bims-pimaco 2024-06-30 papers

Issue of 2024–06–30
two papers selected by
Lucas B. Zeiger

Cell Rep. 2024 Jun 20. pii: S2211-1247(24)00575-8. [Epub ahead of print]43(7): 114247

An iPSC-derived small intestine-on-chip with self-organizing epithelial, mesenchymal, and neural cells.

Renée Moerkens, Joram Mooiweer, Aarón D Ramírez-Sánchez, Roy Oelen, Lude Franke, Cisca Wijmenga, Robert J Barrett, Iris H Jonkers, Sebo Withoff.

Human induced pluripotent stem cell (hiPSC)-derived intestinal organoids are valuable tools for researching developmental biology and personalized therapies, but their closed topology and relative immature state limit applications. Here, we use organ-on-chip technology to develop a hiPSC-derived intestinal barrier with apical and basolateral access in a more physiological in vitro microenvironment. To replicate growth factor gradients along the crypt-villus axis, we locally expose the cells to expansion and differentiation media. In these conditions, intestinal epithelial cells self-organize into villus-like folds with physiological barrier integrity, and myofibroblasts and neurons emerge and form a subepithelial tissue in the bottom channel. The growth factor gradients efficiently balance dividing and mature cell types and induce an intestinal epithelial composition, including absorptive and secretory lineages, resembling the composition of the human small intestine. This well-characterized hiPSC-derived intestine-on-chip system can facilitate personalized studies on physiological processes and therapy development in the human small intestine.

Keywords: CP: Stem cell research; differentiation medium; enteric neuron; gut-on-chip; human; induced pluripotent stem cell; intestinal epithelial barrier; intestine-on-chip; mesenchyme; organ-on-chip; small intestine

DOI: https://doi.org/10.1016/j.celrep.2024.114247

J Dermatol Sci. 2024 Mar 07. pii: S0923-1811(24)00034-3. [Epub ahead of print]

RAS-activated PI3K/AKT signaling sustains cellular senescence via P53/P21 axis in experimental models of psoriasis.

Laura Mercurio, Jacob Bailey, Adam Bleier Glick, Elena Dellambra, Claudia Scarponi, Sabatino Pallotta, Cristina Albanesi, Stefania Madonna.

BACKGROUND: Psoriasis is a chronic immune-mediated skin disease in which upper epidermal keratinocytes exhibit a senescent-like phenotype. In psoriatic skin, a variety of inflammatory cytokines can activate intracellular pathways including phosphatidylinositol 3-kinase (PI3K)/AKT signaling and RAS effectors. AKT and RAS participate to cellular senescence, but currently their role in senescence responses occurring in psoriasis have not yet been investigated.
OBJECTIVE: The role of AKT molecular axis and RAS activation was evaluated in the context of cellular senescence in psoriasis disease.
METHODS: RAS/AKT involvement in senescence was analyzed in psoriatic keratinocytes cultures subjected to multiple passages to promote senescence in vitro, as well as in skin lesions of patients affected by psoriasis. The impact of pharmacological inhibition of PI3K/AKT pathway on senescence and inflammation responses was tested in senescent psoriatic keratinocytes and in a psoriasiform dermatitis murine model induced by RAS overexpression in the upper epidermis of mice.
RESULTS: We found AKT hyperactivation associated to the upregulation of senescence markers, in senescent psoriatic keratinocyte cultures, as well as in skin lesions of psoriatic patients. AKT-induced senescence was sustained by constitutive RAS activation, and down-stream responses were mediated by P53/P21 axis. PI3K/AKT inhibition contrasted senescence processes induced by cytokines in psoriatic keratinocytes. Additionally, RAS-induced psoriasis-like dermatitis in mice was accompanied by AKT upregulation, increase of senescence marker expression and by skin inflammation. In this model, both senescence and inflammation were significantly reduced by selective AKT inhibition.
CONCLUSION: Therefore, targeting RAS-AKT pathway could be a promising novel strategy to counteract multiple psoriasis symptoms.

Keywords: AKT; Keratinocytes; Psoriasis; RAS; Senescence

DOI: https://doi.org/10.1016/j.jdermsci.2024.03.002