Cellular and Molecular Life Sciences

, Volume 75, Issue 5, pp 889–903 | Cite as

Mesenchymal stem cells from preterm to term newborns undergo a significant switch from anaerobic glycolysis to the oxidative phosphorylation

  • Silvia Ravera
  • Marina Podestà
  • Federica Sabatini
  • Chiara Fresia
  • Marta Columbaro
  • Silvia Bruno
  • Ezio Fulcheri
  • Luca Antonio Ramenghi
  • Francesco Frassoni
Original Article


We evaluated the energy metabolism of human mesenchymal stem cells (MSC) isolated from umbilical cord (UC) of preterm (< 37 weeks of gestational age) and term (≥ 37 weeks of gestational age) newborns, using MSC from adult bone marrow as control. A metabolic switch has been observed around the 34th week of gestational age from a prevalently anaerobic glycolysis to the oxidative phosphorylation. This metabolic change is associated with the organization of mitochondria reticulum: preterm MSCs presented a scarcely organized mitochondrial reticulum and low expression of proteins involved in the mitochondrial fission/fusion, compared to term MSCs. These changes seem governed by the expression of CLUH, a cytosolic messenger RNA-binding protein involved in the mitochondria biogenesis and distribution inside the cell; in fact, CLUH silencing in term MSC determined a metabolic fingerprint similar to that of preterm MSC. Our study discloses novel information on the production of energy and mitochondrial organization and function, during the passage from fetal to adult life, providing useful information for the management of preterm birth.


CLUH Endothelial cells Energy metabolism Mesenchymal stem cells OXPHOS Preterm newborns Term newborns 



This work was supported by funds from Cinque per mille e Ricerca Corrente, Ministero della Salute, to Istituto Giannina Gaslini; a Compagnia di San Paolo Grant (2014AAI637.U/812/AR pv 2013.0958 to F.F) and a Grant FIRB (2012# RBFR1299K0_002 to C.F.). The authors are indebted to Dr. Federica Raggi for providing the hypoxia incubator.

Supplementary material

18_2017_2665_MOESM1_ESM.tif (10.1 mb)
Supplementary material 1 Suppl Figure 1 Phenotypical characterization of UC-MSC from preterm and term neonates. Phenotypical characterization of UC-MSC from preterm and term neonates. Panel a shows histograms of flow cytometry analyses demonstrating the expression of surface molecules of preterm MSC (preterm) compared with term MSC (term) and normal bone marrow-derived MSC (NBM). b Reports a representative flow cytometric analysis of Nestin, OCT3/4, NANOG, and SSEA-4 expression by preterm and term MSC. The gray histograms show the region of fluorescent intensity of the specific antibody and bold empty histograms represent staining of respective isotype-matched control immunoglobulins. Values are represented as percentage (%) of positive cells (TIFF 10330 kb)


