Taz protects hematopoietic stem cells from an aging-dependent decrease in PU.1 activity

Kim, Kyung Mok; Mura-Mészáros, Anna; Tollot, Marie; Krishnan, Murali Shyam; Gründl, Marco; Groth, Marco; Rodriguez-Fraticelli, Alejo; Svendsen, Arthur Flohr; Campaner, Stefano; Andreas, Nico; Kamradt, Thomas; Hoffmann, Steve; Camargo, Fernando D.; Heidel, Florian H.; Bystrykh, Leonid; Haan, Gerald de; Eyß, Björn von

doi:10.1038/s41467-022-32970-1

Cited by 18 publications

(3 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our findings regarding the nuclear localization of TAZ, predominantly influenced by ASPP 049, could shed light on its novel characteristics in primitive HSPCs. Similar to findings in murine HSCs, TAZ alone potentially plays a role in protecting aging characteristics in old HSCs [ 60 ]. To verify signal activation, we transcriptionally tested the expression levels of Hippo-targeted genes, including CTGF, CCDN1, cMYC, and CYR61 (TGF-β-induced factor, as same as NanoString® SNAI2 (Slug), which plays a role in maintaining stemness [ 61 ]), which showed upregulation in all genes except cMYC, with no changes as expected from NanoString® mRNA profiling (Additional file 1 : Fig S6A).…”

Section: Discussionsupporting

confidence: 66%

Improving hematopoietic differentiation from human induced pluripotent stem cells by the modulation of Hippo signaling with a diarylheptanoid derivative

Thongsa-ad,

Wongpan,

Wongkummool

et al. 2024

Stem Cell Res Ther

View full text Add to dashboard Cite

Background The diarylheptanoid ASPP 049 has improved the quality of adult hematopoietic stem cell (HSC) expansion ex vivo through long-term reconstitution in animal models. However, its effect on hematopoietic regeneration from human induced pluripotent stem cells (hiPSCs) is unknown. Method We utilized a defined cocktail of cytokines without serum or feeder followed by the supplementation of ASPP 049 to produce hematopoietic stem/progenitor cells (HSPCs). Flow cytometry and trypan blue exclusion analysis were used to identify nonadherent and adherent cells. Nonadherent cells were harvested to investigate the effect of ASPP 049 on multipotency using LTC-IC and CFU assays. Subsequently, the mechanism of action was explored through transcriptomic profiles, which were validated by qRT-PCR, immunoblotting, and immunofluorescence analysis. Result The supplementation of ASPP 049 increased the number of phenotypically defined primitive HSPCs (CD34+CD45+CD90+) two-fold relative to seeded hiPSC colonies, indicating enhanced HSC derivation from hiPSCs. Under ASPP 049-supplemented conditions, we observed elevated HSPC niches, including CD144+CD73− hemogenic- and CD144+CD73+ vascular-endothelial progenitors, during HSC differentiation. Moreover, harvested ASPP 049-treated cells exhibited improved self-renewal and a significantly larger proportion of different blood cell colonies with unbiased lineages, indicating enhanced HSC stemness properties. Transcriptomics and KEGG analysis of sorted CD34+CD45+ cells-related mRNA profiles revealed that the Hippo signaling pathway is the most significant in responding to WWTR1/TAZ, which correlates with the validation of the protein expression. Interestingly, ASPP 049-supplemented HSPCs upregulated 11 genes similarly to umbilical cord blood-derived HSPCs. Conclusion These findings suggest that ASPP 049 can improve HSC-generating protocols with proliferative potentials, self-renewal ability, unbiased differentiation, and a definable mechanism of action for the clinical perspective of hematopoietic regenerative medicine. Graphical abstract

show abstract

Section: Discussionsupporting

confidence: 66%

Improving hematopoietic differentiation from human induced pluripotent stem cells by the modulation of Hippo signaling with a diarylheptanoid derivative

Thongsa-ad,

Wongpan,

Wongkummool

et al. 2024

Stem Cell Res Ther

View full text Add to dashboard Cite

show abstract

“…CUT and RUN experiments were performed as described previously with minor modifications (Kim et al, 2022). Briefly, for each CUT and RUN reaction 200,000 cells were trypsinized, washed, resuspended in 100 µl wash buffer (20 mM HEPES, pH7.5, 150 mM NaCl, 0.5 mM Spermidine) and bound to 10 µl activated Concanavalin A magnetic beads (Polysciences) for 10 min at room temperature.…”

