Epithelial layer unjamming shifts energy metabolism toward glycolysis

Abstract

In development of an embryo, healing of a wound, or progression of a carcinoma, a requisite event is collective epithelial cellular migration. For example, cells at the advancing front of a wound edge tend to migrate collectively, elongate substantially, and exert tractions more forcefully compared with cells many ranks behind. With regards to energy metabolism, striking spatial gradients have recently been reported in the wounded epithelium, as well as in the tumor, but within the wounded cell layer little is known about the link between mechanical events and underlying energy metabolism. Using the advancing confluent monolayer of MDCKII cells as a model system, here we report at single cell resolution the evolving spatiotemporal fields of cell migration speeds, cell shapes, and traction forces measured simultaneously with fields of multiple indices of cellular energy metabolism. Compared with the epithelial layer that is unwounded, which is non-migratory, solid-like and jammed, the leading edge of the advancing cell layer is shown to become progressively more migratory, fluid-like, and unjammed. In doing so the cytoplasmic redox ratio becomes progressively smaller, the NADH lifetime becomes progressively shorter, and the mitochondrial membrane potential and glucose uptake become progressively larger. These observations indicate that a metabolic shift toward glycolysis accompanies collective cellular migration but show, further, that this shift occurs throughout the cell layer, even in regions where associated changes in cell shapes, traction forces, and migration velocities have yet to penetrate. In characterizing the wound healing process these morphological, mechanical, and metabolic observations, taken on a cell-by-cell basis, comprise the most comprehensive set of biophysical data yet reported. Together, these data suggest the novel hypothesis that the unjammed phase evolved to accommodate fluid-like migratory dynamics during episodes of tissue wound healing, development, and plasticity, but is more energetically expensive compared with the jammed phase, which evolved to maintain a solid-like non-migratory state that is more energetically economical.

Pulmonary fibrosis distal airway epithelia are dynamically and structurally dysfunctional

“…A possible explanation for this finding is a shift in cellular metabolism due to increased MUC5B expression from the promoter variant as well as ERBB activation. Alternations in cellular metabolism have been demonstrated previously in the unjammed phase, cytoskeletal reorganization, and endoplasmic reticulum stress 56 – 60 .…”

Fueling the cytoskeleton – links between cell metabolism and actin remodeling

“…Follower cells trail the leaders and rely on them for directionality (Mayor and Etienne-Manneville, 2016). Emerging work indicates that the leader cells take up more glucose, have higher ATP:ADP ratios and are more contractile than follower cells (DeCamp et al, 2020;Zhang et al, 2019). Leader MDA-MB-231 cells need energy levels above a certain threshold in order to remain a leader cell.…”

Enhanced Platelet-Rich Plasma (ePRP) Stimulates Wound Healing through Effects on Metabolic Reprogramming in Fibroblasts

“…Lactate, a glycolysis byproduct, is shown to be raised in the wound site shortly after wounding and to be elevated much above those in blood, demonstrating that the high lactate environment may drive collagen production in fibroblasts [ 47 ]. In recent work using single-cell resolution and the spatiotemporal observation of MDCKII cells, the leading edge of the advancing cell layer is shown to become progressively more migratory and to predominately utilize glycolysis for energy production when compared to the unwounded epithelial layer, which is non-migratory [ 48 , 49 , 50 , 51 ]. This metabolic shift implies that the migratory layer has a higher metabolic demand, which is supplied by glycolytic energy metabolism, which is fast but inefficient compared with OXPHOS [ 51 ].…”

“…In recent work using single-cell resolution and the spatiotemporal observation of MDCKII cells, the leading edge of the advancing cell layer is shown to become progressively more migratory and to predominately utilize glycolysis for energy production when compared to the unwounded epithelial layer, which is non-migratory [ 48 , 49 , 50 , 51 ]. This metabolic shift implies that the migratory layer has a higher metabolic demand, which is supplied by glycolytic energy metabolism, which is fast but inefficient compared with OXPHOS [ 51 ]. In another study, zebrafish with their tails chopped off have a metabolic change that favours glucose metabolism during early regeneration [ 52 ].…”