Keeping an eye on retinoblastoma control of human embryonic stem cells

Abstract

Human embryonic stem cells (hESCs) hold great promise in regenerative medicine. However, before the full potential of these cells is achieved, major basic biological questions need to be addressed. In particular, there are still gaps in our knowledge of the molecular mechanisms underlying the derivation of hESCs from blastocysts, the regulation of the undifferentiated, pluripotent state, and the control of differentiation into specific lineages. Furthermore, we still do not fully understand the tumorigenic potential of hESCs, limiting their use in regenerative medicine. The RB pathway is a key signaling module that controls cellular proliferation, cell survival, chromatin structure, and cellular differentiation in mammalian cells. Members of the RB pathway are important regulators of hESC biology and manipulation of the activity of this pathway may provide novel means to control the fate of hESCs. Here we review what is known about the expression and function of members of the RB pathway in hESCs and discuss areas of interest in this field.

Figure 1. Schematic representation of the RB pathway in hESCs

Members of the RB pathway that are expressed in hESCs are shown. CKIs (INK4 family and Cip/Kip family) are expressed at low or undetectable levels. In contrast to mESCs where RB family members (RBf) are thought to be always hyperphosphorylated (P represents a phosphorylated residue), RB is found in a hypophosphorylated state in G1 in hESCs and becomes hyperphosphorylated for the rest of the cell cycle. Increased size of the Cyclin/CDK complexes reflects an increase of Cyclin E and Cyclin A protein levels and activity near the G1/S transition.

Figure 2. Expression of G1/S Cyclins in embryonic stem cells and adult cells

mESCs display little cell cycle dependent regulation of Cyclins except for Cyclin B. In contrast, Cyclins in hESCs do show cell cycle-dependent expression, except for the D Cyclins, which are expressed at a low level. This suggests that the regulation of the cell cycle of hESCs differs from what has been shown for mESCs in culture, and may more closely resemble mouse epiblast stem cells than mESCs.

Figure 3. Functional interactions between the RB pathway and the core regulatory network maintaining stemness in hESCs

Emerging evidence suggests that members of the RB pathway are regulated by and function with factors involved in the maintenance of self-renewal and stemness in hESCs. See text for references.