Mechanosensitive mTORC1 signaling maintains lymphatic valves

Abstract

Homeostatic maintenance and repair of lymphatic vessels are essential for health. We investigated the dynamics and the molecular mechanisms of lymphatic endothelial cell (LEC) renewal in adult mesenteric quiescent lymphatic vasculature using label-retention, lineage tracing, and cell ablation strategies. Unlike during development, adult LEC turnover and proliferation was confined to the valve regions of collecting vessels, with valve cells displaying the shortest lifespan. Proliferating valve sinus LECs were the main source for maintenance and repair of lymphatic valves. We identified mechanistic target of rapamycin complex 1 (mTORC1) as a mechanoresponsive pathway activated by fluid shear stress in LECs. Depending on the shear stress level, mTORC1 activity drives division of valve cells or dictates their mechanic resilience through increased protein synthesis. Overactivation of lymphatic mTORC1 in vivo promoted supernumerary valve formation. Our work provides insights into the molecular mechanisms of maintenance of healthy lymphatic vascular system.

Developmental progression of lymphatic valve morphology and function

“…The latter equates to 2/22 (9%) of stage 4 valves from Foxo1 fl/fl mice that were slightly leaky (>0.3 cmH 2 O) and is consistent with ~10% of slightly leaky control valves that we have reported in other studies (Lapinski et al, 2017;Munger et al, 2017;Davis et al, 2023). The slight leak in those valves may reflect the higher turnover of LECs in valve leaflets compared to the rest of the vessel (10% vs. 1%), as reported recently (Saygili Demir et al, 2023), and implies that valve function may be temporarily compromised to a slight degree during the turnover of critical LECs.…”

“… Stage 1. Oscillatory shear stress (OSS) is generally considered to be the normal initiator of LV formation ( Sabine et al, 2012 ; Choi et al, 2019 ; Saygili Demir et al, 2023 ), and one effect of OSS is to alter Foxo1 activity in the nucleus ( Scallan et al, 2021 ). If the first step in valve formation is the emergence of a valve-forming cluster of Prox1+ endothelial cells into a ring-shaped valve territory, is the expression of LEC polarity molecules (perhaps when Foxo1 leaves the nucleus) one of the early steps in LV formation?…”

Stepwise Stiffening/Softening of and Cell Recovery from Reversibly Formulated Hydrogel Double Networks

“…Given that both these pathways are downstream of PI3K-AKT and MAPK activity, it is unsurprising that they are highly affected by mechanical stimuli, and have previously been demonstrated as such. [75–78] The protooncogenic protein MYC has been demonstrated to regulate global metabolic reprogramming and plays a pivotal role in 5-fluorouracil resistance in colorectal cancer. [79,80] Many MYC-associated genes were most highly expressed in the stiff condition, while the dynamic conditions displayed the lowest expression of these genes ( Supplementary Figure S10 ), similar to a recent report by Nguyen and Lin in COLO-357 spheroids, [81] potentially signifying that modulating the mechanical environment plays a major role in suppressing this signaling axis.…”