  1. 1.
    Ding D-C, Chang Y-H, Shyu W-C, Lin S-Z (2015) Human umbilical cord mesenchymal stem cells: a new era for stem cell therapy. Cell Transplant 24:339–347. doi: 10.3727/096368915X686841 CrossRefPubMedGoogle Scholar
  2. 2.
    Weiss ML, Troyer DL (2006) Stem cells in the umbilical cord. Stem Cell Rev 2:155–162. doi: 10.1007/s12015-006-0022-y CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Zhao S, Wehner R, Bornhäuser M et al (2010) Immunomodulatory properties of mesenchymal stromal cells and their therapeutic consequences for immune-mediated disorders. Stem Cells Dev 19:607–614. doi: 10.1089/scd.2009.0345 CrossRefPubMedGoogle Scholar
  4. 4.
    Simsek T, Kocabas F, Zheng J et al (2010) The distinct metabolic profile of hematopoietic stem cells reflects their location in a hypoxic niche. Cell Stem Cell 7:380–390. doi: 10.1016/j.stem.2010.07.011 CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Ahlqvist KJ, Suomalainen A, Hämäläinen RH (2015) Stem cells, mitochondria and aging. Biochim Biophys Acta 1847:1380–1386. doi: 10.1016/j.bbabio.2015.05.014 CrossRefPubMedGoogle Scholar
  6. 6.
    Ocampo A, Izpisua Belmonte JC (2015) Stem cells. Holding your breath for longevity. Science 347:1319–1320. doi: 10.1126/science.aaa9608 CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Chen C-T, Hsu S-H, Wei Y-H (2010) Upregulation of mitochondrial function and antioxidant defense in the differentiation of stem cells. Biochim Biophys Acta 1800:257–263. doi: 10.1016/j.bbagen.2009.09.001 CrossRefPubMedGoogle Scholar
  8. 8.
    Lonergan T, Bavister B, Brenner C (2007) Mitochondria in stem cells. Mitochondrion 7:289–296. doi: 10.1016/j.mito.2007.05.002 CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Parker GC, Acsadi G, Brenner CA (2009) Mitochondria: determinants of stem cell fate? Stem Cells Dev 18:803–806. doi: 10.1089/scd.2009.1806.edi CrossRefPubMedGoogle Scholar
  10. 10.
    McBride HM, Neuspiel M, Wasiak S (2006) Mitochondria: more than just a powerhouse. Curr Biol 16:R551–R560CrossRefPubMedGoogle Scholar
  11. 11.
    Shum LC, White NS, Mills BN et al (2016) Energy metabolism in mesenchymal stem cells during osteogenic differentiation. Stem Cells Dev 25:114–122. doi: 10.1089/scd.2015.0193 CrossRefPubMedGoogle Scholar
  12. 12.
    Folmes CDL, Nelson TJ, Martinez-Fernandez A et al (2011) Somatic oxidative bioenergetics transitions into pluripotency-dependent glycolysis to facilitate nuclear reprogramming. Cell Metab 14:264–271. doi: 10.1016/j.cmet.2011.06.011 CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Antico Arciuch VG, Elguero ME, Poderoso JJ, Carreras MC (2012) Mitochondrial regulation of cell cycle and proliferation. Antioxid Redox Signal 16:1150–1180. doi: 10.1089/ars.2011.4085 CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Panfoli I, Ravera S, Podestà M et al (2016) Exosomes from human mesenchymal stem cells conduct aerobic metabolism in term and preterm newborn infants. FASEB J 30:1416–1424. doi: 10.1096/fj.15-279679 CrossRefPubMedGoogle Scholar
  15. 15.
    Almgren M, Schlinzig T, Gomez-Cabrero D et al (2014) Cesarean delivery and hematopoietic stem cell epigenetics in the newborn infant: implications for future health? Am J Obstet Gynecol 211:502.e1–502.e8. doi: 10.1016/j.ajog.2014.05.014 CrossRefGoogle Scholar
  16. 16.
    Capelli C, Gotti E, Morigi M et al (2011) Minimally manipulated whole human umbilical cord is a rich source of clinical-grade human mesenchymal stromal cells expanded in human platelet lysate. Cytotherapy 13:786–801. doi: 10.3109/14653249.2011.563294 CrossRefPubMedGoogle Scholar
  17. 17.
    Dominici M, Le Blanc K, Mueller I et al (2006) Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 8:315–317. doi: 10.1080/14653240600855905 CrossRefPubMedGoogle Scholar
  18. 18.
    Sessarego N, Parodi A, Podestà M et al (2008) Multipotent mesenchymal stromal cells from amniotic fluid: solid perspectives for clinical application. Haematologica 93:339–346. doi: 10.3324/haematol.11869 CrossRefPubMedGoogle Scholar
  19. 19.
