Stem cell decisions: a twist of fate or a niche market?

Abstract

Establishing and maintaining cell fate in the right place at the right time is a key requirement for normal tissue maintenance. Stem cells are at the core of this process. Understanding how stem cells balance self-renewal and production of differentiating cells is key for understanding the defects that underpin many diseases. Both, external cues from the environment and cell intrinsic mechanisms can control the outcome of stem cell division. The role of the orientation of stem cell division has emerged as an important mechanism for specifying cell fate decisions. Although, the alignment of cell divisions can dependent on spatial cues from the environment, maintaining stemness is not always linked to positioning of stem cells in a particular microenvironment or `niche'. Alternate mechanisms that could contribute to cellular memory include differential segregation of centrosomes in asymmetrically dividing cells.

Keywords: Asymmetric cell division; Centrosome segregation; Spindle orientation; Stem cells.

Fig. 1

(I) Spindle orientation can involve establishment of localized domains at the cell cortex that can anchor astral microtubules. In some cases, these domains are established by proteins of the Par complex. Position of these domains can be specified through extrinsic as well as intrinsic signals. Once astral microtubules interact with these anchoring domains torque is exerted on the spindle causing it to rotate toward them. (II) The core components involved in many spindle positioning events are Galphai, Pins/LGN, Mud/Numa and Dynein. Myristylation of Galphai links it to the plasma membrane. Galphai can bind Pins/LGN and regulates the affinity of Pins for Mud. Mud can directly bind to microtubules but also cytoplasmic Dynein. Dynein is believed to provide at least part of the forces required to orient the spindle. (III) The centrosome is found at different configurations during the cell cycle and also provides asymmetry to the spindle since the centrosomes at each spindle pole can be distinguished by the age of the set of centrioles they carry. On the spindle one centrosome, the mother centrosome, contains the older set of centrioles. Centrioles typically duplicate during G1/S phase when a new centriole forms in the vicinity of each old centriole. M: mother centriole, D: daughter centriole, GM: Grandmother centriole (to indicate that one of the two centrioles that qualify as mother centrioles has formed a cell cycle earlier).