related factor 2 (NRF2)/heme oxygenase-1 (HO-1) signaling pathway. Melatonin was also found to exhibit antioxidant effects via NRF2 signaling. In vivo experiments demonstrated that the newly formed bone in the melatonin plus Matrigel group had higher trabecular bone volume per tissue volume (BV/TV) and bone mineral density values with lower IL-6 and TNF-α levels than in the irradiation and the Matrigel groups (P < 0.05). Conclusion This study suggested that melatonin could protect CBSCs against γ-ray radiation and assist in the healing of postradiation bone defects.

scholarly journals Prospective Identification, Isolation by Flow Cytometry, and In Vivo Self-Renewal of Multipotent Mammalian Neural Crest Stem Cells

Cell ◽  
1999 ◽  
Vol 96 (5) ◽  
pp. 737-749 ◽  
Author(s):  
Sean J Morrison ◽  
Patricia M White ◽  
Christiane Zock ◽  
David J Anderson
Keyword(s):  
Stem Cells ◽  
Flow Cytometry ◽  
Neural Crest ◽  
Self Renewal ◽  
Neural Crest Stem Cells

Regeneration of Bone Defects Using Bioactive Glass Combined with Adipose-derived Mesenchymal Stem Cells. An experimental in vivo study

2019 ◽  
Vol 70 (6) ◽  
pp. 1983-1987
Author(s):  
Cristian Trambitas ◽  
Anca Maria Pop ◽  
Alina Dia Trambitas Miron ◽  
Dorin Constantin Dorobantu ◽  
Flaviu Tabaran ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Bioactive Glass ◽  
Bone Repair ◽  
Bone Defects ◽  
Calvarial Bone ◽  
Specific Protocol ◽  
Repair Mechanisms ◽  
Male Wistar Rats

Large bone defects are a medical concern as these are often unable to heal spontaneously, based on the host bone repair mechanisms. In their treatment, bone tissue engineering techniques represent a promising approach by providing a guide for osseous regeneration. As bioactive glasses proved to have osteoconductive and osteoinductive properties, the aim of our study was to evaluate by histologic examination, the differences in the healing of critical-sized calvarial bone defects filled with bioactive glass combined with adipose-derived mesenchymal stem cells, compared to negative controls. We used 16 male Wistar rats subjected to a specific protocol based on which 2 calvarial bone defects were created in each animal, one was filled with Bon Alive S53P4 bioactive glass and adipose-derived stem cells and the other one was considered control. At intervals of one week during the following month, the animals were euthanized and the specimens from bone defects were histologically examined and compared. The results showed that this biomaterial was biocompatible and the first signs of osseous healing appeared in the third week. Bone Alive S53P4 bioactive glass could be an excellent bone substitute, reducing the need of bone grafts.

scholarly journals The Act of Controlling Adult Stem Cell Dynamics: Insights from Animal Models

Biomolecules ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. 667
Author(s):  
Meera Krishnan ◽  
Sahil Kumar ◽  
Luis Johnson Kangale ◽  
Eric Ghigo ◽  
Prasad Abnave
Keyword(s):  
Stem Cells ◽  
Animal Models ◽  
Adult Stem Cells ◽  
The Body ◽  
In Vivo Studies ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Organ Systems

Adult stem cells (ASCs) are the undifferentiated cells that possess self-renewal and differentiation abilities. They are present in all major organ systems of the body and are uniquely reserved there during development for tissue maintenance during homeostasis, injury, and infection. They do so by promptly modulating the dynamics of proliferation, differentiation, survival, and migration. Any imbalance in these processes may result in regeneration failure or developing cancer. Hence, the dynamics of these various behaviors of ASCs need to always be precisely controlled. Several genetic and epigenetic factors have been demonstrated to be involved in tightly regulating the proliferation, differentiation, and self-renewal of ASCs. Understanding these mechanisms is of great importance, given the role of stem cells in regenerative medicine. Investigations on various animal models have played a significant part in enriching our knowledge and giving In Vivo in-sight into such ASCs regulatory mechanisms. In this review, we have discussed the recent In Vivo studies demonstrating the role of various genetic factors in regulating dynamics of different ASCs viz. intestinal stem cells (ISCs), neural stem cells (NSCs), hematopoietic stem cells (HSCs), and epidermal stem cells (Ep-SCs).

