The role of mitochondria in osteogenic, adipogenic and chondrogenic differentiation of mesenchymal stem cells

Abstract

Mesenchymal stem cells (MSCs) are progenitors of connective tissues, which have emerged as important tools for tissue engineering due to their differentiation potential along various cell types. In recent years, accumulating evidence has suggested that the regulation of mitochondria dynamics and function is essential for successful differentiation of MSCs. In this paper, we review and provide an integrated view on the role of mitochondria in MSC differentiation. The mitochondria are maintained at a relatively low activity level inMSCs, and upon induction,mtDNAcopy number, protein levels of respiratory enzymes, the oxygen consumption rate, mRNA levels of mitochondrial biogenesis- associated genes, and intracellular ATP content are increased. The regulated level of mitochondrial ROS is found not only to influence differentiation but also to contribute to the direction determination of differentiation. Understanding the roles ofmitochondrial dynamics during MSC differentiation will facilitate the optimization of differentiation protocols by adjusting biochemical properties, such as energy production or the redox status of stem cells, and ultimately, benefit the development of new pharmacologic strategies in regenerative medicine.

Keywords

mesenchymal stem cells / mitochondria / differentiation

References

[1] AganiFH, PichiuleP, ChavezJC, LaMannaJC (2000) The role of mitochondria in the regulation of hypoxia-inducible factor 1 expression during hypoxia. J Biol Chem275:35863–35867

[2] AkuneT, OhbaS, KamekuraS, YamaguchiM, ChungUI, KubotaN, TerauchiY, HaradaY, AzumaY, NakamuraK (2004) PPARgamma insufficiency enhances osteogenesis through osteoblast formation from bone marrow progenitors. J Clin Investig113:846–855

[3] AtashiF, ModarressiA, PepperMS (2015) The role of reactive oxygen species in mesenchymal stem cell adipogenic and osteogenic differentiation: a review. Stem cells and development24:1150–1163

[4] BoyetteLB, CreaseyOA, GuzikL, LozitoT, TuanRS (2014) Human bone marrow-derived mesenchymal stem cells display enhanced clonogenicity but impaired differentiation with hypoxic preconditioning. Stem cells Transl Med3:241–254

[5] ChenCT, ShihYR, KuoTK, LeeOK, WeiYH (2008a) Coordinated changes of mitochondrial biogenesis and antioxidant enzymes during osteogenic differentiation of human mesenchymal stem cells. Stem Cells26:960–968

[6] ChenY, ShaoJZ, XiangLX, DongXJ, ZhangGR (2008b) Mesenchymal stem cells: a promising candidate in regenerative medicine. Int J Biochem Cell Biol40:815–820

[7] ChenQ, ShouP, ZhengC, JiangM, CaoG, YangQ, CaoJ, XieN, VelletriT, ZhangX (2016) Fate decision of mesenchymal stem cells: adipocytes or osteoblasts? Cell Death Differ23:1128–1139

[8] Collu-MarcheseM, ShuenM, PaulyM, SaleemA, HoodDA (2015) The regulation of mitochondrial transcription factor A (Tfam) expression during skeletal muscle cell differentiation. Biosci Rep35:e00221

[9] DenuRA, HemattiP (2016) Effects of Oxidative Stress on Mesenchymal Stem Cell Biology. Oxidative Med Cell Longev2016:2989076

[10] EjtehadifarM, ShamsasenjanK, MovassaghpourA, AkbarzadehlalehP, DehdilaniN, AbbasiP, MolaeipourZ, SalehM (2015) The effect of hypoxia on mesenchymal stem cell biology. Adv Pharm Bull5:141–149

[11] ForniMF, PeloggiaJ, TrudeauK, ShirihaiO, KowaltowskiAJ (2016) Murine mesenchymal stem cell commitment to differentiation is regulated by mitochondrial dynamics. Stem Cells34:743–755

[12] GeisslerS, TextorM, KuhnischJ, KonnigD, KleinO, OdeA, PfitznerT, AdjayeJ, KasperG, DudaGN (2012) Functional comparison of chronological and in vitro aging: differential role of the cytoskeleton and mitochondria in mesenchymal stromal cells. PLoS ONE7:e52700

