Ligand independent and subtype-selective actions of thyroid hormone receptors in human adipose derived stem cells

Thyroid hormone (TH) receptors (TRs α and β) are homologous ligand-dependent transcriptio factors (TFs). While the TRs display distinct actions in development, metaboli regulation and other processes, comparisons of TRα and TRβ dependent gene regulatio mostly reveal similar mechanisms of action and few TR subtype specific genes. Here, w show that TRα predominates in multipotent human adipose derived stem cells (hADSC whereas TRβ is expressed at lower levels and is upregulated during hADSC differentiation The TRs display several unusual properties in parental hADSC. First, TRs display predominantl cytoplasmic intracellular distribution and major TRα variants TRα1 and TRα2 colocaliz with mitochondria. Second, knockdown experiments reveal that endogenous TR influence hADSC cell morphology and expression of hundreds of genes in the absence o hormone, but do not respond to exogenous TH. Third, TRα and TRβ affect hADSC i completely distinct ways; TRα regulates cell cycle associated processes while TRβ ma repress aspects of differentiation. TRα splice variant specific knockdown reveals that TRα and TRα2 both contribute to TRα-dependent gene expression in a gene specific manner We propose that TRs work in a non-canonical and hormone independent manner i hADSC and that prominent subtype-specific activities emerge in the context of thes unusual actions.