Short-term physiological hypoxia potentiates the therapeutic function of mesenchymal stem cells

Ben Antebi1, Luis Rodríguez1, Kerfoot P. Walker1, Amber M. Asher1, Robin Kamucheka1, Lucero Alvarado1, Arezoo Mohammadipoor1, Leopoldo C. Cancio1
1United States Army Institute of Surgical Research, San Antonio, TX, USA

Tóm tắt

Từ khóa


Tài liệu tham khảo

Weiss DJ. Concise review: current status of stem cells and regenerative medicine in lung biology and diseases. Stem Cells. 2014;32(1):16–25.

Lee JW, Fang X, Krasnodembskaya A, Howard JP, Matthay MA. Concise review: Mesenchymal stem cells for acute lung injury: role of paracrine soluble factors. Stem Cells. 2011;29(6):913–9.

Antebi B, Mohammadipoor A, Batchinsky AI, Cancio LC. The Promise of Mesenchymal Stem Cell Therapy for Acute Respiratory Distress Syndrome. J Trauma Acute Care Surg. 2018;84(1):183–91. https://doi.org/10.1097/TA.0000000000001713 .

Matthay MA, Thompson BT, Read EJ, Jr. McKenna DH, Liu KD, Calfee CS, Lee JW. Therapeutic potential of mesenchymal stem cells for severe acute lung injury. Chest. 2010;138(4):965–72.

Gupta N, Su X, Popov B, Lee JW, Serikov V, Matthay MA. Intrapulmonary delivery of bone marrow-derived mesenchymal stem cells improves survival and attenuates endotoxin-induced acute lung injury in mice. J Immunol. 2007;179(3):1855–63.

Mei SH, McCarter SD, Deng Y, Parker CH, Liles WC, Stewart DJ. Prevention of LPS-induced acute lung injury in mice by mesenchymal stem cells overexpressing angiopoietin 1. PLoS Med. 2007;4(9):e269.

Xu J, Woods CR, Mora AL, Joodi R, Brigham KL, Iyer S, Rojas M. Prevention of endotoxin-induced systemic response by bone marrow-derived mesenchymal stem cells in mice. Am J Physiol Lung Cell Mol Physiol. 2007;293(1):L131–41.

Fang X, Neyrinck AP, Matthay MA, Lee JW. Allogeneic human mesenchymal stem cells restore epithelial protein permeability in cultured human alveolar type II cells by secretion of angiopoietin-1. J Biol Chem. 2010;285(34):26211–22.

Krasnodembskaya A, Song Y, Fang X, Gupta N, Serikov V, Lee JW, Matthay MA. Antibacterial effect of human mesenchymal stem cells is mediated in part from secretion of the antimicrobial peptide LL-37. Stem Cells. 2010;28(12):2229–38.

Lee JW, Fang X, Gupta N, Serikov V, Matthay MA. Allogeneic human mesenchymal stem cells for treatment of E. coli endotoxin-induced acute lung injury in the ex vivo perfused human lung. Proc Natl Acad Sci U S A. 2009;106(38):16357–62.

Kim ES, Chang YS, Choi SJ, Kim JK, Yoo HS, Ahn SY, Sung DK, Kim SY, Park YR, Park WS. Intratracheal transplantation of human umbilical cord blood-derived mesenchymal stem cells attenuates Escherichia coli-induced acute lung injury in mice. Respir Res. 2011;12:108.

Liang ZX, Sun JP, Wang P, Tian Q, Yang Z, Chen LA. Bone marrow-derived mesenchymal stem cells protect rats from endotoxin-induced acute lung injury. Chin Med J. 2011;124(17):2715–22.

Ionescu L, Byrne RN, van Haaften T, Vadivel A, Alphonse RS, Rey-Parra GJ, Weissmann G, Hall A, Eaton F, Thebaud B. Stem cell conditioned medium improves acute lung injury in mice: in vivo evidence for stem cell paracrine action. Am J Physiol Lung Cell Mol Physiol. 2012;303(11):L967–77.

Tai WL, Dong ZX, Zhang DD, Wang DH. Therapeutic effect of intravenous bone marrow-derived mesenchymal stem cell transplantation on early-stage LPS-induced acute lung injury in mice. Nan Fang Yi Ke Da Xue Xue Bao. 2012;32(3):283–90.