Section: Methodsmentioning

confidence: 99%

A YIPF5-GOT1A/B complex directs a transcription-independent function of ATF6 in ER export

Cramer,

Yonemura,

Behrendt

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

Exit from the endoplasmic reticulum is mediated by the Sar1/COPII machinery and a number of accessory factors. How the initial steps of cargo recruitment upstream of Sar1/COPII are mediated remains unclear, but the dihydropyridine FLI-06 inhibits cargo recruitment into ER exit sites. Here, we used chemical genetics screening approaches in conjunction with FLI-06 treatment and identified the ER membrane proteins YIPF5 and GOT1A/B as putative components of early export processes. Surprisingly, the two homologous proteins GOT1A and GOT1B, coded byGOLT1AandGOLT1B, respectively, exhibited opposite functions after treatment with FLI-06: increasing the expression of GOT1A or reducing the expression of GOT1B or YIPF5 prevented inhibition of ER-export by FLI-06. Inhibiting ER export with FLI-06 elicited a specific ER stress-related gene expression signature distinct from the ER-stress signature induced by Thapsigargin. The interactomes of GOT1A and GOT1B suggested a connection to ER-stress mediators. Moreover, RNA-Seq data showed that FLI-06-induced genes are strongly enriched for ATF6 target genes which are suppressed by GOLT1A overexpression or GOLT1B knock-down. This suggests that ATF6 signaling is involved in FLI-06-mediated toxicity, and we could demonstrate that siRNA-mediated knock-down or specific inhibitor of ATF6 rescued cells from FLI-06-mediated cell death. Knock-down or inhibition of ATF6 is sufficient to resume transport from the ER under FLI-06-treatment, suggesting that ATF6 is directly involved in the FLI-06-mediated ER-export block. Surprisingly, our data show that this ATF6 function is independent ofde novotranscription, implying a novel, transcription-independent function of ATF6.

show abstract

“…The Yes-associated protein (YAP) and the transcriptional coactivator with the PDZ-binding domain (TAZ) are critical regulators of tissue regeneration and stem cell circuitry by regulating stem cell renewal, fate, and plasticity [ 112 ]. YAP/TAZ is important in delaying stem cell senescence to prevent stem cell exhaustion [ 113 ]. PA200 depletes the nuclear acetylated YAP in the mesenchymal stem cells (MSC) treated with the histone deacetylase (HDAC) inhibitor apicidin.…”

Section: Pa200 Plays Important Roles In Preventing Cellular Senescencementioning

confidence: 99%

PA200-Mediated Proteasomal Protein Degradation and Regulation of Cellular Senescence

Wen,

Sun,

Jiang

et al. 2024

IJMS

View full text Add to dashboard Cite

Cellular senescence is closely related to DNA damage, proteasome inactivity, histone loss, epigenetic alterations, and tumorigenesis. The mammalian proteasome activator PA200 (also referred to as PSME4) or its yeast ortholog Blm10 promotes the acetylation-dependent degradation of the core histones during transcription, DNA repair, and spermatogenesis. According to recent studies, PA200 plays an important role in senescence, probably because of its role in promoting the degradation of the core histones. Loss of PA200 or Blm10 is a major cause of the decrease in proteasome activity during senescence. In this paper, recent research progress on the association of PA200 with cellular senescence is summarized, and the potential of PA200 to serve as a therapeutic target in age-related diseases is discussed.

show abstract

Taz protects hematopoietic stem cells from an aging-dependent decrease in PU.1 activity

Cited by 18 publications

References 36 publications

Improving hematopoietic differentiation from human induced pluripotent stem cells by the modulation of Hippo signaling with a diarylheptanoid derivative

Improving hematopoietic differentiation from human induced pluripotent stem cells by the modulation of Hippo signaling with a diarylheptanoid derivative

A YIPF5-GOT1A/B complex directs a transcription-independent function of ATF6 in ER export

PA200-Mediated Proteasomal Protein Degradation and Regulation of Cellular Senescence

Contact Info

Product

Resources

About