    Podestà M, Bruschettini M, Cossu C et al (2015) Preterm cord blood contains a higher proportion of immature hematopoietic progenitors compared to term samples. PLoS ONE 10:e0138680. doi: 10.1371/journal.pone.0138680 CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Gao J, Schatton D, Martinelli P et al (2014) CLUH regulates mitochondrial biogenesis by binding mRNAs of nuclear-encoded mitochondrial proteins. J Cell Biol 207:213–223. doi: 10.1083/jcb.201403129 CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Bianchi G, Martella R, Ravera S et al (2015) Fasting induces anti-Warburg effect that increases respiration but reduces ATP-synthesis to promote apoptosis in colon cancer models. Oncotarget ​6:11806–11819. doi: 10.18632/oncotarget.3688 CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Ravera S, Vaccaro D, Cuccarolo P et al (2013) Mitochondrial respiratory chain complex I defects in Fanconi anemia complementation group A. Biochimie 95:1828–1837CrossRefPubMedGoogle Scholar
  23. 23.
    Ravera S, Aluigi MG, Calzia D et al (2011) Evidence for ectopic aerobic ATP production on C6 glioma cell plasma membrane. Cell Mol Neurobiol 31:313–321CrossRefPubMedGoogle Scholar
  24. 24.
    Hinkle PC (2005) P/O ratios of mitochondrial oxidative phosphorylation. Biochim Biophys Acta 1706:1–11. doi: 10.1016/j.bbabio.2004.09.004 CrossRefPubMedGoogle Scholar
  25. 25.
    Ravera S, Bartolucci M, Calzia D et al (2013) Tricarboxylic acid cycle-sustained oxidative phosphorylation in isolated myelin vesicles. Biochimie 95:1991–1998CrossRefPubMedGoogle Scholar
  26. 26.
    Ravera S, Bartolucci M, Cuccarolo P et al (2015) Oxidative stress in myelin sheath: the other face of the extramitochondrial oxidative phosphorylation ability. Free Radic Res. doi: 10.3109/10715762.2015.1050962 PubMedGoogle Scholar
  27. 27.
    Andersen CL, Jensen JL, Ørntoft TF (2004) Normalization of real-time quantitative reverse transcription-PCR data: a model-based variance estimation approach to identify genes suited for normalization, applied to bladder and colon cancer data sets. Cancer Res 64:5245–5250. doi: 10.1158/0008-5472.CAN-04-0496 CrossRefPubMedGoogle Scholar
  28. 28.
    Schefe JH, Lehmann KE, Buschmann IR et al (2006) Quantitative real-time RT-PCR data analysis: current concepts and the novel “gene expression’s CT difference” formula. J Mol Med (Berl) 84:901–910. doi: 10.1007/s00109-006-0097-6 CrossRefGoogle Scholar
  29. 29.
    Schatton D, Pla-Martin D, Marx M-C et al (2017) CLUH regulates mitochondrial metabolism by controlling translation and decay of target mRNAs. J Cell Biol 216:675–693. doi: 10.1083/jcb.201607019 CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Mitchell P (1961) Coupling of phosphorylation to electron and hydrogen transfer by a chemi-osmotic type of mechanism. Nature 191:144–148CrossRefPubMedGoogle Scholar
  31. 31.
    Vander Heiden MG, Cantley LC, Thompson CB (2009) Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324:1029–1033. doi: 10.1126/science.1160809 CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Kondoh H, Lleonart ME, Bernard D, Gil J (2007) Protection from oxidative stress by enhanced glycolysis; a possible mechanism of cellular immortalization. Histol Histopathol 22:85–90PubMedGoogle Scholar
  33. 33.
    Moussaieff A, Kogan NM, Aberdam D (2015) Concise review: Energy metabolites: key mediators of the epigenetic state of pluripotency. Stem Cells 33:2374–2380. doi: 10.1002/stem.2041 CrossRefPubMedGoogle Scholar
  34. 34.
    Daley GQ (2015) Stem cells and the evolving notion of cellular identity. Philos Trans R Soc Lond B Biol Sci 370:20140376. doi: 10.1098/rstb.2014.0376 CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Westermann B (2012) Bioenergetic role of mitochondrial fusion and fission. Biochim Biophys Acta 1817:1833–1838. doi: 10.1016/j.bbabio.2012.02.033 CrossRefPubMedGoogle Scholar
  36. 36.
    Forni MF, Peloggia J, Trudeau K et al (2016) Murine mesenchymal stem cell commitment to differentiation is regulated by mitochondrial dynamics. Stem Cells 34:743–755. doi: 10.1002/stem.2248 CrossRefPubMedGoogle Scholar
  37. 37.
    Dai D-F, Chiao YA, Marcinek DJ et al (2014) Mitochondrial oxidative stress in aging and healthspan. Longev Heal 3:6. doi: 10.1186/2046-2395-3-6 CrossRefGoogle Scholar
  38. 38.
