Differentiation of mesenchymal stem cells to osteoblasts and chondrocytes: A focus on adenosine receptors

Department of Biochemistry, Boston University School of Medicine, Boston, MA, USA.
Expert Reviews in Molecular Medicine (Impact Factor: 5.15). 02/2013; 15:e1. DOI: 10.1017/erm.2013.2
Source: PubMed


Skeletogenesis, either during development, post-injury or for maintenance, is a carefully coordinated process reliant on the appropriate differentiation of mesenchymal stem cells. Some well described, as well as a new regulator of this process (adenosine receptors), are alike in that they signal via cyclic-AMP (cAMP). This review highlights the known contribution of cAMP signalling to mesenchymal stem cell differentiation to osteoblasts and to chondrocytes. Focus has been given to how these regulators influence the commitment of the osteochondroprogenitor to these separate lineages.

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    • "Recent studies have shown that astrocytic-ATP played important roles in regulating the proliferation (Lin et al., 2007; Mishra et al., 2006) and migration (Liu et al., 2008; Striedinger et al., 2007; Weissman et al., 2004) of neural stem cells. More studies confirmed that ATP was also involved in regulating the multi-lineage differentiation of stem cells: ATP induces oligodendrocyte progenitors (OPs) to differentiate into oligodendrocytes (Agresti et al., 2005a,b; Ceruti et al., 2011; Kastritsis and McCarthy, 1993), promotes adipose-derived MSCs to differentiate towards a glial phenotype (Faroni et al., 2013) and contributes to osteogenic differentiation of MSCs (Carroll and Ravid, 2013; Sun et al., 2013). However, it remains to be seen whether astrocytic depolarization would have beneficial effects on promoting MSCs toward neuronal differentiation in vitro and in vivo, and whether astrocyte-derived ATP upon depolarization is involved in regulating MSC's behavior. "
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    ABSTRACT: Astrocytes are key components of the central nervous system (CNS) and release factors to support neural stem cell proliferation, differentiation, and migration. Adenosine 5'-triphosphate (ATP) is one of the key factors released upon activation of astrocytes that regulates the neural stem cell's function. However, it is not clear whether ATP derived from the depolarized astrocytes plays a vital role in promoting the neuronal differentiation of mesenchymal stem cells (MSCs) in vitro and in vivo. Herein, for the first time, we co-cultured MSCs with light-stimulated-channelrhodopsin-2 (ChR2)-astrocytes, and observed that the neuronal differentiation of MSCs was enhanced by expressing more neuronal markers, Tuj1 and NeuN. The ChR2-astrocyte-conditioned medium also stimulated MSCs differentiating into neuronal lineage cells by expressing more Tuj1 and Pax6, which was blocked by the P2X receptor antagonist, TNP-ATP. Then we found that light-depolarization of astrocytes significantly increased ATP accumulation in their bathing medium without impairing the cell membrane. We further found that ATP up-regulated the Tuj1, Pax6, FZD8 and β-catenin mRNA levels of MSCs, which could be reversed by application of TNP-ATP. Together these in vitro data provided convergent evidence that ATP from light-depolarized-astrocytes activated the wnt/β-catenin signaling of MSCs through binding to the P2X receptors, and promoted the neuronal differentiation of MSCs. Finally but importantly, our study also demonstrated in stroke rats that light-controlled astrocytes stimulated endogenous ATP release into the ischemic area to influence the transplanted MSCs, resulting in promoting the MSCs towards neuronal differentiation and improvements of neurological deficit. GLIA 2013;62:106-121.
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    ABSTRACT: Osteoarthritis (OA) is the most common form of chronic musculoskeletal disorders. A migratory stem cell population termed chondrogenic progenitor cells (CPC) with in vitro chondrogenic potential was previously isolated from OA cartilage. Since intracellular Ca(2+) signalling is an important regulator of chondrogenesis, we aimed to provide a detailed understanding of the Ca(2+) homeostasis of CPCs. In this work, CPCs immortalised by lentiviral administration of the human telomerase reverse transcriptase (hTERT) and grown in monolayer cultures were studied. Expressions of all three IP3Rs were confirmed, but no RyR subtypes were detected. Ca(2+) oscillations observed in CPCs were predominantly dependent on Ca(2+) release and store replenishment via store-operated Ca(2+) entry; CPCs express both STIM1 and Orai1 proteins. Expressions of adenosine receptor mRNAs were verified, and adenosine elicited Ca(2+) transients. Various P2 receptor subtypes were identified; P2Y1 can bind ADP; P2Y4 is targeted by UTP; and ATP may evoke Ca(2+) transients via detected P2X subtypes, as well as P2Y1 and P2Y2. Enzymatic breakdown of extracellular nucleotides by apyrase completely abrogated Ca(2+) oscillations, suggesting that an autocrine/paracrine purinergic mechanism may drive Ca(2+) oscillations in these cells. As CPCs possess a broad spectrum of functional molecular elements of Ca(2+) signalling, Ca(2+)-dependent regulatory mechanisms can be supposed to influence their differentiation potential.
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