Cardiomyocyte differentiation of pluripotent stem cells with SB203580 analogues correlates with Wnt pathway CK1 inhibition independent of p38 MAPK signaling

Laco, Filip; Low, Joo-Leng; Seow, Jasmin; Woo, Tsung Liang; Zhong, Qixing; Seayad, Jayasree; Liu, Zhongfan; Wei, Heiming; Reuveny, Shaul; Elliott, David A.; Chai, Christina L. L.; Oh, Steve Kah‐Weng

doi:10.1016/j.yjmcc.2014.12.003

Cited by 18 publications

(21 citation statements)

References 54 publications

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“…These studies suggest that contrary to our previous assertion , the kinase target of TIs, CK1δ/ε, is unlikely to be critical for cardiac differentiation. When the cardiomyogenic activities of the compounds (shown in Fig.…”

Section: Resultscontrasting

confidence: 99%

“…On Day 13, the EBs were harvested and analyzed for NKX2‐5/GFP expression using image‐based microscopy (image examples are shown in Supporting Information Fig. S2B) . From these studies, 11 compounds (TI‐14, TI‐15, TI‐16, TI‐20, TI‐21, TI‐24, TI‐25, TI‐26, TI‐27, TI‐33, and IWP‐2) were found to induce a higher GFP expression than the lead compound TA‐01 (Supporting Information Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The best inducer of cardiomyogenesis was TA‐01 (structure is shown in Supporting information Fig. S1) which showed a threefold increase in the percentage expression of NKX2‐5/GFP‐positive cells over DMSO when added from days 4 to 8 . In this study, an expanded series of TA‐01 analogs with structural variations at the N1, C2, or N3 positions of imidazole (TI‐01 to TI‐50, structures are shown in Supporting information Table S1) were designed and synthesized.…”

Section: Introductionmentioning

confidence: 99%

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Influencing the Fate of Cardiac and Neural Stem Cell Differentiation Using Small Molecule Inhibitors of ALK5

Zhong

Laco

Liao

et al. 2018

Stem Cells Translational Medicine

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In this study, 50 tri‐substituted imidazoles (TIs), which are analogs of the small molecules TA‐01 and SB203580, were synthesized and screened for cardiomyogenic activities. Several TIs displayed cardiomyogenic activities when applied during the differentiation from days 3–5. The TIs did not affect the Wnt/β‐catenin pathway during cardiomyogenesis and the likely mechanism of action is through the inhibition of ALK5 of the TGFβ pathway. Interestingly, these TIs promoted the neural differentiation of human pluripotent stem cells (hPSCs) with a similar potency to that of the dual SMAD inhibitors SB431542/LDN‐193189 when dosed from days 1 to 9. The neural induction activities of the TIs correlated with their ALK5 inhibitory activities. This study reports the discovery of small molecule inhibitors of ALK5, which can promote the differentiation of hPSCs into cardiomyocytes or neural cells depending on the time of dosing, showing potential for the production of clinical‐grade cardiac/neural cells for regenerative therapy. Stem Cells Translational Medicine 2018;7:709–720

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Section: Resultscontrasting

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Influencing the Fate of Cardiac and Neural Stem Cell Differentiation Using Small Molecule Inhibitors of ALK5

Zhong

Laco

Liao

et al. 2018

Stem Cells Translational Medicine

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“…1g, i). The time-dependent variability of SB239063 effects on a phosphorylation cascade in a cell culture system might reflect its multi-kinase inhibitor activity (e.g., [34, 51]), where each kinase target may have a role that varies quantitatively during the phenotypic change. This was not pursued further as part of this investigation.…”

Section: Resultsmentioning

confidence: 99%

“…A variety of small-molecule p38α MAPK inhibitors have been tested in preclinical animal models of CNS diseases. These inhibitors vary in their target specificity, which raises concerns about linkage of target modulation to phenotype—a key aspect of drug discovery target validation, as documented previously [34]. For example, first-generation p38α MAPK inhibitors such as MW01-2-069A-SRM were used in a mouse model of AD-relevant pathophysiology that involves intracerebroventricular (ICV) infusion of oligomeric Aβ 1–42 [35].…”

Section: Introductionmentioning

confidence: 99%

Selective suppression of the α isoform of p38 MAPK rescues late-stage tau pathology

Maphis

Jiang

et al. 2016

Alz Res Therapy

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BackgroundHyperphosphorylation and aggregation of tau protein are the pathological hallmarks of Alzheimer’s disease and related tauopathies. We previously demonstrated that the microglial activation induces tau hyperphosphorylation and cognitive impairment via activation of p38 mitogen-activated protein kinase (p38 MAPK) in the hTau mouse model of tauopathy that was deficient for microglial fractalkine receptor CX3CR1.MethodWe report an isoform-selective, brain-permeable, and orally bioavailable small molecule inhibitor of p38α MAPK (MW181) and its effects on tau phosphorylation in vitro and in hTau mice.ResultsFirst, pretreatment of mouse primary cortical neurons with MW181 completely blocked inflammation-induced p38α MAPK activation and AT8 (pS199/pS202) site tau phosphorylation, with the maximum effect peaking at 60–90 min after stimulation. Second, treatment of old (~20 months of age) hTau mice with MW181 (1 mg/kg body weight; 14 days via oral gavage) significantly reduced p38α MAPK activation compared with vehicle-administered hTau mice. This also resulted in a significant reduction in AT180 (pT231) site tau phosphorylation and Sarkosyl-insoluble tau aggregates. Third, MW181 treatment significantly increased synaptophysin protein expression and resulted in improved working memory. Fourth, MW181 administration reduced phosphorylated MAPK-activated protein kinase 2 (pMK2) and phosphorylated activating transcription factor 2 (pATF2), which are known substrates of p38α MAPK. Finally, MW181 reduced the expression of interferon-γ and interleukin-1β.ConclusionsTaken together, these studies support p38α MAPK as a valid therapeutic target for the treatment of tauopathies.

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Scalable Cardiac Differentiation of Pluripotent Stem Cells Using Specific Growth Factors and Small Molecules

Kempf¹,

Zweigerdt²

2017

Engineering and Application of Pluripotent Stem Cells

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The envisioned routine application of human pluripotent stem cell (hPSC)-derived cardiomyocytes (CMs) for therapies and industry-compliant screening approaches will require efficient and highly reproducible processes for the mass production of well-characterized CM batches.On their way toward beating CMs, hPSCs initially undergo an epithelial-to-mesenchymal transition into a primitive-streak (PS)-like population that later gives rise to all endodermal and mesodermal lineages, including cardiovascular progenies (CVPs). CVPs are multipotent and possess the capability to give rise to all major cell types of the heart, including CMs, endothelial cells, cardiac fibroblasts, and smooth muscle cells. This article provides an historical overview and describes the stepwise development of protocols that typically result in the appearance of beating CMs within 7-12 days of hPSC differentiation.We describe the development of directed and closely controlled cardiomyogenic differentiation, which now enables the induction of >90% CM purity without further lineage enrichment. Although secreted lineage specifiers (revealed from developmental biology) were initially used, we outline the advantages of chemical pathway modulators, as defined by more recent screening approaches. Subsequently, we discuss the use of defined culture media for upscaling the production of hPSC-CMs in controlled bioreactors and how this, in principle, unlimited source of human CMs can be used to progress heart regeneration and stimulate the drug discovery pipeline. Graphical Abstract.

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Cardiomyocyte differentiation of pluripotent stem cells with SB203580 analogues correlates with Wnt pathway CK1 inhibition independent of p38 MAPK signaling

Cited by 18 publications

References 54 publications

Influencing the Fate of Cardiac and Neural Stem Cell Differentiation Using Small Molecule Inhibitors of ALK5

Influencing the Fate of Cardiac and Neural Stem Cell Differentiation Using Small Molecule Inhibitors of ALK5

Selective suppression of the α isoform of p38 MAPK rescues late-stage tau pathology

Scalable Cardiac Differentiation of Pluripotent Stem Cells Using Specific Growth Factors and Small Molecules

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