scholarly journals Lithium and Copper Induce the Osteogenesis-Angiogenesis Coupling of Bone Marrow Mesenchymal Stem Cells via Crosstalk between Canonical Wnt and HIF-1α Signaling Pathways

2021 ◽  
Vol 2021 ◽  
pp. 1-15
Author(s):  
Zhen Tan ◽  
Baochun Zhou ◽  
Jianrui Zheng ◽  
Yongcan Huang ◽  
Hui Zeng ◽  
...  
Keyword(s):  
Stem Cells ◽  
Signaling Pathways ◽  
Signaling Pathway ◽  
Wnt Signaling Pathway ◽  
Underlying Mechanism ◽  
Related Factor ◽  
Bioactive Scaffolds ◽  
Marrow Mesenchymal Stem Cells ◽  
Angiogenesis Process ◽  
Canonical Wnt

The combination of osteogenesis and angiogenesis dual-delivery trace element-carrying bioactive scaffolds and stem cells is a promising method for bone regeneration and repair. Canonical Wnt and HIF-1α signaling pathways are vital for BMSCs’ osteogenic differentiation and secretion of osteogenic factors, respectively. Simultaneously, lithium (Li) and copper (Cu) can activate the canonical Wnt and HIF-1α signaling pathway, respectively. Moreover, emerging evidence has shown that the canonical Wnt and HIF signaling pathways are related to coupling osteogenesis and angiogenesis. However, it is still unclear whether the lithium- and copper-doped bioactive scaffold can induce the coupling of the osteogenesis and angiogenesis in BMSCs and the underlying mechanism. So, we fabricated a lithium- (Li+-) and copper- (Cu2+-) doped organic/inorganic (Li 2.5-Cu 1.0-HA/Col) scaffold to evaluate the coupling osteogenesis and angiogenesis effects of lithium and copper on BMSCs and further explore its mechanism. We investigated that the sustained release of lithium and copper from the Li 2.5-Cu 1.0-HA/Col scaffold could couple the osteogenesis- and angiogenesis-related factor secretion in BMSCs seeding on it. Moreover, our results showed that 500 μM Li+ could activate the canonical Wnt signaling pathway and rescue the XAV-939 inhibition on it. In addition, we demonstrated that the 25 μM Cu2+ was similar to 1% oxygen environment in terms of the effectiveness of activating the HIF-1α signaling pathway. More importantly, the combination stimuli of Li+ and Cu2+ could couple the osteogenesis and angiogenesis process and further upregulate the osteogenesis- and angiogenesis-related gene expression via crosstalk between the canonical Wnt and HIF-1α signaling pathway. In conclusion, this study revealed that lithium and copper could crosstalk between the canonical Wnt and HIF-1α signaling pathways to couple the osteogenesis and angiogenesis in BMSCs when they are sustainably released from the Li-Cu-HA/Col scaffold.

scholarly journals Icariin Regulates the Bidirectional Differentiation of Bone Marrow Mesenchymal Stem Cells through Canonical Wnt Signaling Pathway

2017 ◽  
Vol 2017 ◽  
pp. 1-12 ◽  
Author(s):  
Jun-ming Huang ◽  
Yuan Bao ◽  
Wei Xiang ◽  
Xing-zhi Jing ◽  
Jia-chao Guo ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Mesenchymal Stem Cells ◽  
Western Blot ◽  
Wnt Signaling ◽  
Signaling Pathway ◽  
Wnt Signaling Pathway ◽  
Canonical Wnt Signaling ◽  
Marrow Mesenchymal Stem Cells ◽  
Canonical Wnt

Fat infiltration within the bone marrow is easily observed in some postmenopausal women. Those fats are mainly derived from bone marrow mesenchymal stem cells (BMMSCs). The increment of adipocytes derived from BMMSCs leads to decreased osteoblasts derived from BMMSCs, so the bidirectional differentiation of BMMSCs significantly contributes to osteoporosis. Icariin is the main extractive of Herba Epimedii which is widely used in traditional Chinese medicine. In this experiment, we investigated the effect of icariin on the bidirectional differentiation of BMMSCs through quantitative real-time PCR, immunofluorescence, western blot, and tissue sections in vitro and in vivo. We found that icariin obviously promotes osteogenesis and inhibits adipogenesis through detecting staining and gene expression. Micro-CT analysis showed that icariin treatment alleviated the loss of cancellous bone of the distal femur in ovariectomized (OVX) mice. H&E staining analysis showed that icariin-treated OVX mice obtained higher bone mass and fewer bone marrow lipid droplets than OVX mice. Western blot and immunofluorescence showed that icariin regulates the bidirectional differentiation of BMMSCs via canonical Wnt signaling. This study demonstrates that icariin exerts its antiosteoporotic effect by regulating the bidirectional differentiation of BMMSCs through the canonical Wnt signaling pathway.

