Proliferation without differentiation

A novel pathway controls stem-cell proliferation independently from differentiation

The ability of stem cells to self-renew depends, among other things, on their ability to divide. However, the typical mechanism that controls cellular proliferation — the G1 checkpoint — is associated with differentiation in stem cells. How can stem cells proliferate without losing multipotency? Reporting in Nature, Patrik Ernfors of the Karolinska Institutet in Sweden and colleagues show that proliferation is controlled in some stem cells during the DNA synthesis phase, or S phase, rather than during the G1 phase.

The authors initially observed that embryonic stem (ES) cells possess functional γ-aminobutyric acid A receptors (GABA_ARs), Treating these cells with the GABA_AR-specific agonist muscimol reduced the number of stem cells in culture by causing the accumulation of cells in S phase (and thereby preventing cells from undergoing cell division). While fewer in number, treated cells could differentiate normally.

Further analysis revealed that this GABA_AR signalling affects proliferation only if histone H2AX, a component of the S/G2 DNA-damage checkpoint, can be phosphorylated by PIKK kinases. Intriguingly, and unlike other cases that involve this checkpoint, GABA_AR-mediated H2AX phosphorylation does not require DNA damage.

The authors also showed that knocking out a crucial GABA_AR subunit makes blastocyst-stage mouse embryos develop more rapidly. That is, decreased GABA_AR signalling results in faster ES cell proliferation.

These results provide the first mechanism by which stem cells can control proliferation independently from multipotency. The authors not only demonstrate that this mechanism controls division in cultured and mouse blastocyst ES cells, they also show that it functions in neural crest stem cells. Thus, GABA_AR signalling may represent a homeostatic control for stem cell numbers, such that fewer stem cells are produced at high levels of signalling. If this is the case, this pathway could be used to regulate the number of stem cells in adult stem cell niches, with potential applications for neurological diseases and cancer. Further work, however, is needed to determine whether this pathway is conserved in other types of stem cells.