Paracrine induction of stem cell renewal by LIF-deficient cells: a new ES cell regulatory pathway.

The propagation of pluripotential mouse embryonic stem (ES) cells is sustained by leukemia inhibitory factor (LIF) or related cytokines that act through a common receptor complex comprising the LIF receptor subunit (LIF-R) and the signal transducer gp130. However, the findings that embryos lacking LIF-R or gp130 can develop beyond gastrulation argue for the existence of an alternative pathway(s) governing the maintenance of pluripotency in vivo. In order to define those factors that contribute to self-renewal in ES cell cultures, we have generated ES cells in which both copies of the lif gene are deleted. These cells showed a significantly reduced capacity for regeneration of stem cell colonies when induced to differentiate, confirming that LIF is the major endogenous regulatory cytokine in ES cell cultures. However, self-renewal was not abolished and undifferentiated ES cell colonies were still obtained in the complete absence of LIF. A differentiated, LIF-deficient, parietal endoderm-like cell line was derived and shown to support ES cell propagation via production of a soluble, macromolecular, trypsin-sensitive activity. This activity, which we name ES cell renewal factor (ESRF), is distinct from members of the IL-6/LIF family because (i) it is effective on ES cells lacking LIF-R; (ii) it is not blocked by anti-gp130 neutralizing antibodies; and (iii) it acts without activation of STAT3. ES cells propagated clonally using ESRF alone can contribute fully to chimaeras and engender germline transmission. These findings establish that ES cell pluripotency can be sustained via a LIF-R/gp130-independent, STAT-3 independent, signaling pathway. Operation of this pathway in vivo could play an important role in the regulation of pluripotency in the epiblast and account for the viability of lifr -/- and gp130 -/- embryos.

Dani C ，Chambers I ，Johnstone S ，Robertson M ，Ebrahimi B ，Saito M ，Taga T ，Li M ，Burdon T ，Nichols J ，Smith A ... -  《DEVELOPMENTAL BIOLOGY》

STAT3 is dispensable for maintenance of self-renewal in nonhuman primate embryonic stem cells.

Sumi T ，Fujimoto Y ，Nakatsuji N ，Suemori H ... -  《STEM CELLS》

A selective switch-on system for self-renewal of embryonic stem cells using chimeric cytokine receptors.

Nakamura T ，Arai T ，Takagi M ，Sawada T ，Matsuda T ，Yokota T ，Heike T ... -  《BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS》

LIF/STAT3 signaling fails to maintain self-renewal of human embryonic stem cells.

Dahéron L ，Opitz SL ，Zaehres H ，Lensch MW ，Andrews PW ，Itskovitz-Eldor J ，Daley GQ ... -  《STEM CELLS》

Ligand/receptor signaling threshold (LIST) model accounts for gp130-mediated embryonic stem cell self-renewal responses to LIF and HIL-6.

Viswanathan S ，Benatar T ，Rose-John S ，Lauffenburger DA ，Zandstra PW ... -  《STEM CELLS》