Some Reflections on Growth and Differentiation

SOME REFLECTIONS ON GROWTH AND DIFFERENTIATION WERNER R. LOEWENSTEIN* It has become clear over the last three years that a wide variety ofcells formjunctions so structured as to allow direct flow ofsubstances from one cell interior to the next [i]. This kind of cellular communication has a number of implications in cellular growth and differentiation. To point these out is the object ofthis paper. Functional Organization ofCellJunctions Figure ? (top) gives a generalized scheme ofa cell membranejunction derived from electrical measurements and from permeability studies in a variety of cell systems. The scheme focuses on a region of cell junction (junctional membranes, C) where the membranes are markedly different in permeability from the rest of the cell surfaces (non-junctional membranes , O). At thesejunctional membrane regions, permeability to small ions is more than 10,000 times greater than at the rest ofthe cell surface. The permeability at these regions is high even to relativelylarge molecules, io3 mol. wt., and, possibly, up to io4 mol. wt. The region ofhigh membrane permeability is completely surrounded by a diffusion barrier (perijunctional insulation, 5) insulating the system from the exterior. The arrangement ofmany such connected cells in series forms thus an efficient communication system in which substances can flow rather freely from one cell interior to another without leaking to the exterior [1-3]. This is one aspect ofjunctional systems on which I shall bear below in relation to control ofgrowth and differentiation. Another aspect on which I shall focus in this relation is the lability ofcell junctions as communication devices. Effective communication requires that the permeability of the junctional membranes be high and that the permeabilities ofthe perijunctional and non-junctional elements S and O * Cell Physics Laboratory, Department of Physiology, Columbia University, College of Physicians and Surgeons, New York. 260 Werner R. Loewenstein · Growth and Differentiation Perspectives in Biology and Medicine · Winter 1968 be relatively low. Thejunctional membrane is here the most vulnerable element. The high permeability is chiefly, if not entirely, due to low Ca++ and Mg++ activities at both sides of the membrane (activities of these ions in the inside ofthe cell system are below io~5 M). These low activities, in turn, are due (a) to pumping of Ca++ and Mg++ to the outside of the cell system where the Ca++ and Mg++ activities are relatively high ( > io~3 M) and (b) to insulation of the system from the outside provided by the barriers S and O restricting the influx of extracellular Ca++ and Mg++ [4-6]. O G I 44 w (¿0 M- («0 Fig. i.—Top: Elements of a cell junction, O, non-junctional surface membrane; C, junctional membrane; S, perijunctional insulation. The normal high permeability of C requires that the Ca++ and Mg++ activities in the intracellular compartments be 2-3 orders ofmagnitude lower than the activities normally prevailing in the extracellular compartment. The intracellular activities are kept low against the steep gradients (straight arrows point in the direction of high to low concentrations) by outward Ca+"1" and Mg+-1" pumping (wiggly arrows) and by low permeabilities of S and O to passive Ca4+ and Mg+"1" influx [see ref. 5]. Bottom: Three causes ofjunctional uncoupling: (i) slowing ofCa++ and Mg++ pump; (H) rise ofCa+1" and Mg++ permeability in S; or (???) in O. Permeability of C falls as Ca++ and Mg++ activities rise in the intracellular compartment (see text). This close dependence ofjunctional membrane permeability on the permeabilities ofS and O and on Ca++ and Mg++ pumping is what makes communication so vulnerable. In the normal extracellular fluids which have relatively high Ca++ and Mg++ concentrations, communication may be interfered with (i) by agents directly affecting Ca++ and Mg++pumping across the cell surface; (»') by agents increasing the permeability of S to 261 Ca++and Mg++, or (Hi) by agents increasing thepermeability ofO to these ions (and this long before S or O become leaky enough to impair communication by loss ofthe substances themselves which serve as communication signals) (Fig. I, bottom). A number ofmetabolic inhibitors are agents of type i [6]; chelators, alcali, trypsine, anisotonicity, and membrane injury are agents oftype ii and/or type Ui [4, 5, 7, 8]. The main thesis I...