APPLICATION OF DENDRIMER/PLASMID hBMP-2 COMPLEXES LOADED INTO β-TCP/COLLAGEN SCAFFOLD IN THE TREATMENT OF FEMORAL DEFECTS IN RATS

2014 ◽  
Vol 26 (01) ◽  
pp. 1450005 ◽  
Author(s):  
Tingwei Bao ◽  
Huiming Wang ◽  
Wentao Zhang ◽  
Xuefeng Xia ◽  
Jiabei Zhou ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Type I Collagen ◽  
Cell Attachment ◽  
Collagen Scaffold ◽  
Bone Defects ◽  
Bone Morphogenetic Protein 2 ◽  
Porous Scaffolds ◽  
Type I

Purpose: Plasmid loading into scaffolds to enhance sustained release of growth factors is an important focus of regenerative medicine. The aim of this study was to build gene-activated matrices (GAMs) and examine the bone augmentation properties. Methods: Generation 5 polyamidoamine dendrimers (G5 dPAMAM)/plasmid recombinant human bone morphogenetic protein-2 (rhBMP-2) complexes were immobilized into beta-tricalcium phosphate (β-TCP)/type I collagen porous scaffolds. After cultured with rat mesenchymal stem cells (rMSCs), transfection efficiencies were examined. The secretion of rhBMP-2 and alkaline phosphatase (ALP) were detected to evaluate the osteogenic properties. Scanning electron microscopy (SEM) was used to observe attachment and proliferation. Moreover, we applied these GAMs directly into freshly created segmental bone defects in rat femurs, and their osteogenic efficiencies were evaluated. Results: Released plasmid complexes were transfected into stem cells and were expressed, which caused osteogenic differentiations of rat mesenchymal stem cells (rMSCs). SEM analysis showed excellent cell attachment. Bioactivity of plasmid rhBMP-2 was maintained in vivo, and the X-ray observation, histological analysis and immunohistochemistry (IHC) of bone tissue demonstrated that the bone healing in segmental femoral defects was enhanced by implantation of GAMs. Conclusions: Such biomaterials offer therapeutic opportunities in critical-sized bone defects.

scholarly journals Maintenance of Hematopoietic Stem Cells Through Regulation of Wnt and mTOR Pathways.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2309-2309
Author(s):  
Jian Huang ◽  
Peter S. Klein
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Signaling Pathways ◽  
Glycogen Synthase ◽  
Dependent Manner ◽  
Mtor Inhibition ◽  
Self Renewal ◽  
Hematopoietic Stem

Abstract Abstract 2309 Hematopoietic stem cells (HSCs) maintain the ability to self-renew and to differentiate into all lineages of the blood. The signaling pathways regulating hematopoietic stem cell (HSCs) self-renewal and differentiation are not well understood. We are very interested in understanding the roles of glycogen synthase kinase-3 (Gsk3) and the signaling pathways regulated by Gsk3 in HSCs. In our previous study (Journal of Clinical Investigation, December 2009) using loss of function approaches (inhibitors, RNAi, and knockout) in mice, we found that Gsk3 plays a pivotal role in controlling the decision between self-renewal and differentiation of HSCs. Disruption of Gsk3 in bone marrow transiently expands HSCs in a b-catenin dependent manner, consistent with a role for Wnt signaling. However, in long-term repopulation assays, disruption of Gsk3 progressively depletes HSCs through activation of mTOR. This long-term HSC depletion is prevented by mTOR inhibition and exacerbated by b-catenin knockout. Thus GSK3 regulates both Wnt and mTOR signaling in HSCs, with opposing effects on HSC self-renewal such that inhibition of Gsk3 in the presence of rapamycin expands the HSC pool in vivo. In the current study, we found that suppression of the mammalian target of rapamycin (mTOR) pathway, an established nutrient sensor, combined with activation of canonical Wnt/ß-catenin signaling, allows the ex vivo maintenance of human and mouse long-term HSCs under cytokine-free conditions. We also show that combining two clinically approved medications that activate Wnt/ß-catenin signaling and inhibit mTOR increases the number of long-term HSCs in vivo. Disclosures: No relevant conflicts of interest to declare.

