The role of reactive oxygen species in mesenchymal stem cell adipogenic and osteogenic differentiation: a review

Abstract

Mesenchymal stromal cells (MSCs) are promising candidates for tissue engineering and regenerative medicine. The multipotent stem cell component of MSC isolates is able to differentiate into derivatives of the mesodermal lineage including adipocytes, osteocytes, chondrocytes, and myocytes. Many common pathways have been described in the regulation of adipogenesis and osteogenesis. However, stimulation of osteogenesis appears to suppress adipogenesis and vice-versa. Increasing evidence implicates a tight regulation of these processes by reactive oxygen species (ROS). ROS are short-lived oxygen-containing molecules that display high chemical reactivity toward DNA, RNA, proteins, and lipids. Mitochondrial complexes I and III, and the NADPH oxidase isoform NOX4 are major sources of ROS production during MSC differentiation. ROS are thought to interact with several pathways that affect the transcription machinery required for MSC differentiation including the Wnt, Hedgehog, and FOXO signaling cascades. On the other hand, elevated levels of ROS, defined as oxidative stress, lead to arrest of the MSC cell cycle and apoptosis. Tightly regulated levels of ROS are therefore critical for MSC terminal differentiation, although the precise sources, localization, levels and the exact species of ROS implicated remain to be determined. This review provides a detailed overview of the influence of ROS on adipogenic and osteogenic differentiation in MSCs.

FIG. 1.

Sources of reactive oxygen species (ROS). ROS can be intracellulary generated by mitochondria and diverse NOX isoforms, peroxisome, endoplasmic reticulum (ER), xanthine oxidase, and lipogenase. It can also be applied from exogenous sources. Irrespective of its source, it may cause cell proliferation, differentiation, and/or cell cycle arrest, and this effect appears to be concentration dependent. Color images available online at www.liebertpub.com/scd

FIG. 2.

Mitochondrial ROS production. The production of the superoxide anion, O₂^•−, by complex I and complex III in the matrix or the inter-membrane space forms H₂O₂ through the activity of SOD catalase dismutation. H₂O₂ can then be converted to H₂O and O₂ by glutathione peroxidase (GPX) and catalase or may play a second messenger role in essential signaling pathways. Color images available online at www.liebertpub.com/scd

FIG. 3.

NADPH oxidases. NOX enzymes reduce oxygen to O₂^•− by using pyridine nucleotide NADPH as an electron donor and molecular oxygen as an electron acceptor. ROS will be generated as the secondary product. A part of O₂^•− can directly react with nitric oxide (NO^•) to form a toxic peroxynitrite. It can also be dismutated by superoxide dismutase to form hydrogen peroxide to induce cell signaling cascades or directly react with Fe³⁺ to form hydroxyl radical. Color images available online at www.liebertpub.com/scd

FIG. 4.

ROS control signaling cascades involved in osteogenesis/adipogenesis. Wnt/β-catenin, MAPK (NELL-1), and Hh signaling induce osteogenesis while FOXO, PPARγ, and CEBPs signaling stimulate adipogenesis. BMP and IGF signaling have a dual effect in inducing both of these terminal fates. Induction of osteogenesis is optimal in the absence of ROS while induction of adipogenesis is optimal in the presence of ROS. Color images available online at www.liebertpub.com/scd

FIG. 5.

ROS suppress important osteogenic signaling pathways while they promote adipogenic signaling pathways. Wnt/β-catenin and Hh signaling cascades induce osteogenesis and this is inhibited in the presence of high levels of ROS, which favors adipogenesis. MAPK signaling induces osteogenesis and is stimulated by ROS. In response to oxidative stress, FOXOs are phosphorylated and translocate to the nucleus where they attenuate the transcription of osteogenic genes while inducing adipogenic differentiation. The active form FOXO also induces the regulation of antioxidant and cell cycle arrest genes. The expression of antioxidants also increases adipogenic differentiation. Color images available online at www.liebertpub.com/scd