The role of PIN1 on odontogenic and adipogenic differentiation in human dental pulp stem cells.
Recently, the involvement of PIN1, a peptidyl-prolyl cis/trans isomerase, has been reported in age-related bone homeostasis and adipogenesis. However, the role of PIN1 during odontogenic and adipogenic differentiation remains to be fully understood, particularly regarding human dental pulp stem cells (HDPSCs). Thus, in the present study, we have investigated the role of PIN1 in odontogenic and adipogenic differentiation of HDPSCs and signaling pathways possibly involved. PIN1 mRNA and protein level were upregulated in a time-dependent manner during adipogenic differentiation, increasing until 1 day of odontogenic induction and then steadily declined during odontogenic differentiation. Treatment of a known PIN1 inhibitor, juglone, significantly increased odontogenic differentiation as confirmed by alkaline phosphatase (ALP) activity, calcium deposition, and mRNAs induction of odontogenic markers [ALP, osteopontin (OPN), osteocalcin (OCN), dentin sialophosphoprotein (DSPP), and dentin matrix protein 1 (DMP-1)]. On the contrary, adipogenic differentiation was dramatically reduced upon juglone treatment, with concomitant downregulation of lipid droplet accumulation and adipogenic marker genes [peroxisome proliferation-activated receptor gamma (PPARγ), lipoprotein lipase (LPL), and adipocyte fatty acid-binding protein (AP2)]. In contrast to PIN1 inhibition, the overexpression of PIN1 via adenoviral infection (Ad-PIN1) in HDPSCs inhibited odontogenic differentiation but increased adipogenic differentiation, in which stem cell property markers such as stage-specific embryonic antigen-4 (SSEA-4) and STRO-1 were upregulated during odontogenic differentiation but downregulated in adiopogenic differentiation. Consistently, juglone-mediated inhibition of PIN1 augmented the osteogenic medium (OM)-induced activation of bone morphogenetic protein (BMP), Wnt/β-catenin, extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and nuclear factor-kappa B (NF-κB) pathway, which response was reversed by Ad-PIN1. Moreover, juglone blocked the adipogenic induction medium-induced activation of PPARγ, C/EBPα, C/EBPβ, ERK, and NF-κB pathways, which was rescued by Ad-PIN1 infection. In summary, the present study shows for the first time that PIN1 acts as an important modulator of odontogenic and adipogenic differentiation of HDPSCs and may have clinical implications for regenerative dentistry.
1 Department of Maxillofacial Tissue Regeneration, Research Center for Tooth and Periodontal Regeneration (MRC), School of Dentistry, Kyung Hee University , Seoul, Republic of Korea.
Young-Man
YM
Lee
Seung-Yun
SY
Shin
Seong-Suk
SS
Jue
Il-Keun
IK
Kwon
Eun-Hee
EH
Cho
Eui-Sic
ES
Cho
Sang-Hyuk
SH
Park
Eun-Cheol
EC
Kim
D050156:Adipogenesis / Q000502:physiology*; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D003782:Dental Pulp / Q000166:cytology*; D006801:Humans; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D009805:Odontogenesis / Q000502:physiology*; D019696:Peptidylprolyl Isomerase / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D013234:Stem Cells / Q000166:cytology*; D016212:Transforming Growth Factor beta / Q000235:genetics; D051176:beta Catenin / Q000378:metabolism
D019485:Bone Morphogenetic Proteins; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D016212:Transforming Growth Factor beta; D051176:beta Catenin; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase