Wnt5a Supports Osteogenic Lineage Decisions in Embryonic Stem Cells

Keller, Kevin C.; Ding, Huawen; Tieu, Rudy; Sparks, Nicole R L; Ehnes, Devon; Nieden, Nicole I. zur

doi:10.1089/scd.2015.0367

Cited by 28 publications

(28 citation statements)

References 56 publications

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“…wnt 5a to limit IVD inflammation by inhibiting the action of TNFα. Nevertheless, in vivo application does require caution, as multiple reports have presented the ability of wnt5a to induce or support osteogenesis, [78][79][80] tissue-fibrosus, 81,82 and M2 polarization of macrophages. 83 Similarly, wnt3a has been associated with the progression of a variety of tumors.…”

Section: Wnt3a and Wnt5a As Tools For Regeneration Of The Intervertebmentioning

confidence: 99%

Wnt3a and wnt5a as Potential Chondrogenic Stimulators for Nucleus Pulposus Cell Induction: A Comprehensive Review

et al. 2020

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Low back pain remains a highly prevalent pathology engendering a tremendous socioeconomic burden. Low back pain is generally associated with intervertebral disc (IVD) degeneration, a process involving the deterioration of nucleus pulpous (NP) cells and IVD matrix. Scientific interest has directed efforts to restoring cell numbers as a strategy to enable IVD regeneration. Currently, mesenchymal stromal cells (MSCs) are being explored as cell therapy agents, due to their easy accessibility and differentiation potential. For enhancement of MSCs, growth factor supplementation is commonly applied to induce differentiation towards a chondrogenic (NP) cell phenotype. The wnt signaling pathways play a crucial role in chondrogenesis, nonetheless, literature appears to present controversies with regard to wnt3a and wnt5a for the induction of NP cells, chondrocytes, and MSCs. This review aims to summarize the reporting on wnt3a/wnt5a mediated NP cell differentiation, and to elucidate the mechanisms involved in wnt3a and wnt5a mediated chondrogenesis for potential application as cell therapy supplements for IVD regeneration. Our review suggests that wnt3a, subsequently replaced with a chondrogenic stimulating growth factor, can enhance the chondrogenic potential of MSCs in vitro. Contrariwise, wnt5a is suggested to play a role in maintaining cell potency of differentiated NP or chondrogenic cells.

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Section: Wnt3a and Wnt5a As Tools For Regeneration Of The Intervertebmentioning

confidence: 99%

Wnt3a and wnt5a as Potential Chondrogenic Stimulators for Nucleus Pulposus Cell Induction: A Comprehensive Review

et al. 2020

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“…It also regulates the expression of MESP1 and cardiomyocyte differentiation via non-Wnt/β-catenin signaling [38]. Wnt-5a is expressed at an early of in vitro osteogenesis differentiation [39]. Together, these experiments show that Wnt-5a can activate multiple receptors to influence various cellular processes during embryonic development.…”

Section: Discussionmentioning

confidence: 89%

Wnt-5a Promotes Neural Development and Differentiation by Regulating CDK5 via Ca2+/Calpain Pathway

Yang

Xiang

Zhang

et al. 2018

Cell Physiol Biochem

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Background/Aims: The Wnt signaling pathway has essential functions in the central nervous system, where it regulates the major physiological functions of neurons, including development, differentiation, and plasticity. Wnt signaling controls these cellular events; however, how Wnt pathways integrate into a coherent developmental program remains unclear. Methods: The expression and secretion of different WNT ligands (Wnt-1, Wnt-3a, Wnt-4, Wnt-5a, Wnt-11), and the levels and activities of cyclin-dependent kinases (CDK2, CDK4, CDK6/cyclin D, cyclin E) or CDK5 (CDK5/p35 and p25) were measured in Rat cortex at different embryonic stages, and in RA/BDNF-induced differentiated SH-SY5Y cell model, by Quantitative real-time PCR (qPCR), western blotting, ELISA, and in vitro CDK5 kinase assays. MAP2-BrdU double staining was used to assess cell differentiation and cell cycle exit in an RA/BDNF-induced differentiated SH-SY5Y cell model. The effects of CDK5 and Ca²⁺/calpain signaling were assessed using specific chemical inhibitors. Results: We found that Wnt-1 was unchanged and Wnt-3a was attenuated, whereas Wnt-4, Wnt-5a, and Wnt-11 were markedly up-regulated, during the development of neurons and differentiated SH-SY5Y cells. Simultaneously, the activity of CDK5 was elevated. Furthermore, we describe crosstalk between non-canonical Wnt signaling and CDK5 in the development of neurons and differentiated SH-SY5Y cells. Wnt-5a, a non-canonical Wnt ligand, regulated CDK5 via Ca²⁺/calpain signaling in both neuronal development and differentiation. Inhibition of Wnt-5a diminished CDK5 kinase activity via the Ca²⁺/calpain pathway, thereby attenuating RA-BDNF induced SH-SY5Y cell differentiation. Conclusion: Wnt-5a signaling is a significant regulator of neuronal development and differentiation and upregulates CDK5 kinase activity via Ca²⁺/calpain signaling.