Adenosine from Niche-Associated Tregs Maintains Hematopoietic Stem Cell Quiescence

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 91-91
Author(s):  
Yuichi Hirata ◽  
Kazuhiro Furuhashi ◽  
Hiroshi Ishi ◽  
Hao-Wei Li ◽  
Sandra Pinho ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Pool Size ◽  
Immune Privilege ◽  
Haematopoietic Stem Cell ◽  
Hematopoietic Stem ◽  
Conditional Deletion ◽  
Radiation Induced

Abstract A crucial player in immune regulation, FoxP3+ regulatory T cells (Tregs) are drawing attention for their heterogeneity and noncanonical functions. For example, specific subsets of Tregs in the adipose tissue control metabolic indices; muscle Tregs potentiate muscle repair, and lung Tregs prevent tissue damage. These studies, together with a previous finding that Tregs are enriched in the primary site for hematopoiesis, the bone marrow (BM), prompted us to examine whether there is a special Treg population which controls hematopoietic stem cells (HSCs). We showed that HSCs within the BM were frequently adjacent to distinctly activated FoxP3+ Tregs which highly expressed an HSC marker, CD150. Moreover, specific reduction of BM Tregs achieved by conditional deletion of CXCR4in Tregs, increased reactive oxygen species (ROSs) in HSCs. The reduction of BM Tregs further induced loss of HSC quiescence and increased HSC numbers in a manner inhibited by anti-oxidant treatment. Additionally, this increase in HSC numbers in mice lacking BM Tregs was reversed by transfer of CD150high BM Tregs but not of CD150low BM Tregs. These results indicate that CD150high niche-associated Tregs maintain HSC quiescence and pool size by preventing oxidative stress. We next sought to identify an effector molecule of niche Tregs which regulates HSCs. Among molecules highly expressed by niche Tregs, we focused on CD39 and CD73, cell surface ecto-enzymes which are required for generation of extracellular adenosine, because 1) CD39highCD73high cells within the BM were prevalent among CD150high Tregs and 2) HSCs highly expressed adenosine 2a receptors (A2AR). We showed that both conditional deletion of CD39 in Tregs and in vivo A2AR antagonist treatment induced loss of HSC quiescence and increased HSC pool size in a ROS-dependent manner, which is consistent with the findings in mice lacking BM Tregs. In addition, transfer of CD150high BM Tregs but not of CD150low BM Tregs reversed the increase in HSC numbers in FoxP3cre CD39flox mice. The data indicate that niche Treg-derived adenosine regulates HSCs. We further investigated the protective role of niche Tregs and adenosine in radiation injury against HSCs. Conditional deletion of CD39 in Tregs increased radiation-induced HSC apoptosis. Conversely, transfer of as few as 15,000 CD150high BM Tregs per B6 mouse (iv; day-1) rescued lethally-irradiated (9.5Gy) mice by preventing hematopoiesis failure. These observations indicate that niche Tregs protect HSCs from radiation stress. Finally, we investigated the role of niche Tregs in allogeneic (allo-) HSC transplantation. Our previous study showed that allo-hematopoietic stem and progenitor cells but not allo-Lin+ cells persisted in the BM of non-conditioned immune-competent recipients without immune suppression in a manner reversed by systemic Treg depletion1. This observation suggests that HSCs have a limited susceptibility to immune attack, as germline and embryonic stem cells are located within immune privileged sites. Because the study employed systemic Treg depletion and non-conditioned recipients, it remains unknown whether niche Tregs play a critical role in immune privilege of HSCs and in allo-HSC engraftment following conditioning. We showed here that the reduction of BM Tregs and conditional deletion of CD39 in Tregs abrogated allo-HSC persistence in non-conditioned immune-competent mice as well as allo-HSC engraftment following nonmyeloablative conditioning. Furthermore, transfer of CD150high BM Tregs but not of other Tregs (15,000 cells/recipient; day -2) significantly improved allo-HSC engraftment. This effect of niche Treg transfer is noteworthy given that 1-5 million Tregs per mouse were required in case of transfer of spleen or lymph node Tregs. These observations suggest that niche Tregs maintain immune privilege of HSCs and promote allo-HSC engraftment. In summary, our studies identify a unique niche-associated Treg subset and adenosine as regulators of HSC quiescence, numbers, stress response, engraftment, and immune privilege, further highlighting potential clinical utility of niche Treg transfer in radiation-induced hematopoiesis failure and in allo-HSC engraftment (under revision in Cell Stem Cell). 1 Fujisaki, J. et al. In vivo imaging of Treg cells providing immune privilege to the haematopoietic stem-cell niche. Nature474, 216-219, doi:10.1038/nature10160 (2011). Disclosures No relevant conflicts of interest to declare.

