The special case of hepatocytes: unique tissue architecture calls for a distinct mode of cell division

Abstract

Columnar epithelia (e.g., kidney, intestine) and hepatocytes embody the two major organizational phenotypes of non-stratified epithelial cells. Columnar epithelia establish their apical and basal domains at opposing poles and organize in monolayered cysts and tubules, in which their apical surfaces form a single continuous lumen whereas hepatocytes establish their apical domains in the midst of their basolateral domains and organize a highly branched capillary luminal network, the bile canaliculi, in which a single hepatocyte can engage in lumen formation with multiple neighbors. To maintain their distinct tissue architectures, columnar epithelial cells bisect their luminal domains during symmetric cell divisions, while the cleavage furrow in dividing hepatocytes avoids bisecting the bile canalicular domains. We discuss recently discovered molecular mechanisms that underlie the different cell division phenotypes in columnar and hepatocytic model cell lines. The serine/threonine kinase Par1b determines both the epithelial lumen polarity and cell division phenotype via cell adhesion signaling that converges on the small GTPase RhoA.

Keywords: LGN/NuMA; Par1b/MARK2; RhoA; columnar and hepatocyte polarity; epithelial cells; hepatocyte polarity; mitotic spindle orientation.

Figure 1. Columnar vs. hepatocytic polarity. Columnar epithelial cells form monolayers where multiple cells surround a central lumen (i.e., columnar polarity), whereas hepatocytes organize around tubular networks were the luminal domain is shared by no more than two cells (i.e., hepatocytic polarity), and each cell can have multiple luminal domains. Red arrowheads indicate the luminal domains marked by Ezrin. MDCK and WIF-B9 cells are kidney- and hepatocyte-derived culture models, respectively.

Figure 2. Columnar and hepatocytic division phenotypes are regulated by Par1b. (A) Columnar epithelial cells orient their metaphase plates perpendicular to the lumen. The resulting cleavage furrow bisects their luminal surface (red domains in the schematics, marked by dipeptidyl peptidase-IV (DPPIV)). Hepatocytes attach their astral microtubules adjacent to their luminal domain(s), thereby avoiding the bisection of their lumina during cell divisions. In cultured hepatocytic cells with a single luminal surface, as depicted in the schematic, the luminal domain is distributed to only one of the daughters. In multipolar hepatocytes in vivo, as shown in the fluorescent image on the right, one of the two DPPIV-positive luminal surfaces (yellow arrowheads) will segregate to each daughter. Si = sinusoids. (B) Par1b overexpression in MDCK cells promotes polarization with lateral rather than apical lumina (see x-z views, the apical domains (red) are marked by Ezrin) and mitotic spindles that are oriented toward the lateral lumen, instead of aligning with the basal surface. The β angle represents the angle between the spindle axis (dashed line) and the substratum.

Figure 3. NuMA localization in polarized MDCK and HepG2 and in non-polarized HeLa cells. In polarized epithelial cells, such as MDCK and HepG2 cells, cortical NuMA in metaphase localizes below or adjacent to the luminal domain, coinciding with cell-cell adhesion sites (white arrowheads). The schematic illustrates the example of columnar epithelia (“Columnar Polarized”), In transformed epithelial cells such as HeLa cells, which lack adherens junctions, cortical NuMA coincides with the strongest retraction fibers (schematic “Non-Polarized”). In both instances, these are cortical areas under tension that likely feature high RhoA activity. Metaphase chromatin emits a Ran GTPase gradient that antagonizes cortical NuMA where the chromosomes come closest to the cortex, (blue circles in the schematics), resulting in two NuMA crescents. F-actin and an apical marker (AP) are in red.