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2015 ; 112
(35
): 10938-43
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Mechanobiological oscillators control lymph flow
#MMPMID26283382
Kunert C
; Baish JW
; Liao S
; Padera TP
; Munn LL
Proc Natl Acad Sci U S A
2015[Sep]; 112
(35
): 10938-43
PMID26283382
show ga
The ability of cells to sense and respond to physical forces has been recognized
for decades, but researchers are only beginning to appreciate the fundamental
importance of mechanical signals in biology. At the larger scale, there has been
increased interest in the collective organization of cells and their ability to
produce complex, "emergent" behaviors. Often, these complex behaviors result in
tissue-level control mechanisms that manifest as biological oscillators, such as
observed in fireflies, heartbeats, and circadian rhythms. In many cases, these
complex, collective behaviors are controlled--at least in part--by physical
forces imposed on the tissue or created by the cells. Here, we use mathematical
simulations to show that two complementary mechanobiological oscillators are
sufficient to control fluid transport in the lymphatic system: Ca(2+)-mediated
contractions can be triggered by vessel stretch, whereas nitric oxide produced in
response to the resulting fluid shear stress causes the lymphatic vessel to relax
locally. Our model predicts that the Ca(2+) and NO levels alternate
spatiotemporally, establishing complementary feedback loops, and that the
resulting phasic contractions drive lymph flow. We show that this mechanism is
self-regulating and robust over a range of fluid pressure environments, allowing
the lymphatic vessels to provide pumping when needed but remain open when flow
can be driven by tissue pressure or gravity. Our simulations accurately reproduce
the responses to pressure challenges and signaling pathway manipulations observed
experimentally, providing an integrated conceptual framework for lymphatic
function.
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