Neural Differentiation of Human Adipose Tissue-Derived Stem Cells Involves Activation of the Wnt5a/JNK Signalling

Jang, Sujeong; Park, Jong-Seong; Jeong, Han-Seong

doi:10.1155/2015/178618

Cited by 42 publications

(39 citation statements)

References 31 publications

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“…These observations suggest that the WNT pathway is turned off and differentiation of MSCs is induced by JQ1. This is in partial agreement with a previous report where downregulation of WNT2 , FZD2 , and FZD4 and upregulation of CTNNB1 was involved in neural differentiation of human adipose-derived stem cells [ 49 ]. Taken together, these observations suggested that JQ1 modulates WNT signaling, which is known to be involved in self-renewal and differentiation of MSCs.…”

Section: Discussionsupporting

confidence: 93%

BET protein inhibitor JQ1 inhibits growth and modulates WNT signaling in mesenchymal stem cells

et al. 2016

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BackgroundEfficacy and safety of anticancer drugs are traditionally studied using cancer cell lines and animal models. The thienodiazepine class of BET inhibitors, such as JQ1, has been extensively studied for the potential treatment of hematological malignancies and several small molecules belonging to this class are currently under clinical investigation. While these compounds are well known to inhibit cancer cell growth and cause apoptosis, their effects on stem cells, particularly mesenchymal stem cells (MSCs), which are important for regeneration of damaged cells and tissues, are unknown. In this study we employed umbilical cord derived MSCs as a model system to evaluate the safety of JQ1.MethodsCord derived MSCs were treated with various doses of JQ1 and subjected to cell metabolic activity, apoptosis, and cell cycle analyses using MTT assay, Annexin-V/FITC and PI staining, and flow cytometry, respectively. The effect of JQ1 on gene expression was determined using microarray and quantitative real-time reverse transcriptase polymerase chain reaction analysis. Furthermore, protein expression of apoptotic and neuronal markers was carried out using western blot and immunostaining, respectively.ResultsOur results showed that JQ1 inhibited cell growth and caused cell cycle arrest in G1 phase but did not induce apoptosis or senescence. JQ1 also down-regulated genes involved in self-renewal, cell cycle, DNA replication, and mitosis, which may have negative implications on the regenerative potential of MSCs. In addition, JQ1 interfered with signaling pathways by down regulating the expression of WNT, resulting in limiting the self-renewal. These results suggest that anticancer agents belonging to the thienodiazepine class of BET inhibitors should be carefully evaluated before their use in cancer therapy.ConclusionsThis study revealed for the first time that JQ1 adversely affected MSCs, which are important for repair and regeneration. JQ1 specifically modulated signal transduction and inhibited growth as well as self-renewal. These findings suggest that perinatal MSCs could be used to supplement animal models for investigating the safety of anticancer agents and other drugs.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-016-0278-3) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 93%

BET protein inhibitor JQ1 inhibits growth and modulates WNT signaling in mesenchymal stem cells

et al. 2016

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“…In this study, it was shown that Wnt1 upregulates Tlx3, and a forced expression of Tlx3 improved neurogenic differentiation [89]. Wnt5a promoted neurogenic differentiation in human ADSCs, binding to Fz3 and Fz5, and signalling through the Wnt5a-JNK pathway [90]. In summary, activation of Wnt signalling plays a key role in promoting the differentiation of MSCs towards a neuronal fate.…”

Section: Accepted Manuscriptmentioning

confidence: 63%

Multi-lineage differentiation of mesenchymal stem cells – To Wnt, or not Wnt

Visweswaran

Pöhl

Arfuso

et al. 2015

The International Journal of Biochemistry & Cell Biology

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Mesenchymal stem cells (MSCs) are multipotent precursor cells originating from several adult connective tissues. MSCs possess the ability to self-renew and differentiate into several lineages, and are recognized by the expression of unique cell surface markers. Several lines of evidence suggest that various signal transduction pathways and their interplay regulate MSC differentiation. To that end, a critical player in regulating MSC differentiation is a group of proteins encoded by the Wnt gene family, which was previously known for influencing various stages of embryonic development and cell fate determination. As MSCs have gained significant clinical attention for their potential applications in regenerative medicine, it is imperative to unravel the mechanisms by which molecular regulators control differentiation of MSCs for designing cell-based therapeutics. It is rather coincidental that the functional outcome(s) of Wnt-induced signals share similarities with cellular redox-mediated networks from the standpoint of MSC biology. Furthermore, there is evidence for a crosstalk between Wnt and redox signalling, which begs the question whether Wnt-mediated differentiation signals involve the intermediary role of reactive oxygen species. In this review, we summarize the impact of Wnt signalling on multi-lineage differentiation of MSCs, and attempt to unravel the intricate interplay between Wnt and redox signals.

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“…10,11 Recent studies in the adult CNS after injury demonstrate that canonical Wnt signaling induces axonal regeneration and neurite growth, suggesting that the developmental role for Wnt can be repurposed in adults by exogenous stimulation of the pathway. Non-canonical Wnt signaling including Wnt/ Ryk, Wnt/Ca + , and Wnt/JNK pathways have been reported to have a positive effect in neural differentiation, [18][19][20] but the further mechanism in promoting neural differentiation is unclear. 16 These two Wnt target genes are suppressed by the Notch effectors Hes1 and Hes5, leading to a competition between stem cell maintenance caused by Notch signaling and differentiation caused by Wnt signaling.…”

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confidence: 99%

Wnt4‐modified NSC transplantation promotes functional recovery after spinal cord injury

Peng

Long

et al. 2019

The FASEB Journal

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Spinal cord injury (SCI) can lead to severe motor and sensory dysfunction, yet there are no effective therapies currently due to the failure of reconstructing the interruption of the neuroanatomical circuit. While neural stem cell (NSC) transplantation has been considered a potential strategy to repair the neural circuit after SCI, the efficacy of this strategy remains unproven. The main reason is that most of the transplanted NSC differentiates into astrocyte rather than neuron in the microenvironment of SCI. Our results demonstrated that Wnt4 significantly promotes the differentiation of NSC into neuron by activating both β‐catenin and MAPK/JNK pathways and suppressing the activation of Notch signaling, which is acknowledged as prevention of NSC differentiation into neuron, through downregulating NICD expression, translocating and preventing the combination of NICD and RbpJ in nucleus. In addition, Wnt4 rescues the negative effect of Jagged, the ligand of Notch signaling, to promote neuronal differentiation. Moreover, in vivo study, transplantation of Wnt4‐modified NSC efficaciously repairs the injured spinal cord and recovers the motor function of hind limbs after SCI. This study sheds new light into mechanisms that Wnt4‐modified NSC transplantation is sufficient to repair the injured spinal cord and recover the motor dysfunction after SCI.

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Neural Differentiation of Human Adipose Tissue-Derived Stem Cells Involves Activation of the Wnt5a/JNK Signalling

Cited by 42 publications

References 31 publications

BET protein inhibitor JQ1 inhibits growth and modulates WNT signaling in mesenchymal stem cells

BET protein inhibitor JQ1 inhibits growth and modulates WNT signaling in mesenchymal stem cells

Multi-lineage differentiation of mesenchymal stem cells – To Wnt, or not Wnt

Wnt4‐modified NSC transplantation promotes functional recovery after spinal cord injury

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