Canonical Wnt signaling pathway contributes to the proliferation and survival in porcine pancreatic stem cells (PSCs)

2015 ◽  
Vol 362 (2) ◽  
pp. 379-388 ◽  
Author(s):  
Xin He ◽  
Wei Han ◽  
Shu-xian Hu ◽  
Ming-zhi Zhang ◽  
Jin-lian Hua ◽  
...  
Keyword(s):  
Stem Cells ◽  
Wnt Signaling ◽  
Signaling Pathway ◽  
Wnt Signaling Pathway ◽  
Canonical Wnt Signaling ◽  
Pancreatic Stem Cells ◽  
Canonical Wnt

Polycomb Repressive Complex 1 Enhances HSC Self-Renewal through Repressing the Canonical Wnt Signaling Pathway

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2378-2378
Author(s):  
Sisi Chen ◽  
Xicheng Liu ◽  
Rui Gao ◽  
Michihiro Kobayashi ◽  
Hao Yu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Wnt Signaling ◽  
Signaling Pathway ◽  
Wnt Signaling Pathway ◽  
Canonical Wnt Signaling ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Canonical Wnt

Abstract Polycomb group (PcG) proteins are epigenetic gene silencers that have been implicated in stem cell maintenance and cancer development. Genetic and biochemical studies indicate that Polycomb group proteins exist in at least two protein complexes, Polycomb repressive complex 2 (PRC2) and Polycomb repressive complex 1 (PRC1), that act in concert to initiate and maintain stable gene repression. While studies on individual PRC1 component suggest that PRC1 plays an important role in hematopoiesis, how PRC1 regulates transcriptional repression in hematopoietic stem cells (HSCs) is largely unknown. Bmi1 and Mel18 are two major homologs of the PCGF subunit within the PRC1 complex. Bmi1 is a positive regulator of HSC self-renewal; however, the role of Mel18 in hematopoiesis has been controversial. To determine whether Bmi1 and Mel18 play redundant or distinct role in HSC self-renewal, we have generated Bmi1 and Mel18 conditional knockout mice. While acute deletion of Mel18 affects neither HSC frequency nor lineage commitment, we found that Mel18-deficent hematopoietic progenitor cells showed enhanced replating potential compared to wild type cells. To determine the role of Mel18 in HSC self-renewal, we performed serial HSC transplantation assays and found that the repopulating ability of Mel18-/- HSCs was significantly higher than WT HSCs in both primary and secondary transplantation assays, demonstrating that the loss of Mel18 enhances HSC self-renewal in vivo. We hypothesize that loss of Bmi1 and Mel18 in hematopoietic stem cells will disrupt PRC1 complex and impairs HSC self-renewal. To determine the role of PRC1 complex in HSCs, we analyzed the HSC behavior in Bmi1 and Mel18 double-deficient mice. While we found that Bmi1-deficient HSCs showed decreased repopulating potential compared to WT HSCs 16 weeks following transplantation, loss of both Bmi1 and Mel18 in HSCs resulted in even more severe self-renewal defects. In addition, loss of both Bmi1 and Mel18 resulted in decreased myeloid differentiation and increased B cell differentiation compared to WT, Mel18 KO, and Bmi1 KO mice. These data demonstrate that Bmi1 and Mel18 have non-overlapping role in HSC maintenance and lineage commitment. Given that Bmi1 plays a dominant role in the PRC1 complex, we decided to identify Bmi1 target genes in hematopoietic stem cells to understand how PRC1 complex regulates HSC self-renewal. We performed transcript profiling assays to compare gene expression in HSCs isolated from wild type and Bmi1-/- mice. The Ingenuity Pathways indicates that the canonical Wnt signaling is significantly elevated in Bmi1 null HSCs compared to WT HSCs. We confirmed the upregulation of several genes of the Wnt pathway in Bmi1 null HSCs by quantitative real-time PCR analysis. To determine whether Bmi1 can repress the activation of Wnt signaling in cells, we utilized the Top-Flash Wnt reporter system. Stimulation of 293T cells with Wnt3a activates the Wnt reporter and this activation can be efficiently repressed by Bmi1. Furthermore, we detected the association of Bmi1 with the Lef1, Tcf4, and Axin2 promoters in Baf3 cells by ChIP experiment. Thus, Bmi1 directly represses the expression of several Wnt genes in hematopoietic cells. To determine the functional significance of activation of Wnt signaling in Bmi1 null HSCs, we have generated R26StopFL Bmi1-Apcf/f-Mx1-Cre+ and Bmi1f/f-Ctnnb1f/f-Mx1-Cre+ mice. Loss of Apc in hematopoietic cells activates the Wnt signaling pathway and impairs HSC self-renewal. We found that expressing three-copies of Bmi1 from the Rosa26 locus enhanced the self-renewal capabilities of Apc deficient HSCs in transplantation assays. Ctnnb1 encodes b-catenin and loss of Ctnnb1 in HSCs diminishes Wnt signaling. Acute deletion of Bmi1 in hematopoietic compartments resulted in decreased bone marrow cellularity and enhanced apoptosis of hematopoietic stem and progenitor cells. Deletion of Ctnnb1 in Bmi1 null hematopoietic cells rescued these defects. Thus, impaired HSC self-renewal seen in Bmi1 null mice is, at least in part, due to activation of the canonical Wnt signaling pathway. Taken together, we demonstrate that PRC1 complex enhances HSC self-renewal through inhibiting the canonical Wnt signaling. Disclosures No relevant conflicts of interest to declare.