Devaney J, Horie S, Masterson C, Elliman S, Barry F, O'Brien T, Curley GF, O'Toole D, Laffey JG. Human mesenchymal stromal cells decrease the severity of acute lung injury induced by E. coli in the rat. Thorax. 2015;70(7):625–35.

Shalaby SM, El-Shal AS, Abd-Allah SH, Selim AO, Selim SA, Gouda ZA, Abd El Motteleb DM, Zanfaly HE, El-Assar HM, Abdelazim S. Mesenchymal stromal cell injection protects against oxidative stress in Escherichia coli-induced acute lung injury in mice. Cytotherapy. 2014;16(6):764–75.

Rojas M, Cardenes N, Kocyildirim E, Tedrow JR, Caceres E, Deans R, Ting A, Bermudez C. Human adult bone marrow-derived stem cells decrease severity of lipopolysaccharide-induced acute respiratory distress syndrome in sheep. Stem Cell Res Ther. 2014;5(2):42.

Asmussen S, Ito H, Traber DL, Lee JW, Cox RA, Hawkins HK, McAuley DF, McKenna DH, Traber LD, Zhuo H, et al. Human mesenchymal stem cells reduce the severity of acute lung injury in a sheep model of bacterial pneumonia. Thorax. 2014;69(9):819–25.

Simonson OE, Mougiakakos D, Heldring N, Bassi G, Johansson HJ, Dalen M, Jitschin R, Rodin S, Corbascio M, El Andaloussi S, et al. In vivo effects of mesenchymal stromal cells in two patients with severe acute respiratory distress syndrome. Stem Cells Transl Med. 2016;5(6):845.

Wilson JG, Liu KD, Zhuo H, Caballero L, McMillan M, Fang X, Cosgrove K, Vojnik R, Calfee CS, Lee JW, et al. Mesenchymal stem (stromal) cells for treatment of ARDS: a phase 1 clinical trial. Lancet Respir Med. 2015;3(1):24–32.

Zheng G, Huang L, Tong H, Shu Q, Hu Y, Ge M, Deng K, Zhang L, Zou B, Cheng B, et al. Treatment of acute respiratory distress syndrome with allogeneic adipose-derived mesenchymal stem cells: a randomized, placebo-controlled pilot study. Respir Res. 2014;15:39.

Liu KD, Wilson JG, Zhuo H, Caballero L, McMillan ML, Fang X, Cosgrove K, Calfee CS, Lee JW, Kangelaris KN, et al. Design and implementation of the START (STem cells for ARDS Treatment) trial, a phase 1/2 trial of human mesenchymal stem/stromal cells for the treatment of moderate-severe acute respiratory distress syndrome. Ann Intensive Care. 2014;4:22.

Spencer JA, Ferraro F, Roussakis E, Klein A, Wu J, Runnels JM, Zaher W, Mortensen LJ, Alt C, Turcotte R, et al. Direct measurement of local oxygen concentration in the bone marrow of live animals. Nature. 2014;508(7495):269–73.

Ceradini DJ, Kulkarni AR, Callaghan MJ, Tepper OM, Bastidas N, Kleinman ME, Capla JM, Galiano RD, Levine JP, Gurtner GC. Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat Med. 2004;10(8):858–64.

Berniakovich I, Giorgio M. Low oxygen tension maintains multipotency, whereas normoxia increases differentiation of mouse bone marrow stromal cells. Int J Mol Sci. 2013;14(1):2119–34.

Boregowda SV, Krishnappa V, Chambers JW, Lograsso PV, Lai WT, Ortiz LA, Phinney DG. Atmospheric oxygen inhibits growth and differentiation of marrow-derived mouse mesenchymal stem cells via a p53-dependent mechanism: implications for long-term culture expansion. Stem Cells. 2012;30(5):975–87.

Horwitz EM, Gordon PL, Koo WK, Marx JC, Neel MD, McNall RY, Muul L, Hofmann T. Isolated allogeneic bone marrow-derived mesenchymal cells engraft and stimulate growth in children with osteogenesis imperfecta: Implications for cell therapy of bone. Proc Natl Acad Sci U S A. 2002;99(13):8932–7.

Le Blanc K, Rasmusson I, Sundberg B, Gotherstrom C, Hassan M, Uzunel M, Ringden O. Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet. 2004;363(9419):1439–41.

