Eccrine sweat gland development and sweat secretion

Abstract

Eccrine sweat glands help to maintain homoeostasis, primarily by stabilizing body temperature. Derived from embryonic ectoderm, millions of eccrine glands are distributed across human skin and secrete litres of sweat per day. Their easy accessibility has facilitated the start of analyses of their development and function. Mouse genetic models find sweat gland development regulated sequentially by Wnt, Eda and Shh pathways, although precise subpathways and additional regulators require further elucidation. Mature glands have two secretory cell types, clear and dark cells, whose comparative development and functional interactions remain largely unknown. Clear cells have long been known as the major secretory cells, but recent studies suggest that dark cells are also indispensable for sweat secretion. Dark cell-specific Foxa1 expression was shown to regulate a Ca(2+) -dependent Best2 anion channel that is the candidate driver for the required ion currents. Overall, it was shown that cholinergic impulses trigger sweat secretion in mature glands through second messengers - for example InsP3 and Ca(2+) - and downstream ion channels/transporters in the framework of a Na(+) -K(+) -Cl(-) cotransporter model. Notably, the microenvironment surrounding secretory cells, including acid-base balance, was implicated to be important for proper sweat secretion, which requires further clarification. Furthermore, multiple ion channels have been shown to be expressed in clear and dark cells, but the degree to which various ion channels function redundantly or indispensably also remains to be determined.

Keywords: Best2; Ca2+; FoxA1; InsP3R2; Itpk; Nkcc1; Shh; Wnt; clear cell; dark cell; ectodysplasin.

Figure 1

A mouse eccrine sweat gland and cellular constituents are depicted. As labelled, the eccrine gland comprises a secretory coil in the deep dermis and a relatively straight duct open to the skin surface (left panel). The secretory coil contains three types of cells, clear, dark and myoepithelial, all derived from embryonic ectoderm. Clear and dark cells are secretory cells, and myoepithelial cells form a major niche for sweat gland stem/progenitor cells (right lower panel). The sweat duct consists of suprabasal (luminal) and basal layers where ions partially reabsorbed (right upper panel).

Figure 2

Working models for calcium action and dark cell function in sweat secretion. Panel a: A possible cascade of Ca²⁺ release and influx. Acetylcholine binds to Chrm3 receptor and activates phospholipase C (PLC) to generate InsP3 from PIP2. InsP3 in turn activates InsP3R2 in the endoplasmic reticulum to release Ca²⁺ from reserves (blue). At the same time, InsP3 can be phosphorylated by Itpks to generate InsP4, which may induce Ca²⁺ influx from extracellular interstitium (red). These events most likely occur in clear cells (81), but it remains to be seen whether InsP3 and P4 spread to dark cells. Panel b: Possible involvement of dark cells in sweat secretion. Dark cell-specific Best2 may be a ${\text{HCO}}_3^{-}$ and Cl⁻ channel (see text). Elevated Ca²⁺ ions (red) activate Best2 (blue) and could secrete ${\text{HCO}}_3^{-}$ and/or Cl⁻ into the extracellular region. ${\text{HCO}}_3^{-}$ may then affect acid–base balance and the functions of channels and transporters in intercellular canaliculi and at the luminal surface, interacting with proteins such as acidic sialomucin. CA XII may also be involved in the formation of a pH gradient and thereby affect the function of alkaline phosphatases. In parallel, ${\text{Cl}}^{-}/{\text{HCO}}_3^{-}$ secretion may create a chemical gradient in dark cells that spreads to clear cells through gap junctions, and could thereby maximize sweat secretion in cooperation with clear cells.