Autotaxin-mediated lipid signaling intersects with LIF and BMP signaling to promote the naive pluripotency transcription factor program

Abstract

Developmental signaling molecules are used for cell fate determination, and understanding how their combinatorial effects produce the variety of cell types in multicellular organisms is a key problem in biology. Here, we demonstrate that the combination of leukemia inhibitory factor (LIF), bone morphogenetic protein 4 (BMP4), lysophosphatidic acid (LPA), and ascorbic acid (AA) efficiently converts mouse primed pluripotent stem cells (PSCs) into naive PSCs. Signaling by the lipid LPA through its receptor LPAR1 and downstream effector Rho-associated protein kinase (ROCK) cooperated with LIF signaling to promote this conversion. BMP4, which also stimulates conversion to naive pluripotency, bypassed the need for exogenous LPA by increasing the activity of the extracellular LPA-producing enzyme autotaxin (ATX). We found that LIF and LPA-LPAR1 signaling affect the abundance of signal transducer and activator of transcription 3 (STAT3), which induces a previously unappreciated Kruppel-like factor (KLF)2-KLF4-PR domain 14 (PRDM14) transcription factor circuit key to establish naive pluripotency. AA also affects this transcription factor circuit by controlling PRDM14 expression. Thus, our study reveals that ATX-mediated autocrine lipid signaling promotes naive pluripotency by intersecting with LIF and BMP4 signaling.

Involvement of autotaxin in the pathophysiology of elevated intraocular pressure in Posner-Schlossman syndrome

“…Fifth, we could not investigate the relationship between CMV infection and possible transcriptional factors for ATX. Several transcriptional factors have been implicated for ATX up-regulation in other cells, including c-Jun and STAT3 (signal transducer and activator of transcription 3) [50][51][52] . We would like to further explore molecular basis for the CMV induced autotaxin upregulation in the trabecular meshwork cells in the future study.…”

Energy Metabolism Regulates Stem Cell Pluripotency

“…In addition to their metabolic roles, lipids may also regulate the primed-to-naïve conversion as a signaling molecule (Kime et al, 2016). Lysophosphatidic acid (LPA) lipid signaling and the LPA-producing enzyme autotoxin have been implicated in establishing naïve PSCs in coordination with LIF and bone morphogenetic protein 4 (BMP4) signaling (Kime et al, 2016). These elegant studies support the importance of nutrient availability for defining stem cell features and suggest that manipulating energy metabolism may be sufficient to promote the transition between stem cell states.…”

Lysophosphatidic Acid and Hematopoiesis: From Microenvironmental Effects to Intracellular Signaling

“…Moreover, conditional overexpression of ATX promotes the differentiation of monocytes into macrophages in mice [31]. ATX is also involved in the regulation of the pluripotency transcriptional program, which is mediated by leukemia inhibitory factor (LIF) and bone morphogenetic proteins (BMP) in HSCs [32]. On the other hand, intracellular LPA is synthesized by three enzymes localized in the endoplasmic reticulum (ER) or the mitochondrial membrane: glycerophosphate acyltransferase (GPAT), phospholipase A (PLA), and acylglycerol kinase (AGK) [33][34][35].…”

“…In recent years, accumulating studies have revealed the importance of LPA-LPAR signaling in stem cell biology. ATX-LPA axis is reported to regulate the pluripotency of ESCs through the activation of PLC/Ca 2+ signaling and c-myc expression [18,20,32]. LPA receptors have been identified in HSCs, vascular stem cells, bone marrow stromal cells (BMSCs), neurospheres from neural stem cells (NSCs), and embryonic stem cells (ESCs) [53].…”