    Cadenas E, Davies KJA (2000) Mitochondrial free radical generation, oxidative stress, and aging 11. This article is dedicated to the memory of our dear friend, colleague, and mentor Lars Ernster (1920–1998), in gratitude for all he gave to us. Free Radic Biol Med 29:222–230. doi: 10.1016/S0891-5849(00)00317-8 CrossRefPubMedGoogle Scholar
  39. 39.
    Kadenbach B (2003) Intrinsic and extrinsic uncoupling of oxidative phosphorylation. Biochim Biophys Acta Bioenerg 1604:77–94. doi: 10.1016/S0005-2728(03)00027-6 CrossRefGoogle Scholar
  40. 40.
    Chen C-T, Shih Y-RV, Kuo TK et al (2008) Coordinated changes of mitochondrial biogenesis and antioxidant enzymes during osteogenic differentiation of human mesenchymal stem cells. Stem Cells 26:960–968. doi: 10.1634/stemcells.2007-0509 CrossRefPubMedGoogle Scholar
  41. 41.
    Lawrence J, Xiao D, Xue Q et al (2008) Prenatal nicotine exposure increases heart susceptibility to ischemia/reperfusion injury in adult offspring. J Pharmacol Exp Ther 324:331–341. doi: 10.1124/jpet.107.132175 CrossRefPubMedGoogle Scholar
  42. 42.
    Reynolds JD, Penning DH, Dexter F et al (1996) Ethanol increases uterine blood flow and fetal arterial blood oxygen tension in the near-term pregnant ewe. Alcohol 13:251–256CrossRefPubMedGoogle Scholar
  43. 43.
    Patterson AJ, Zhang L (2010) Hypoxia and fetal heart development. Curr Mol Med 10:653–666CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Covello KL, Kehler J, Yu H et al (2006) HIF-2alpha regulates Oct-4: effects of hypoxia on stem cell function, embryonic development, and tumor growth. Genes Dev 20:557–570. doi: 10.1101/gad.1399906 CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Semenza GL, Agani F, Iyer N et al (1999) Regulation of cardiovascular development and physiology by hypoxia-inducible factor 1. Ann N Y Acad Sci 874:262–268CrossRefPubMedGoogle Scholar
  46. 46.
    Adelman DM, Gertsenstein M, Nagy A et al (2000) Placental cell fates are regulated in vivo by HIF-mediated hypoxia responses. Genes Dev 14:3191–3203CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Pattappa G, Heywood HK, de Bruijn JD, Lee DA (2011) The metabolism of human mesenchymal stem cells during proliferation and differentiation. J Cell Physiol 226:2562–2570. doi: 10.1002/jcp.22605 CrossRefPubMedGoogle Scholar
  48. 48.
    Wyburn GM (1939) The formation of the umbilical cord and the umbilical region of the anterior abdominal wall. J Anat 73:289–310PubMedPubMedCentralGoogle Scholar
  49. 49.
    Malgieri A, Kantzari E, Patrizi MP, Gambardella S (2010) Bone marrow and umbilical cord blood human mesenchymal stem cells: state of the art. Int J Clin Exp Med 3:248–269PubMedPubMedCentralGoogle Scholar
  50. 50.
    Lavoie PM, Lavoie J-C, Watson C et al (2010) Inflammatory response in preterm infants is induced early in life by oxygen and modulated by total parenteral nutrition. Pediatr Res 68:248–251. doi: 10.1203/PDR.0b013e3181eb2f18 CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    O’Donovan DJ, Fernandes CJ (2004) Free radicals and diseases in premature infants. Antioxid Redox Signal 6:169–176CrossRefPubMedGoogle Scholar
  52. 52.
    Perrone S, Tataranno LM, Stazzoni G et al (2015) Brain susceptibility to oxidative stress in the perinatal period. J Matern Fetal Neonatal Med 28(Suppl 1):2291–2295. doi: 10.3109/14767058.2013.796170 CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • Silvia Ravera
    • 1
  • Marina Podestà
    • 1
  • Federica Sabatini
    • 1
  • Chiara Fresia
    • 2
  • Marta Columbaro
    • 3
  • Silvia Bruno
    • 4
  • Ezio Fulcheri
    • 5
  • Luca Antonio Ramenghi
    • 6
  • Francesco Frassoni
    • 1
  1. 1.Stem Cell Laboratory and Cell Therapy CenterIRCCS Istituto Giannina GasliniGenoaItaly
  2. 2.Section of Biochemistry, Department of Experimental MedicineUniversity of GenoaGenoaItaly
  3. 3.SC Laboratory of Musculoskeletal Cell BiologyIRCCS Rizzoli Orthopedic InstituteBolognaItaly
  4. 4.Section of Human Anatomy, Department of Experimental MedicineUniversity of GenoaGenoaItaly
  5. 5.Laboratory Medicine and Diagnostic Services, Division of Perinatal Pathology, Department of Translational ResearchIRCCS Istituto Giannina GasliniGenoaItaly
  6. 6.Neonatal Intensive Care UnitIRCCS Istituto Giannina GasliniGenoaItaly

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