Transit Amplifying Cells (TACs): a still not fully understood cell population

Abstract

Maintenance of tissue homeostasis and tissue regeneration after an insult are essential functions of adult stem cells (SCs). In adult tissues, SCs proliferate at a very slow rate within "stem cell niches", but, during tissue development and regeneration, before giving rise to differentiated cells, they give rise to multipotent and highly proliferative cells, known as transit-amplifying cells (TACs). Although differences exist in diverse tissues, TACs are not only a transitory phase from SCs to post-mitotic cells, but they also actively control proliferation and number of their ancestor SCs and proliferation and differentiation of their progeny toward tissue specific functional cells. Autocrine signals and negative and positive feedback and feedforward paracrine signals play a major role in these controls. In the present review we will consider the generation and the role played by TACs during development and regeneration of lining epithelia characterized by a high turnover including epidermis and hair follicles, ocular epithelial surfaces, and intestinal mucosa. A comparison between these different tissues will be made. There are some genes and molecular pathways whose expression and activation are common to most TACs regardless their tissue of origin. These include, among others, Wnt, Notch, Hedgehog and BMP pathways. However, the response to these molecular signals can vary in TACs of different tissues. Secondly, we will consider cultured cells derived from tissues of mesodermal origin and widely adopted for cell therapy treatments. These include mesenchymal stem cells and dedifferentiated chondrocytes. The possible correlation between cell dedifferentiation and reversion to a transit amplifying cell stage will be discussed.

Keywords: cell dedifferentiation; cell reprogramming; cultured cells; hair follicle; intestinal crypt; stem cells; tissue differentiation; tissue regeneration.

FIGURE 1

Cartoons of two distinct hair cycle stages (telogen and anagen) showing SCs (greenish cells) and their relative positions. TACs are absent in telogen and are formed at mid-anagen. Feedback circuitry between TACs and SCs play a significant role. TACs contribute to generating the SCs niche and stimulate quiescent SCs to self-renew. Proteins of the Wnt pathway activate the transformation of hair follicle SCs to TACs. While primed SCs generate TACs, quiescent-SCs only proliferate after TACs form and begin expressing Sonic Hedgehog (SHH). SHH also controls several signaling pathways in dermal papilla cells thus regulating the papilla inductive effects on the follicle epithelium by feeding back TACs. IFE = Inter Follicular Epidermis (modification of figure templates created with BioRender.com).

FIGURE 2

Cell turnover and proliferation in the intestinal epithelium. Resident SCs, dispersed at the crypt base among Paneth cells, double each day. Maintenance of the stem status depends upon the exposure of SCs to a Wnt signal released by Paneth cells. The Wnt signal also induces the crypt surrounding stroma to release R-spondin, Delta-ligand and other factors that stimulate SCs to exit quiescence. When SCs divide, they generate both new SCs and TACs. Notch-Delta signaling in combination with Wnt control proliferation and differentiation of TACs. Hedgehog signals are secreted by proliferating intestinal cells, stimulate surrounding mesenchyme to release BMPs and to block TAC proliferation favoring their differentiation. Nogging produced at the crypt base prevent the BMP action on the crypt cells allowing SC and TAC proliferation to continue (modification of figure templates created with BioRender.com).

FIGURE 3

In vitro differentiation and de-differentiation of avian chondrocytes. Chondrocytes obtained from the digestion of tibiae of stage 29–31 chick embryos were cultured in anchorage non-permissive dishes and passaged weekly by direct dilution in fresh medium without prior harvesting by centrifugation [Panels (A–F)]. Chondrocytes were also plated at the same density in anchorage permissive dishes and passaged weekly 1:3/1:4 after trypsin digestion [Panels (G–H)]. Cells were observed by phase-contrast microscopy at different time intervals after the beginning of the culture. Bar: 200 microns (A–F); 100 microns (G–H) [Modified from (Castagnola et al., 1986)].