scholarly journals JKAMP Inhibits the Osteogenic Capacity of Adipose-derived Stem Cells in Diabetic Osteoporosis by Modulating the Wnt Signaling Pathway Through Intragenic DNA Methylation

2020 ◽  
Author(s):  
Shuanglin Peng ◽  
Sirong Shi ◽  
Gang Tao ◽  
Yanjing Li ◽  
Dexuan Xiao ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Stem Cells ◽  
Wnt Signaling ◽  
Signaling Pathway ◽  
Wnt Signaling Pathway ◽  
Underlying Mechanism ◽  
Osteogenic Potential ◽  
Adipose Derived Stem Cells ◽  
Alizarin Red ◽  
Diabetic Osteoporosis

Abstract Background: Diabetic osteoporosis (DOP) is a systemic metabolic bone disease caused by diabetes mellitus (DM). Adipose-derived stem cells (ASCs) play an important role in bone regeneration. Our previous study confirmed that ASCs from DOP mice (DOP-ASCs) have a lower osteogenesis potential compared with control ASCs (CON-ASCs). However, the cause of this poor osteogenesis has not been elucidated. Therefore, this study investigated the underlying mechanism of the decline in the osteogenic potential of DOP-ASCs from the perspective of epigenetics and explored methods to enhance their osteogenic capacity. Methods: The expression level of JNK1-associated membrane protein (JKAMP) and degree of DNA methylation in CON-ASCs and DOP-ASCs were measured by mRNA expression profiling and MeDIP sequencing, respectively. JKAMP small interfering RNA (siRNA) and a Jkamp overexpression plasmid were used to assess the role of JKAMP in osteogenic differentiation of CON-ASCs and DOP-ASCs. Immunofluorescence, qPCR, and western blotting were used to measure changes in expression of Wnt signaling pathway-related genes and osteogenesis-related molecules after osteogenesis induction. Alizarin red and ALP staining was used to confirm the osteogenic potential of stem cells. Bisulfite-specific PCR (BSP) was used to detect JKAMP methylation degree. Results: Expression of JKAMP and osteogenesis-related molecules (RUNX2 and OPN) in DOP-ASCs was decreased significantly in comparison with CON-ASCs. JKAMP silencing inhibited the Wnt signaling pathway and reduced the osteogenic ability of CON-ASCs. Overexpression of JKAMP in DOP-ASCs rescued the impaired osteogenic capacity caused by DOP. Moreover, JKAMP in DOP-ASCs contained intragenic DNA hypermethylated regions related to the downregulation of JKAMP expression. Conclusions: Intragenic DNA methylation inhibits the Wnt signaling pathway by suppressing expression of JKAMP and the osteogenic ability of DOP-ASCs. This study shows an epigenetic explanation for the reduced osteogenic ability of DOP-ASCs, and provides a potential therapeutic target to prevent and treat osteoporosis.

scholarly journals miR-142 regulates the tumorigenicity of human breast cancer stem cells through the canonical WNT signaling pathway

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Taichi Isobe ◽  
Shigeo Hisamori ◽  
Daniel J Hogan ◽  
Maider Zabala ◽  
David G Hendrickson ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cells ◽  
Wnt Signaling ◽  
Signaling Pathway ◽  
Human Breast Cancer ◽  
Wnt Signaling Pathway ◽  
Breast Cancer Stem Cells ◽  
Human Breast ◽  
Canonical Wnt

MicroRNAs (miRNAs) are important regulators of stem and progenitor cell functions. We previously reported that miR-142 and miR-150 are upregulated in human breast cancer stem cells (BCSCs) as compared to the non-tumorigenic breast cancer cells. In this study, we report that miR-142 efficiently recruits the APC mRNA to an RNA-induced silencing complex, activates the canonical WNT signaling pathway in an APC-suppression dependent manner, and activates the expression of miR-150. Enforced expression of miR-142 or miR-150 in normal mouse mammary stem cells resulted in the regeneration of hyperproliferative mammary glands in vivo. Knockdown of endogenous miR-142 effectively suppressed organoid formation by BCSCs and slowed tumor growth initiated by human BCSCs in vivo. These results suggest that in some tumors, miR-142 regulates the properties of BCSCs at least in part by activating the WNT signaling pathway and miR-150 expression.

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