The primary function of lymphatics is to maintain tissue fluid balance by collecting blood capillary filtrates via the interstitial space. This fluid flux into draining lymphatics is very slow and is referred to as interstitial flow.
We have identified a phenomenon that we have termed autologous chemotaxis whereby a cell can receive directional cues while at the same time being the source of such cues. This phenomenon is a consequence of the subtle convective forces in the biophysical environment. Using computer modeling and novel in vitro co-culture models we have demonstrated that slow interstitial flow is sufficient to create and amplify transcellular chemokine gradients which a cell can utilize and chemotact along; in the case of cancer, a cell can directionally chemotact along autologously generated CCL21 gradients with interstitial flow towards draining lymphatics and subsequently disseminate. The phenomenon of autologous chemotaxis is a fundamentally important mechanism in relation to cell trafficking hence we are also investigating how interstitial flow can influence immune cell transport via lymphatics and the limits of transcellular gradient detection.
Mechanobiology of interstitial flow
We have demonstrated that fibroblasts-connective tissue cells found throughout the body-respond to interstitial flow by remodeling the extracellular matrix, resulting in both cell and collagen fiber alignment perpendicular to the direction of fluid flow. Interstitial fluid flow also induces fibroblasts to differentiate into myofibroblasts. Myofibroblasts are highly contractile and secrete a host of factors, making them important players in wound healing, but their persistent presence is also associated with pathological conditions such as fibrosis and cancer.
- “Interstitial flow in a 3D microenvironment increases glioma invasion by a CXCR4-dependent mechanism”, JM Munson, RV Bellamkonda, MA Swartz. Cancer Research, 2013
- “Tumor cell invasion is promoted by interstitial flow-induced matrix priming by stromal fibroblasts”, Shieh AC, Rozansky HA, Hinz B, Swartz MA. Cancer Research, 2011
- “Autologous chemotaxis as a mechanism of tumor cell homing to lymphatics via interstitial flow and autocrine CCR7 signaling”, Shields JD, Fleury ME, Yong C, Tomei AA, Randolph GJ, Swartz MA. Cancer Cell, 2007
- “Autologous morphogen gradients by subtle interstitial flow and matrix interactions”, Fleury ME, Boardman KC, and Swartz MA. Biophysical Journal, 2006