Functional dissection of human cardiac enhancers and noncoding de novo variants in congenital heart disease
Rare coding mutations cause ~45% of congenital heart disease (CHD). Noncoding mutations that perturb cis-regulatory elements (CREs) likely contribute to the remaining cases,but their identification has been problematic. Using a lentiviral massively parallel reporter assay (lentiMPRA) in human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs),we functionally evaluated 6,590 noncoding de novo variants (ncDNVs) prioritized from the whole-genome sequencing of 750 CHD trios. A total of 403 ncDNVs substantially affected cardiac CRE activity. A majority increased enhancer activity,often at regions with undetectable reference sequence activity. Of ten DNVs tested by introduction into their native genomic context,four altered the expression of neighboring genes and iPSC-CM transcriptional state. To prioritize future DNVs for functional testing,we used the MPRA data to develop a regression model,EpiCard. Analysis of an independent CHD cohort by EpiCard found enrichment of DNVs. Together,we developed a scalable system to measure the effect of ncDNVs on CRE activity and deployed it to systematically assess the contribution of ncDNVs to CHD.
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产品类型：
产品号#：
85850
85857
产品名：
mTeSR™1
mTeSR™1
(Mar 2025)
Communications Medicine 5
H105A peptide eye drops promote photoreceptor survival in murine and human models of retinal degeneration
BackgroundPhotoreceptor death leads to inherited blinding retinal diseases,such as retinitis pigmentosa (RP). As disease progression often outpaces therapeutic advances,developing effective treatments is urgent. This study evaluates the efficacy of small peptides derived from pigment epithelium-derived factor (PEDF),which are known to restrict common cell death pathways associated with retinal diseases.MethodsWe tested chemically synthesized peptides (17-mer and H105A) with affinity for the PEDF receptor,PEDF-R,delivered as eye drops to two RP mouse models: rd10 (phosphodiesterase 6b mutation) and RhoP23H/+ (rhodopsin P23H mutation). Additionally,we engineered AAV-H105A vectors for intravitreal delivery in RhoP23H/+ mice. To assess peptide effects in human tissue,we used retinal organoids exposed to cigarette smoke extract,a model of oxidative stress. Photoreceptor survival,morphology and function were evaluated.ResultsHere we show that peptides 17-mer and H105A delivered via eye drops successfully reach the retina,promote photoreceptor survival,and improve retinal function in both RP mouse models. Intravitreal delivery of a AAV-H105A vector delays photoreceptor degeneration in RhoP23H/+ mice up to six months. In human retinal organoids,peptide H105A specifically prevents photoreceptor death induced by oxidative stress,a contributing factor to RP progression.ConclusionsPEDF peptide-based eye drops offer a promising,minimally invasive therapy to prevent photoreceptor degeneration in retinal disorders,with a favorable safety profile. Plain language summaryRetinitis pigmentosa (RP) is a rare inherited condition that causes the gradual death of photoreceptors (light-sensing cells) in the eye,leading to vision loss. There is currently no cure. This study tested a potential treatment using small protein fragments (peptides) from PEDF,a protective protein naturally found in the eye. Researchers delivered these peptides through eye drops or gene therapy in mouse models of RP and to human retinal organoids (lab-grown retina tissue). Mice treated early maintained healthy vision cells,while untreated mice experienced rapid cell loss and vision decline. These results suggest that peptide-based eye drops could be a simple,safe,and effective way to slow vision loss in patients with RP. Bernardo-Colón et al. evaluate small peptides derived from the neurotrophic region of pigment epithelium-derived factor (PEDF) as potential therapeutics for retinitis pigmentosa using mouse models and human retinal organoids. A significant delay in photoreceptor death with eye drop or gene therapy delivery is seen.
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产品类型：
产品号#：
85850
85857
产品名：
mTeSR™1
mTeSR™1
M. Gijsbertsen et al. (Sep 2025)
Disease Models & Mechanisms 18 10
Generation of human induced pluripotent stem cell lines from patients with FGFR2 -linked syndromic craniosynostosis
Craniosynostosis is a multigenic congenital condition in which one or more calvarial sutures have prematurely fused during the development of the fetus. Pathogenic variants in FGFR2 are associated with the development of syndromic craniosynostosis,such as Crouzon,Apert and Pfeifer syndromes. Investigation of FGFR2 -linked craniosynostosis is hindered by the lack of appropriate in vitro models. Patient-derived human induced pluripotent stem cell (hiPSC) in vitro disease models provide the opportunity to investigate the disease,identify molecular targets for pharmaceutical treatments,and enable the generation of autologous pluripotent stem cell catalogues. Here,we report three patient-derived hiPSC lines carrying the C342Y,S252W or E565G FGFR2 pathogenic variant. The patient hiPSC lines express characteristic pluripotency markers and display distinct phosphorylation profiles under unstimulated conditions. FGFR2 C342Y showed autophosphorylation in the absence of bFGF ligand,although downstream docking proteins PLCγ and FRS2α were not phosphorylated. FGFR2 S252W and FGFR2 E565G hiPSCs showed increased phosphorylation of docking proteins PLCγ and FRS2α,whereas FGFR2 was not phosphorylated. These patient hiPSC lines provide molecular and cellular options to investigate FGFR2 -linked craniosynostosis in the patient-specific genomic context and develop therapeutic modalities.
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产品类型：
产品号#：
05230
100-0483
100-0484
100-0276
100-1130
05946
85850
85857
产品名：
STEMdiff™ 三胚层分化试剂盒
Hausser Scientificᵀᴹ 明线血球计数板
ReLeSR™
mTeSR™ Plus
mTeSR™ Plus
TeSR™-E6
mTeSR™1
mTeSR™1
Yang et al. (Dec 2024)
PLOS ONE 19 12
Unveiling immune cell response disparities in human primary cancer-associated fibroblasts between two- and three-dimensional cultures
Cancer-associated fibroblasts (CAFs) play pivotal roles in solid tumor initiation,growth,and immune evasion. However,the optimal biomimetic modeling conditions remain elusive. In this study,we investigated the effects of 2D and 3D culturing conditions on human primary CAFs integrated into a modular tumor microenvironment (TME). Using single-nucleus RNA sequencing (snRNAseq) and Proteomics’ Proximity Extension Assays,we characterized CAF transcriptomic profiles and cytokine levels. Remarkably,when cultured in 2D,CAFs exhibited a myofibroblast (myCAF) subtype,whereas in 3D tumor spheroid cultures,CAFs displayed a more inflammatory (iCAF) pathological state. By integrating single-cell gene expression data with functional interrogations of critical TME-related processes [natural killer (NK)-mediated tumor killing,monocyte migration,and macrophage differentiation],we were able to reconcile form with function. In 3D TME spheroid models,CAFs enhance cancer cell growth and immunologically shield cells from NK cell-mediated cytotoxicity,in striking contrast with their 2D TME counterparts. Notably,3D CAF-secreted proteins manifest a more immunosuppressive profile by enhancing monocyte transendothelial migration and differentiation into M2-like tumor-associated macrophages (TAMs). Our findings reveal a more immunosuppressive and clinically relevant desmoplastic TME model that can be employed in industrial drug discovery campaigns to expand the cellular target range of chemotherapeutics.
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Lane ME et al. ( 2001)
Cancer research 61 16 6170--6177
A novel cdk2-selective inhibitor, SU9516, induces apoptosis in colon carcinoma cells.
Recent studies have indicated that the development of cyclin-dependent kinase (cdk)2 inhibitors that deregulate E2F are a plausible pharmacological strategy for novel antineoplastic agents. We show here that 3-[1-(3H-Imidazol-4-yl)-meth-(Z)-ylidene]-5-methoxy-1,3-dihydro-indol-2-one (SU9516),a novel 3-substituted indolinone compound,binds to and selectively inhibits the activity of cdk2. This inhibition results in a time-dependent decrease (4-64%) in the phosphorylation of the retinoblastoma protein pRb,an increase in caspase-3 activation (5-84%),and alterations in cell cycle resulting in either a G(0)-G(1) or a G(2)-M block. We also report here cell line differences in the cdk-dependent phosphorylation of pRb. These findings demonstrate that SU9516 is a selective cdk2 inhibitor and support the theory that compounds that inhibit cdk2 are viable resources in the development of new antineoplastic agents.
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产品类型：
产品号#：
73452
产品名：
SU9516
Kordes C et al. ( 2008)
Biochemical and biophysical research communications 367 1 116--123
Canonical Wnt signaling maintains the quiescent stage of hepatic stellate cells.
It is well known that hepatic stellate cells (HSC) develop into cells,which are thought to contribute to liver fibrogenesis. Recent data suggest that HSC are progenitor cells with the capacity to differentiate into cells of endothelial and hepatocyte lineages. The present study shows that beta-catenin-dependent canonical Wnt signaling is active in freshly isolated HSC of rats. Mimicking of the canonical Wnt pathway in cultured HSC by TWS119,an inhibitor of the glycogen synthase kinase 3beta,led to reduced beta-catenin phosphorylation,induced nuclear translocation of beta-catenin,elevated glutamine synthetase production,impeded synthesis of alpha-smooth muscle actin and Wnt5a,but promoted the expression of glial fibrillary acidic protein,Wnt10b,and paired-like homeodomain transcription factor 2c. In addition,canonical Wnt signaling lowered DNA synthesis and hindered HSC from entering the cell cycle. The findings demonstrate that beta-catenin-dependent Wnt signaling maintains the quiescent state of HSC and,similar to stem and progenitor cells,influences their developmental fate.
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产品类型：
产品号#：
73512
73514
产品名：
TWS119
TWS119
Mathieu C et al. (AUG 2008)
Molecular and cellular neurosciences 38 4 569--77
Endothelial cell-derived bone morphogenetic proteins control proliferation of neural stem/progenitor cells.
Neurogenesis persists in the adult brain subventricular zone where neural stem/progenitor cells (NSPCs) lie close to brain endothelial cells (BECs). We show in mouse that BECs produce bone morphogenetic proteins (BMPs). Coculture of embryonic and adult NSPCs with BECs activated the canonical BMP/Smad pathway and reduced their proliferation. We demonstrate that coculture with BECs in the presence of EGF and FGF2 induced a reversible cell cycle exit of NSPCs (LeX+) and an increase in the amount of GFAP/LeX-expressing progenitors thought to be stem cells. Levels of the phosphatidylinositol phosphatase PTEN were upregulated in NSPCs after coculture with BECs,or treatment with recombinant BMP4,with a concomitant reduction in Akt phosphorylation. Silencing Smad5 with siRNA or treatment with Noggin,a BMP antagonist,demonstrated that upregulation of PTEN in NSPCs required BMP/Smad signaling and that this pathway regulated cell cycle exit of NSPCs. Therefore,BECs may provide a feedback mechanism to control the proliferation of NSPCs.
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产品类型：
产品号#：
05700
05701
05702
产品名：
NeuroCult™ 基础培养基（小鼠和大鼠）
NeuroCult™ 扩增添加物（小鼠和大鼠）
NeuroCult™扩增试剂盒（小鼠和大鼠）
Navarro F et al. (SEP 2009)
Blood 114 10 2181--92
miR-34a contributes to megakaryocytic differentiation of K562 cells independently of p53.
The role of miRNAs in regulating megakaryocyte differentiation was examined using bipotent K562 human leukemia cells. miR-34a is strongly up-regulated during phorbol ester-induced megakaryocyte differentiation,but not during hemin-induced erythrocyte differentiation. Enforced expression of miR-34a in K562 cells inhibits cell proliferation,induces cell-cycle arrest in G(1) phase,and promotes megakaryocyte differentiation as measured by CD41 induction. miR-34a expression is also up-regulated during thrombopoietin-induced differentiation of CD34(+) hematopoietic precursors,and its enforced expression in these cells significantly increases the number of megakaryocyte colonies. miR-34a directly regulates expression of MYB,facilitating megakaryocyte differentiation,and of CDK4 and CDK6,to inhibit the G(1)/S transition. However,these miR-34a target genes are down-regulated rapidly after inducing megakaryocyte differentiation before miR-34a is induced. This suggests that miR-34a is not responsible for the initial down-regulation but may contribute to maintaining their suppression later on. Previous studies have implicated miR-34a as a tumor suppressor gene whose transcription is activated by p53. However,in p53-null K562 cells,phorbol esters induce miR-34a expression independently of p53 by activating an alternative phorbol ester-responsive promoter to produce a longer pri-miR-34a transcript.
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产品类型：
产品号#：
02696
09850
70008
70008.1
70008.2
70008.3
70008.4
70008.5
70008.6
04971
04902
04901
04963
04962
200-0002
200-0001
200-0000
产品名：
StemSpan™巨核细胞扩增添加物 (100X)
冻存的人脐带血CD34+细胞
冻存的人脐带血CD34+细胞
冻存的人脐带血CD34+细胞
冻存的人脐带血CD34+细胞
冻存的人脐带血CD34+细胞
冻存的人脐带血CD34+细胞
MegaCult™-C含细胞因子全套试剂盒
胶原蛋白溶液
MegaCult™-C含细胞因子培养基
双室载玻片套件
MegaCult™-C CFU-Mk染色试剂盒
冻存的人脐带血CD34+细胞
冻存的人脐带血CD34+细胞
冻存的人脐带血CD34+细胞
Kern J et al. (OCT 2009)
Blood 114 18 3960--7
GRP-78 secreted by tumor cells blocks the antiangiogenic activity of bortezomib.
Antiangiogenic effects of the proteasome inhibitor bortezomib were analyzed on tumor xenografts in vivo. Bortezomib strongly inhibited angiogenesis and vascularization in the chicken chorioallantoic membrane. Bortezomib's inhibitory effects on chorioallantoic membrane vascularization were abrogated in the presence of distinct tumor xenografts,thanks to a soluble factor secreted by tumor cells. Through size-exclusion and ion-exchange chromatography as well as mass spectroscopy,we identified GRP-78,a chaperone protein of the unfolded protein response,as being responsible for bortezomib resistance. Indeed,a variety of bortezomib-resistant solid tumor cell lines (PC-3,HRT-18),but not myeloma cell lines (U266,OPM-2),were able to secrete high amounts of GRP-78. Recombinant GRP-78 conferred bortezomib resistance to endothelial cells and OPM-2 myeloma cells. Knockdown of GRP78 gene expression in tumor cells and immunodepletion of GRP-78 protein from tumor cell supernatants restored bortezomib sensitivity. GRP-78 did not bind or complex bortezomib but induced prosurvival signals by phosphorylation of extracellular signal-related kinase and inhibited p53-mediated expression of proapoptotic Bok and Noxa proteins in endothelial cells. From our data,we conclude that distinct solid tumor cells are able to secrete GRP-78 into the tumor microenvironment,thus demonstrating a hitherto unknown mechanism of resistance to bortezomib.
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EasySep™小鼠TIL（CD45）正选试剂盒
研究综述Mesenchymal Stromal Cells: Markers, Isolation and Culture, Differentiation, and Therapeutic Potential
科学海报Isolation of Highly Purified Mouse CD4+CD25+Foxp3+ Regulatory T Cells in Less
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