Publications

Mammalian epidermal stem cells maintain homeostasis of the skin epidermis and contribute to its regeneration throughout adult life. While 2D mouse epidermal stem cell cultures have been established decades ago, a long-term, feeder cell- and serum-free culture system recapitulating murine epidermal architecture has not been available. Here we describe an epidermal organoid culture system that allows long-term, genetically stable expansion of adult epidermal stem cells. Our epidermal expansion media combines atypically high calcium concentrations, activation of cAMP, FGF, and R-spondin signaling with inhibition of bone morphogenetic protein (BMP) signaling. Organoids are established robustly from adult mouse skin and expand over at least 6 mo, while maintaining the basal-apical organization of the mouse interfollicular epidermis. The system represents a powerful tool to study epidermal homeostasis and disease in vitro.

Additional file 3. Table S3

No abstract is provided for this article.

Abstract Nephropathic cystinosis is a severe monogenetic kidney disorder caused by mutations in CTNS , encoding the lysosomal transporter cystinosin, resulting in lysosomal cystine accumulation. The sole treatment, cysteamine, slows down the disease progression, but does not correct the established proximal tubulopathy. Here, we developed a new therapeutic strategy by applying an omics-based strategy to expand our knowledge on the complexity of the disease and prioritize drug targets in cystinosis. We identified alpha-ketoglutarate as a key metabolite linking cystinosin loss, lysosomal autophagy defect and proximal tubular impairment in cystinosis. This insight offered a bicalutamide-cysteamine combination treatment as a novel dual target pharmacological approach for the phenotypical correction of cystinotic proximal tubule cells, patient-derived kidney tubuloids and cystinotic zebrafish.

This study contributes to our understanding of work engagement within teams by using aggregated data at the work-unit level in order to test the factorial structure of a Team Work Engagement Scale (i.e., vigor, dedication, and absorption) in a sample of 511 employees nested in 54 teams and 12 small and medium-sized enterprises. Items were aggregated from team members’ perceptions using the ADM(J) index. After an item-reduction procedure from the original 18-item scale, confirmatory factor analyses by AMOS: (1) confirmed the expected three-factor structure of team work engagement, and (2) offered a reliable scale with which to test work engagement at the team level. Theoretical and practical implications about team work engagement are discussed according to the findings.

Abstract With recent progress in modeling liver organogenesis and regeneration, the lack of vasculature is becoming the bottleneck in progressing our ability to model human hepatic tissues in vitro. Here, we introduce a platform for routine grafting of liver and other tissues on an in vitro grown microvascular bed. The platform consists of 64 microfluidic chips patterned underneath a 384-well microtiter plate. Each chip allows the formation of a microvascular bed between two main lateral vessels by inducing angiogenesis. Chips consist of an open-top microfluidic chamber, which enables addition of a target tissue by manual or robotic pipetting. Upon grafting a liver microtissue, the microvascular bed undergoes anastomosis, resulting in a stable, perfusable vascular network. Interactions with vasculature were found in spheroids and organoids upon 7 days of co-culture with space of Disse-like architecture in between hepatocytes and endothelium. Veno-occlusive disease was induced by azathioprine exposure, leading to impeded perfusion of the vascularized spheroid. The platform holds the potential to replace animals with an in vitro alternative for routine grafting of spheroids, organoids, or (patient-derived) explants.

No abstract is provided for this article.

Homeostasis of intestinal stem cells (ISCs) is maintained by the orchestration of niche factors and intrinsic signaling networks. Here we found that deletion of Erk1/2 in intestinal epithelial cells at embryonic stages resulted in an unexpected increase in cell proliferation and migration, expansion of ISCs and formation of polyp-like structures, leading to postnatal death. Deficiency of epithelial Erk1/2 results in defects in secretory cell differentiation as well as impaired mesenchymal cell proliferation and maturation. Deletion of Erk1/2 strongly activated Wnt signaling through both cell-autonomous and non-autonomous mechanisms. In epithelial cells, Erk1/2 depletion resulted in loss of the feedback regulation leading to Ras/Raf cascade activation which transactivated Akt activity to stimulate the mTor and Wnt/β-catenin pathways. Moreover, Erk1/2 deficiency reduced the Indian hedgehog level and the expression of downstream pathway components including mesenchymal Bmp4, a Wnt suppressor in intestines. Inhibition of mTor signaling by rapamycin partially rescued Erk1/2 depletion-induced intestinal defects and significantly prolonged mutant mice life span. These data demonstrate that Erk/Mapk signaling functions as a key modulator of Wnt signaling through coordination of epithelial-mesenchymal interactions during intestinal development.