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“…Other studies have found that the canonical WNT3A and the non-canonical WNT5A have the effect of promoting bone formation in collaboration with each other. If Cellular Physiology and Biochemistry Cellular Physiology and Biochemistry rWNT3A was supplemented during a time window following rWNT5A treatment, osteogenic differentiation was enhanced both in murine and human ESCs [39]. Sphingosine-1-phosphate (S1P) -enhanced Wnt5a promotes low-density lipoprotein receptor-related protein 5 or 6 (LRP5/6) expression, resulting in the trigger of osteogenic differentiation of C3H10T1/2 cells [40].…”

Section: Discussionmentioning

confidence: 99%

miR-16-2* Interferes with WNT5A to Regulate Osteogenesis of Mesenchymal Stem Cells

Duan

Zhao

Xiong

et al. 2018

Cell Physiol Biochem

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Background/Aims: Osteoporosis is a bone metabolic disease characterized by a systemic impairment of bone mass, which results in increased propensity of fragility fractures. A reduction in the differentiation of MSCs into osteoblasts contributes to the impaired bone formation observed in osteoporosis. Mesenchymal stem cells (MSCs) are induced to differentiate into preosteoblasts, which are regulated by the signaling cascades initiated by the various signals, including miRNAs. miR-16-2* is a newly discovered miRNA that participates in diagnosis and prognosis of hepatocellular carcinoma, cervical cancer and chronic lymphocytic leukemia. However, the effect of miR-16-2* on the regulation of osteoblast differentiation and the mechanism responsible are still unclear. Here we discuss the contribution of miR-16-2* to osteoporosis, osteoblast differentiation and mineralization. Methods: The expression pattern of miR-16-2* during osteogenesis or in osteoporosis bone samples was validated by quantitative real-time PCR (qRT-PCR). The human bone marrow mesenchymal stem cells (hBMSCs) were induced to differentiate into osteoblasts by osteogenic induced medium containing dexamethasone, ascorbate-2-phosphat, beta-glycerophosphate and vitamin-D3. The target genes of miR-16-2* were predicted by TargetScan and PicTar. The mRNA and protein levels of osteogenic key markers were detected using qRT-PCR or western blot respectively. The WNT signal activity was analyzed by TOP/FOP reporter assay. Results: The expression of miR-16-2* in patient bone tissue with osteoporosis was negatively correlated with bone formation related genes. During osteoblast differentiation process, the expression of miR-16-2* was significantly decreased. Upregulation of miR-16-2* in hBMSCs impaired the osteogenic differentiation while the downregulation of miR-16-2* increased this process. Upregulation the expression of miR-16-2* could also block the WNT signal pathway by directly target WNT5A. Furthermore, knockdown of miR-16-2* could promote the activation of RUNX2, possibly by lifting the inhibitory effect of miR-16-2* on WNT pathway. Conclusion: Taken together, we report a novel biological role of miR-16-2* in osteogenesis through regulating WNT5A response for the first time. Our data support the potential utilization of miRNA-based therapies in regenerative medicine.

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Wnt5a Supports Osteogenic Lineage Decisions in Embryonic Stem Cells

Cited by 28 publications

References 56 publications

Wnt3a and wnt5a as Potential Chondrogenic Stimulators for Nucleus Pulposus Cell Induction: A Comprehensive Review

Wnt3a and wnt5a as Potential Chondrogenic Stimulators for Nucleus Pulposus Cell Induction: A Comprehensive Review

Wnt-5a Promotes Neural Development and Differentiation by Regulating CDK5 via Ca2+/Calpain Pathway

miR-16-2* Interferes with WNT5A to Regulate Osteogenesis of Mesenchymal Stem Cells

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