Abstract
IntroductionMesenchymal stem cells (MSCs) are an attractive cell source for cartilage and bone tissue engineering given their ability to differentiate into chondrocytes and osteoblasts. However, the common origin of these two specialized cell types raised the question about the identification of regulatory pathways determining the differentiation fate of MSCs into chondrocyte or osteoblast.MethodsChondrogenesis, osteoblastogenesis, and adipogenesis of human and mouse MSC were induced by using specific inductive culture conditions. Expression of promyelocytic leukemia zinc-finger (PLZF) or differentiation markers in MSCs was determined by RT-qPCR. PLZF-expressing MSC were implanted in a mouse osteochondral defect model and the neotissue was analyzed by routine histology and microcomputed tomography.ResultsWe found out that PLZF is not expressed in MSCs and its expression at early stages of MSC differentiation is the mark of their commitment toward the three main lineages. PLZF acts as an upstream regulator of both Sox9 and Runx2, and its overexpression in MSC enhances chondrogenesis and osteogenesis while it inhibits adipogenesis. In vivo, implantation of PLZF-expressing MSC in mice with full-thickness osteochondral defects resulted in the formation of a reparative tissue resembling cartilage and bone.ConclusionsOur findings demonstrate that absence of PLZF is required for stemness maintenance and its expression is an early event at the onset of MSC commitment during the differentiation processes of the three main lineages.
Highlights
Mesenchymal stem cells (MSCs) are an attractive cell source for cartilage and bone tissue engineering given their ability to differentiate into chondrocytes and osteoblasts
Induction of promyelocytic leukemia zinc-finger (PLZF) expression during chondrogenesis In a previous study, we performed a transcriptomic analysis of MSCs isolated from three different donors and differentiated into chondrocytes by using the micropellet culture conditions and either transforming growth factor (TGF)-β3 or bone morphogenetic protein (BMP)-2 as inducers, or osteoblasts or adipocytes
We found that PLZF ranked first of 1,248 transcription factors (TFs) at 7 and 21 days of chondrogenesis, whatever the chondrogenic inducer
Summary
Mesenchymal stem cells (MSCs) are an attractive cell source for cartilage and bone tissue engineering given their ability to differentiate into chondrocytes and osteoblasts. Together with Gli (GLI-Kruppel family member 3), PLZF has been described to be required for stylopod and zeugopod element formation at very early stages of limb development, before the initiation of cartilage condensations [9]. In line with these in vivo studies, it has been shown that PLZF overexpression in human MSCs enhances chondrogenesis [10]. Its overexpression was reported to be repressive, and RNAi-mediated knockdown of PLZF enhances adipogenesis [13] This is in contrast with results described by Liu and coworkers [10], showing that PLZF knockdown in MSC decreases adipogenic genes as well as lipid deposit during adipogenesis. Because it is well established that a competition or mutual suppression exists between the genetic pathways that lead to either chondrocyte or osteoblast differentiation in mesenchymal progenitors [14], it is still not clear whether PLZF acts as an inducer of chondrogenesis or osteogenesis
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