Pdcd4 restrains the self-renewal and white-to-beige transdifferentiation of adipose-derived stem cells

Abstract

The stemness maintenance of adipose-derived stem cells (ADSCs) is important for adipose homeostasis and energy balance. Programmed cell death 4 (Pdcd4) has been demonstrated to be involved in the development of obesity, but its possible roles in ADSC function and adipogenic capacity remain unclear. In this study, we demonstrate that Pdcd4 is a key controller that limits the self-renewal and white-to-beige transdifferentiation of ADSCs. Pdcd4 deficiency in mice caused stemness enhancement of ADSCs as evidenced by increased expression of CD105, CD90, Nanog and Oct4 on ADSCs, together with enhanced in situ proliferation in adipose tissues. Pdcd4 deficiency promoted proliferation, colony formation of ADSCs and drove more ADSCs entering the S phase accompanied by AKT activation and cyclinD1 upregulation. Blockade of AKT signaling in Pdcd4-deficient ADSCs led to a marked decline in cyclinD1, S-phase entry and cell proliferation, revealing AKT as a target for repressing ADSC self-renewal by Pdcd4. Intriguingly, depletion of Pdcd4 promoted the transdifferentiation of ADSCs into beige adipocytes. A reduction in lipid contents and expression levels of white adipocyte markers including C/EBPα, PPAR-γ, adiponectin and αP2 was detected in Pdcd4-deficient ADSCs during white adipogenic differentiation, substituted by typical beige adipocyte characteristics including small, multilocular lipid droplets and UCP1 expression. More lactate produced by Pdcd4-deficient ADSCs might be an important contributor to the expression of UCP1 and white-to-beige transdifferentiation. In addition, an elevation of UCP1 expression was confirmed in white adipose tissues from Pdcd4-deficient mice upon high-fat diet, which displayed increased energy expenditure and resistance to obesity as compared with wild-type obese mice. These findings provide evidences that Pdcd4 produces unfavorable influences on ADSC stemness, which contribute to adipose dysfunction, obesity and metabolic syndromes, thereby proposing Pdcd4 as a potential intervening target for regulating ADSC function.

CD90 serves as differential modulator of subcutaneous and visceral adipose-derived stem cells by regulating AKT activation that influences adipose tissue and metabolic homeostasis

“…Compared with V-ADSCs, S-ADSCs showed marked increases in AKT activation, CyclinD1 expression, and G1-S phase transition. Consistent with previous studies showing the critical role of AKT activation in promoting proliferation of cancer cells and ADSCs [45, 46, 51], we demonstrated that AKT activation in S-ADSCs may promote their proliferation via S phase entry driven by CyclinD1, thereby facilitating their self-renewal in SAT. Although there is still controversy over adipogenesis of SAT and VAT [18–20], our findings showed that S-ADSCs had higher efficiency in adipogenesis than V-ADSCs, indicating that S-ADSCs are more prone to adipocyte hyperplasia than V-ADSCs.…”

“…A recent study showed an important role of CD90 in AKT activation in human cytomegalovirus-infected cells [41]. AKT activation is involved in the survival or proliferation of various cells and can promote the proliferation of human and mice ADSCs by upregulating cell cycle protein CyclinD1 [42–46]. However, it remains largely unknown whether CD90 regulates ADSC potentials via AKT and whether CD90 produces different impacts on S-ADSCs and V-ADSCs to influence adipose tissue and metabolic homeostasis.…”

Lactate fluxes mediated by the monocarboxylate transporter-1 are key determinants of the metabolic activity of beige adipocytes

“…This occurs through intracellular redox modifications subsequent to its transport. The regulation of UCP1 expression by lactate has been confirmed by others (21,22). This mechanism might be part of a redox regulatory and adaptive loop (17,23) where a high redox (NADH/NAD + ) pressure drives UCP1 expression, just as mitochondrial ROS positively control UCP1 protein activity (24).…”

Adipocyte biology: It is time to upgrade to a new model

“…Zhu et al, 2009 (Bai et al, 2016). Pdcd4 KO ASCs also displayed enhanced expression of stemness genes, as well as increased proliferation and self-renewal through the upregulation of AKT signaling (Bai et al, 2016), consistent with Pdcd4 being a suppressor of stemness factors and neoplastic transformation (Haghpanah et al, 2016). Similar to Pdcd4, KO studies have shown that phospholipase C also promotes diet-induced obesity, insulin resistance, and adipocyte hypertrophy, while suppressing thermogenesis and the differentiation of ASCs into brown adipocytes (Hirata et al, 2011).…”

“…Alt et al, 2012;Hauner et al, 1989;Kirkland, Hollenberg, & Gillon, 1993), other studies did not support this (Van Harmelen et al, 2003;M. Zhu et al, 2009 (Bai et al, 2016). Pdcd4 KO ASCs also displayed enhanced expression of stemness genes, as well as increased proliferation and self-renewal through the upregulation of AKT signaling (Bai et al, 2016), consistent with Pdcd4 being a suppressor of stemness factors and neoplastic transformation (Haghpanah et al, 2016).…”