CBIO-13. THOC1 DRIVES GBM AGGRESSION THROUGH MODULATION OF R-LOOPS AND GENOMIC STABILITY

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi29-vi30
Author(s):  
Shreya Budhiraja ◽  
Shivani Baisiwala ◽  
Khizar Nandoliya ◽  
Li Chen ◽  
Crismita Dmello ◽  
...  
Keyword(s):  
Stem Cells ◽  
Dna Damage ◽  
Neural Stem Cells ◽  
Histone Deacetylase ◽  
Genomic Stability ◽  
Loop Formation ◽  
Driver Genes ◽  
A Genome

Abstract Glioblastoma (GBM) is the most aggressive and common type of adult malignant brain tumor, with a median survival of only 21 months. To identify which genes drive its highly aggressive phenotype, we performed a genome-wide CRISPR-Cas9 knockout screen. Results showed substantial enrichment of ~160 novel essential oncogenic driver genes and pathways, including a previously unstudied gene THOC1—involved in RNA processing—that showed significant elevations in expression at RNA and protein levels (p&lt; 0.05) in GBM, as well as a significant survival benefit in patient datasets when downregulated (p&lt; 0.05). Knocking out THOC1 resulted in cell death in multiple GBM patient-derived xenograft (PDX) lines and extended survival compared to the controls (p&lt; 0.01) in vivo. Overexpression of THOC1 in neural stem cells resulted in transformation to a cancerous phenotype, as evidenced by sphere formation in a soft agar assay (p&lt; 0.01) and in vivo tumor engraftment assays. Further investigation of THOC1 through immunoprecipitation in neural stem cells and multiple GBM lines showed significant interaction in GBM with histone deacetylase complex SIN3A, involved in recruiting major histone deacetylases in order to close the DNA and prevent the accumulation of R-loops, RNA:DNA hybrids that pose a threat to genomic stability. Additional investigation revealed that THOC1-knockdowns in vitro induced R-loop formation and DNA damage, while THOC1-overexpression in vitro resulted in an untenable decrease in R-loops and DNA damage, suggesting that the THOC1-SIN3A axis is elevated in GBM in order to prevent the accumulation of genotoxic R-loops. Additionally, histone deacetylase activity was shown to be elevated in THOC1-overexpression conditions and reduced in THOC1-knockdown conditions, confirming that the THOC1-SIN3A axis functions to prevent R-loop accumulation through the epigenetic regulation. In summary, our whole-genome CRISPR-Cas9 knockout screen has identified a promising therapeutic target for GBM—a disease desperately in need of therapeutic innovations.

scholarly journals Silencing of long noncoding RNA HOXA11-AS inhibits the Wnt signaling pathway via the upregulation of HOXA11 and thereby inhibits the proliferation, invasion, and self-renewal of hepatocellular carcinoma stem cells

2019 ◽  
Vol 51 (11) ◽  
pp. 1-20 ◽  
Author(s):  
Jun-Cheng Guo ◽  
Yi-Jun Yang ◽  
Jin-Fang Zheng ◽  
Jian-Quan Zhang ◽  
Min Guo ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Stem Cells ◽  
Stem Cell ◽  
Wnt Signaling ◽  
Signaling Pathway ◽  
Methylation Level ◽  
Wnt Signaling Pathway ◽  
The Self ◽  
Self Renewal

