Cell chirality in three-dimensional epithelial tissue morphogenesis

Chin, Amanda S.
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Wan, Leo Q.
Gilbert, Ryan
Hahn, Mariah
Herschkowitz, Jason
Dai, Guohao
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Biomedical engineering
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This electronic version is a licensed copy owned by Rensselaer Polytechnic Institute, Troy, NY. Copyright of original work retained by author.
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To investigate inherent cellular chirality in 3D, we developed a dual layered Matrigel system and studied the role of chirality in morphogenesis and tumor development, as well as its mediating factors. Cultivation of Madin-Darby canine kidney (MDCK) epithelial cells embedded within our system assembled into 3D microtissues, which are representative of fundamental acinar and ductal network formations. These primary structures are essential to morphogenesis and the development of human kidneys, lungs and breasts. The microtissues underwent coordinated rotational behavior that was directionally biased and consistent with 2D chiral cultures. The chiral rotational movements were an intrinsic property of the epithelial cells, exhibited by single cells and throughout the progression to multicellular microtissues. Our data suggests an actin-dependent mechanism underlying the chiral behavior of epithelial cells, regulated by alpha-actinin-1 expression. We also utilized our platform to examine the vortical movements of mouse and human mammary epithelial cells, and uncovered an association between chirality and the expression of the H-Ras oncogene. Activation of protein kinase C (PKC), via a cancer promoting drug, enhanced the LR bias of cancer cells and induced invasive behavior with the formation of multicellular extensions. The extensions exhibited chiral twisting while invading the surrounding environment. Overall, these findings highlight the importance of collective cellular chirality in 3D epithelial microtissue self-assembly and tumorigenic tissue development.
August 2018
School of Engineering
Dept. of Biomedical Engineering
Rensselaer Polytechnic Institute, Troy, NY
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