[13] HeywoodHK, LeeDA (2016) Bioenergetic reprogramming of articular chondrocytes by exposure to exogenous and endogenous reactive oxygen species and its role in the anabolic response to low oxygen. J Tissue Eng Regen Med10:1–9

[14] HofmannAD, BeyerM, Krause-BuchholzU, WobusM, BornhauserM, RodelG (2012) OXPHOS supercomplexes as a hallmark of the mitochondrial phenotype of adipogenic differentiated human MSCs. PLoS ONE7:e35160

[15] HsuYC, WuYT, YuTH, WeiYH (2016) Mitochondria in mesenchymal stem cell biology and cell therapy: From cellular differentiation to mitochondrial transfer. Semin Cell Dev Biol52:119–131

[16] HuangPI, ChenYC, ChenLH, JuanCC, KuHH, WangST, ChiouSH, ChiouGY, ChiCW, HsuCC (2011) PGC-1alpha mediates differentiation of mesenchymal stem cells to brown adipose cells. J Atheroscler Thromb18:966–980

[17] JallaliN, RidhaH, ThrasivoulouC, ButlerP, CowenT (2007) Modulation of intracellular reactive oxygen species level in chondrocytes by IGF-1, FGF, and TGF-beta1. Connect Tissue Res48:149–158

[18] KandaY, HinataT, KangSW, WatanabeY (2011) Reactive oxygen species mediate adipocyte differentiation in mesenchymal stem cells. Life Sci89:250–258

[19] KimKS, ChoiHW, YoonHE, KimIY (2010) Reactive oxygen species generated by NADPH oxidase 2 and 4 are required for chondrogenic differentiation. J Biol Chem285:40294–40302

[20] KimM, KimC, ChoiYS, KimM, ParkC, SuhY (2012) Age-related alterations in mesenchymal stem cells related to shift in differentiation from osteogenic to adipogenic potential: implication to age-associated bone diseases and defects. Mech Ageing Dev133:215–225

[21] LambertiniE, PenolazziL, MorgantiC, LisignoliG, ZiniN, AngelozziM, BonoraM, FerroniL, PintonP, ZavanB (2015) Osteogenic differentiation of human MSCs: Specific occupancy of the mitochondrial DNA by NFATc1 transcription factor. Int J Biochem Cell Biol64:212–219

[22] LeeDH, LimBS, LeeYK, YangHC (2006) Effects of hydrogen peroxide (H2O2) on alkaline phosphatase activity and matrix mineralization of odontoblast and osteoblast cell lines. Cell Biol Toxicol22:39–46

[23] Min-WenJC, Jun-HaoET, Shyh-ChangN (2016) Stem cell mitochondria during aging. Semin Cell Dev Biol52:110–118

[24] MoritaK, MiyamotoT, FujitaN, KubotaY, ItoK, TakuboK, MiyamotoK, NinomiyaK, SuzukiT, IwasakiR (2007) Reactive oxygen species induce chondrocyte hypertrophy in endochondral ossification. J Exp Med204:1613–1623

[25] NuschkeA, RodriguesM, StolzDB, ChuCT, GriffithL, WellsA (2014) Human mesenchymal stem cells/multipotent stromal cells consume accumulated autophagosomes early in differentiation. Stem cell Res Ther5:140

[26] PanH, GuanD, LiuX, LiJ, WangL, WuJ, ZhouJ, ZhangW, RenR, ZhangW (2016) SIRT6 safeguards human mesenchymal stem cells from oxidative stress by coactivating NRF2. Cell Res26:190–205

[27] PapandreouI, CairnsRA, FontanaL, LimAL, DenkoNC (2006) HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell Metab3:187–197

[28] ParekkadanB, MilwidJM (2010) Mesenchymal stem cells as therapeutics. Annu Rev Biomed Eng12:87–117

[29] PatelJJ, ButtersOR, ArnettTR (2014) PPAR agonists stimulate adipogenesis at the expense of osteoblast differentiation while inhibiting osteoclast formation and activity. Cell Biochem Funct32:368–377

[30] PietilaM, PalomakiS, LehtonenS, RitamoI, ValmuL, NystedtJ, LaitinenS, LeskelaHV, SormunenR, PesalaJ (2012) Mitochondrial function and energy metabolism in umbilical cord blood- and bone marrow-derived mesenchymal stem cells. Stem Cells Dev21:575–588