AbstractHepatocellular carcinoma (HCC) is a major cause of cancer-related deaths, but its molecular mechanisms are not yet well characterized. Long noncoding RNAs (lncRNAs) play crucial roles in tumorigenesis, including that of HCC. However, the role of homeobox A11 antisense (HOXA11-AS) in determining HCC stem cell characteristics remains to be explained; hence, this study aimed to investigate the effects of HOXA11-AS on HCC stem cell characteristics. Initially, the expression patterns of HOXA11-AS and HOXA11 in HCC tissues, cells, and stem cells were determined. HCC stem cells, successfully sorted from Hep3B and Huh7 cells, were transfected with short hairpin or overexpression plasmids for HOXA11-AS or HOXA11 overexpression and depletion, with an aim to study the influences of these mediators on the self-renewal, proliferation, migration, and tumorigenicity of HCC stem cells in vivo. Additionally, the potential relationship and the regulatory mechanisms that link HOXA11-AS, HOXA11, and the Wnt signaling pathway were explored through treatment with Dickkopf-1 (a Wnt signaling pathway inhibitor). HCC stem cells showed high expression of HOXA11-AS and low expression of HOXA11. Both HOXA11-AS silencing and HOXA11 overexpression suppressed the self-renewal, proliferation, migration, and tumorigenicity of HCC stem cells in vivo, as evidenced by the decreased expression of cancer stem cell surface markers (CD133 and CD44) and stemness-related transcription factors (Nanog, Sox2, and Oct4). Moreover, silencing HOXA11-AS inactivated the Wnt signaling pathway by decreasing the methylation level of the HOXA11 promoter, thereby inhibiting HCC stem cell characteristics. Collectively, this study suggested that HOXA11-AS silencing exerts an antitumor effect, suppressing HCC development via Wnt signaling pathway inactivation by decreasing the methylation level of the HOXA11 promoter.

scholarly journals MicroRNA-28-5p Regulates Liver Cancer Stem Cell Expansion via IGF-1 Pathway

2019 ◽  
Vol 2019 ◽  
pp. 1-16 ◽  
Author(s):  
Qing Xia ◽  
Tao Han ◽  
Pinghua Yang ◽  
Ruoyu Wang ◽  
Hengyu Li ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Liver Cancer ◽  
Critical Role ◽  
Self Renewal ◽  
Sorafenib Treatment ◽  
The Impact

Background. MicroRNAs (miRNAs) play a critical role in the regulation of cancer stem cells (CSCs). However, the role of miRNAs in liver CSCs has not been fully elucidated. Methods. Real-time PCR was used to detect the expression of miR-miR-28-5p in liver cancer stem cells (CSCs). The impact of miR-28-5p on liver CSC expansion was investigated both in vivo and in vitro. The correlation between miR-28-5p expression and sorafenib benefits in HCC was further evaluated in patient-derived xenografts (PDXs). Results. Our data showed that miR-28-5p was downregulated in sorted EpCAM- and CD24-positive liver CSCs. Biofunctional investigations revealed that knockdown miR-28-5p promoted liver CSC self-renewal and tumorigenesis. Consistently, miR-28-5p overexpression inhibited liver CSC’s self-renewal and tumorigenesis. Mechanistically, we found that insulin-like growth factor-1 (IGF-1) was a direct target of miR-28-5p in liver CSCs, and the effects of miR-28-5p on liver CSC’s self-renewal and tumorigenesis were dependent on IGF-1. The correlation between miR-28-5p and IGF-1 was confirmed in human HCC tissues. Furthermore, the miR-28-5p knockdown HCC cells were more sensitive to sorafenib treatment. Analysis of patient-derived xenografts (PDXs) further demonstrated that the miR-28-5p may predict sorafenib benefits in HCC patients. Conclusion. Our findings revealed the crucial role of the miR-28-5p in liver CSC expansion and sorafenib response, rendering miR-28-5p an optimal therapeutic target for HCC.

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