class="head no_bottom_margin" id="sec1title">IntroductionTissue engineering technology has become one of the most prospective therapeutic approaches for bone regeneration in bone defects (, ). As a type of adult mesenchymal stem cells (MSCs), human adipose-derived mesenchymal stem cells (hASCs) are capable of self-renewal and differentiation into cells such as osteoblasts, chondrocytes, and adipocytes (). Because they can be obtained from adipose tissue in abundance by means of a minimally invasive procedure, hASCs are a valuable source of adult MSCs for bone tissue engineering and bone regeneration (). Therefore, how to effectively promote the osteogenic differentiation of hASCs has become dramatically important in bone tissue engineering.MicroRNAs (miRNAs) are a class of endogenously small non-coding RNAs that function as post-transcriptional regulators through binding to complementary sites on target mRNAs (). Evolutionary conserved, miRNAs have been implicated in various biological processes, including the cell fate of embryonic stem cells, cell proliferation, apoptosis, differentiation, and carcinogenesis (, , ). A number of miRNAs participate in the osteogenic differentiation of MSCs, such as miR-21 (), miR-31 (), miR-34a (), and miR-196a (). Targeting miRNAs as a therapeutic approach has shed light on bone tissue regeneration, but the mechanism of their regulation of osteogenesis in MSCs remains to be determined ().microRNA-375 (miR-375) was identified early as a pancreatic islet-specific miRNA regulating insulin secretion (). Subsequent studies revealed that miR-375 participated in multiple biological processes, including glucose homeostasis, mucosal immunity, and cancer development (, href="#bib10" rid="bib10" class=" bibr popnode">EI Ouaamari et al., 2008, href="#bib50" rid="bib50" class=" bibr popnode">Yan et al., 2014). Moreover, miR-375 is significantly downregulated in several types of tumors, and suppresses their proliferation by targeting some important genes, e.g., JAK2, YAP1, and PDK1 (href="#bib8" rid="bib8" class=" bibr popnode">Ding et al., 2010, href="#bib52" rid="bib52" class=" bibr popnode">Zhang et al., 2013, href="#bib55" rid="bib55" class=" bibr popnode">Zhou et al., 2014). Research has shown that miR-375 is a negative regulator of adipogenic differentiation by targeting bone morphogenetic protein receptor 2 (BMPR2) (href="#bib29" rid="bib29" class=" bibr popnode">Liu et al., 2016a). Osteoblastic and adipocytic lineages have alternative fates during development and aging, and increased adipogenesis correlates with decreased osteogenesis (href="#bib46" rid="bib46" class=" bibr popnode">Takada et al., 2009, href="#bib48" rid="bib48" class=" bibr popnode">Verma et al., 2002), which led us to speculate that miR-375 might play a role in the differentiation of stem cells toward osteogenic lineage.Osteogenic differentiation is a complex process governed by interplay of several signaling pathways (href="#bib35" rid="bib35" class=" bibr popnode">Novack, 2011, href="#bib39" rid="bib39" class=" bibr popnode">Salazar et al., 2016). Phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) and Hippo are two major pathways involved in the regulation of cell proliferation and differentiation (href="#bib16" rid="bib16" class=" bibr popnode">Hansen et al., 2015a, href="#bib25" rid="bib25" class=" bibr popnode">Laplante and Sabatini, 2012). Crosstalk between the two pathways plays a significant role in regulating cell proliferation and differentiation (href="#bib17" rid="bib17" class=" bibr popnode">Hansen et al., 2015b, href="#bib43" rid="bib43" class=" bibr popnode">Shimobayashi and Hall, 2014). The PI3K/AKT/mTOR pathway governs a variety of cellular and molecular responses by regulating protein synthesis (href="#bib7" rid="bib7" class=" bibr popnode">Dibble and Cantley, 2015). Perturbation of this pathway contributes to the maintenance of bone homeostasis and MSC lineage differentiation (href="#bib32" rid="bib32" class=" bibr popnode">Martin et al., 2015). The Hippo pathway plays a crucial role in organ-size control by modulating cell proliferation and apoptosis (href="#bib54" rid="bib54" class=" bibr popnode">Zhao et al., 2011). Yes-associated protein 1 (YAP1), major downstream effector of the Hippo pathway, inhibits the osteogenic differentiation of bone marrow-derived MSCs (BMSCs) (href="#bib41" rid="bib41" class=" bibr popnode">Sen et al., 2015, href="#bib42" rid="bib42" class=" bibr popnode">Seo et al., 2013). In this study, we evaluated the effects of miR-375 in hASC osteogenesis and demonstrated that miR-375 promoted the osteogenic differentiation of hASCs via a YAP1/DEPTOR/AKT regulatory network, suggesting its potential utility in hASC-based bone tissue engineering.
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