Multiple intracellular signaling pathways orchestrate adipocytic differentiation of human bone marrow stromal stem cells

Abstract

Bone marrow adipocyte formation plays a role in bone homeostasis and whole body energy metabolism. However, the transcriptional landscape and signaling pathways associated with adipocyte lineage commitment and maturation are not fully delineated. Thus, we performed global gene expression profiling during adipocyte differentiation of human bone marrow stromal (mesenchymal) stem cells (hMSCs) and identified 2,589 up-regulated and 2,583 down-regulated mRNA transcripts. Pathway analysis on the up-regulated gene list untraveled enrichment in multiple signaling pathways including insulin receptor signaling, focal Adhesion, metapathway biotransformation, a number of metabolic pathways e.g. selenium metabolism, Benzo(a)pyrene metabolism, fatty acid, triacylglycerol, ketone body metabolism, tryptophan metabolism, and catalytic cycle of mammalian flavin-containing monooxygenase (FMOs). On the other hand, pathway analysis on the down-regulated genes revealed significant enrichment in pathways related to cell cycle regulation. Based on these data, we assessed the effect of pharmacological inhibition of FAK signaling using PF-573228, PF-562271, and InsR/IGF-1R using NVP-AEW541 and GSK-1904529A on adipocyte differentiation. hMSCs exposed to FAK or IGF-1R/InsR inhibitors exhibited fewer adipocyte formation (27–58% inhibition, P<0005). Concordantly, the expression of adipocyte-specific genes AP2, AdipoQ, and CEBPα was significantly reduced. On the other hand, we did not detect significant effects on cell viability as a result of FAK or IGF-1R/InsR inhibition. Our data identified FAK and insulin signaling as important intracellular signaling pathways relevant to bone marrow adipogenesis.

Identification of key genes of human bone marrow stromal cells adipogenesis at an early stage

“…Cell division, DNA replication, mitotic nuclear division, G1/S transition of mitotic cell cycle and DNA replication-dependent nucleosome assembly were the top five biological function (BP) terms related to cell cycle and cell division. The present study found that genes involved in these categories were mostly down-regulated, in agreement with previous studies (Ali et al, 2018;Menssen et al, 2011). In order to obtain more significant GO terms, we performed analysis on the top 200 DEGs with lower p values.…”

“…0A 0A 0A 0A 0 0 0 0 0A 0A A A A A 0A 0A A A 0A 0A A 0A 0A 0 0A 0 0 0 0A 0 0A A 0A A A A 0A A 0A A 0 0 0A 0A A 0 0 0 0A 0 0 0A A 0A 0 0A A A 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 between BMA and osteogenic lineage is still a mystery. Global gene expression profiling by Ali et al (2018) using microarray assay on day 7 after adipogenic differentiation of hMSC-TERT identified FAK and IGF1R signaling as important pathways during bone marrow adipogenesis. However, intrinsic connection of DEGs remains unexplored.…”

Selenium and Selenoproteins in Adipose Tissue Physiology and Obesity

“…Furthermore, adipogenic differentiation of human bone marrow stromal stem cells was shown to be associated with up-regulation of SELENOF, -M, -P, and SELENBP1, along with FABP4, ADIPOQ, and C/EBPα. Se metabolism pathway was considered as one of the top ten enriched pathway categories [143]. Correspondingly, in pigs feeding a HFD reduced selenoprotein mRNA expression in perirenal adipose tissue (SELENOH, -K, -P, -V, and -W) and SAT (SELENOI, -M, and MSRB1) [30].…”

Modeling Fragile X Syndrome in Drosophila

“…Insulin and insulin-like growth factors (IGF) are evolutionarily highly conserved proteins that play an important role in growth and metabolism, but also in neurogenesis through their role in neuronal stem-cell homeostasis (reviewed in Lee et al, 2016 ; Ali et al, 2018 ). In Drosophila , expression of dFMR1 specifically in the insulin-producing cells (IPSs) or in the whole nervous system is able to rescue the defective free-running locomotor rhythmicity of dFMR1 mutants, as well as short-term and long-term memory defects in olfactory learning tests (Monyak et al, 2016 ).…”