[31] QuinnKP, SridharanGV, HaydenRS, KaplanDL, LeeK, GeorgakoudiI (2013) Quantitative metabolic imaging using endogenous fluorescence to detect stem cell differentiation. Sci Rep3:3432

[32] Salas-VidalE, LomeliH, Castro-ObregonS, CuervoR, Escalante-AlcaldeD, CovarrubiasL (1998) Reactive oxygen species participate in the control of mouse embryonic cell death. Exp Cell Res238:136–147

[33] Sanchez-AragoM, Garcia-BermudezJ, Martinez-ReyesI, SantacatterinaF, CuezvaJM (2013) Degradation of IF1 controls energy metabolism during osteogenic differentiation of stem cells. EMBO Rep14:638–644

[34] SartS, SongL, LiY (2015) Controlling redox status for stem cell survival, expansion, and differentiation. Oxidative Med Cell Longev2015:105135

[35] SavkovicV, LiH, SeonJK, HackerM, FranzS, SimonJC (2014) Mesenchymal stem cells in cartilage regeneration. Curr Stem Cell Res Ther9:469–488

[36] SchnabelD, Salas-VidalE, NarvaezV, Sanchez-Carbente MdelR, Hernandez-GarciaD, CuervoR, CovarrubiasL (2006) Expression and regulation of antioxidant enzymes in the developing limb support a function of ROS in interdigital cell death. Dev Biol291:291–299

[37] SongBQ, ChiY, LiX, DuWJ, HanZB, TianJJ, LiJJ, ChenF, WuHH, HanLX (2015) Inhibition of notch signaling promotes the adipogenic differentiation of mesenchymal stem cells through autophagy activation and PTEN-PI3K/AKT/mTOR pathway. Cell Physiol Biochem36:1991–2002

[38] StechschulteLA, CzernikPJ, RotterZC, TausifFN, CorzoCA, MarcianoDP, AsteianA, ZhengJ, BruningJB, KameneckaTM (2016) PPARG post-translational modifications regulate bone formation and bone resorption. EBioMedicine10:174–184

[39] TaharaEB, NavareteFD, KowaltowskiAJ (2009) Tissue-, substrate-, and site-specific characteristics of mitochondrial reactive oxygen species generation. Free Radic Biol Med46:1283–1297

[40] TanJ, XuX, TongZ, LinJ, YuQ, LinY, KuangW (2015) Decreased osteogenesis of adult mesenchymal stem cells by reactive oxygen species under cyclic stretch: a possible mechanism of age related osteoporosis. Bone Res3:15003

[41] TormosKV, AnsoE, HamanakaRB, EisenbartJ, JosephJ, KalyanaramanB, ChandelNS (2011) Mitochondrial complex III ROS regulate adipocyte differentiation. Cell Metab14:537–544

[42] Varela-ReyM, EmbadeN, ArizU, LuSC, MatoJM, Martinez-ChantarML (2009) Non-alcoholic steatohepatitis and animal models: understanding the human disease. Int J Biochem Cell Biol41:969–976

[43] WageggM, GaberT, LohanathaFL, HahneM, StrehlC, FangradtM, TranCL, SchonbeckK, HoffP, OdeA (2012) Hypoxia promotes osteogenesis but suppresses adipogenesis of human mesenchymal stromal cells in a hypoxia-inducible factor-1 dependent manner. PLoS ONE7:e46483

[44] WanY (2010) PPARgamma in bone homeostasis. Trends Endocrinol metab21:722–728

[45] WanetA, RemacleN, NajarM, SokalE, ArnouldT, NajimiM, RenardP (2014) Mitochondrial remodeling in hepatic differentiation and dedifferentiation. Int J Biochem Cell Biol54:174–185

[46] WangW, ZhangY, LuW, LiuK (2015) Mitochondrial reactive oxygen species regulate adipocyte differentiation of mesenchymal stem cells in hematopoietic stress induced by arabinosylcytosine. PLoS ONE10:e0120629

[47] ZhangY, MarsboomG, TothPT, RehmanJ (2013) Mitochondrial respiration regulates adipogenic differentiation of human mesenchymal stem cells. PLoS ONE8:e77077

RIGHTS & PERMISSIONS

The Author(s) 2017. This article is published with open access at Springerlink.com and journal.hep.com.cn