Duijvestein M, Vos AC, Roelofs H, Wildenberg ME, Wendrich BB, Verspaget HW, Kooy-Winkelaar EM, Koning F, Zwaginga JJ, Fidder HH, et al. Autologous bone marrow-derived mesenchymal stromal cell treatment for refractory luminal Crohn's disease: results of a phase I study. Gut. 2010;59(12):1662–9.

Grayson WL, Zhao F, Bunnell B, Ma T. Hypoxia enhances proliferation and tissue formation of human mesenchymal stem cells. Biochem Biophys Res Commun. 2007;358(3):948–53.

Choi JR, Pingguan-Murphy B, Wan Abas WA, Yong KW, Poon CT, Noor Azmi MA, Omar SZ, Chua KH, Xu F, Wan Safwani WK. In situ normoxia enhances survival and proliferation rate of human adipose tissue-derived stromal cells without increasing the risk of tumourigenesis. PLoS One. 2015;10(1):e0115034.

Chang CP, Chio CC, Cheong CU, Chao CM, Cheng BC, Lin MT. Hypoxic preconditioning enhances the therapeutic potential of the secretome from cultured human mesenchymal stem cells in experimental traumatic brain injury. Clin Sci (Lond). 2013;124(3):165–76.

Bobyleva PI, Andreeva ER, Gornostaeva AN, Buravkova LB. Tissue-Related Hypoxia Attenuates Proinflammatory Effects of Allogeneic PBMCs on Adipose-Derived Stromal Cells In Vitro. Stem Cells Int. 2016;2016:4726267.

Holzwarth C, Vaegler M, Gieseke F, Pfister SM, Handgretinger R, Kerst G, Muller I. Low physiologic oxygen tensions reduce proliferation and differentiation of human multipotent mesenchymal stromal cells. BMC Cell Biol. 2010;11:11.

Roemeling-van Rhijn M, Mensah FK, Korevaar SS, Leijs MJ, van Osch GJ, Ijzermans JN, Betjes MG, Baan CC, Weimar W, Hoogduijn MJ. Effects of hypoxia on the immunomodulatory properties of adipose tissue-derived mesenchymal stem cells. Front Immunol. 2013;4:203.

Zhu W, Chen J, Cong X, Hu S, Chen X. Hypoxia and serum deprivation-induced apoptosis in mesenchymal stem cells. Stem Cells. 2006;24(2):416–25.

Huang YC, Parolini O, Deng L, Yu BS. Should hypoxia preconditioning become the standardized procedure for bone marrow MSCs preparation for clinical use? Stem Cells. 2016;34(7):1992–3.

Boyette LB, Creasey OA, Guzik L, Lozito T, Tuan RS. Human bone marrow-derived mesenchymal stem cells display enhanced clonogenicity but impaired differentiation with hypoxic preconditioning. Stem Cells Transl Med. 2014;3(2):241–54.

McDaniel JS, Antebi B, Pilia M, Hurtgen BJ, Belenkiy S, Necsoiu C, Cancio LC, Rathbone CR, Batchinsky AI. Quantitative assessment of optimal bone marrow site for the isolation of porcine mesenchymal stem cells. Stem Cells Int. 2017;2017:1836960.

Antebi B, Zhang Z, Wang Y, Lu Z, Chen XD, Ling J. Stromal-cell-derived extracellular matrix promotes the proliferation and retains the osteogenic differentiation capacity of mesenchymal stem cells on three-dimensional scaffolds. Tissue Eng Part C Methods. 2015;21(2):171–81.

Antebi B, Cheng X, Harris JN, Gower LB, Chen XD, Ling J. Biomimetic collagen-hydroxyapatite composite fabricated via a novel perfusion-flow mineralization technique. Tissue Eng Part C Methods. 2013;19(7):487–96.

Saraswati S, Guo Y, Atkinson J, Young PP. Prolonged hypoxia induces monocarboxylate transporter-4 expression in mesenchymal stem cells resulting in a secretome that is deleterious to cardiovascular repair. Stem Cells. 2015;33(4):1333–44.

Pattappa G, Thorpe SD, Jegard NC, Heywood HK, de Bruijn JD, Lee DA. Continuous and uninterrupted oxygen tension influences the colony formation and oxidative metabolism of human mesenchymal stem cells. Tissue Eng Part C Methods. 2013;19(1):68–79.

Overath JM, Gauer S, Obermuller N, Schubert R, Schafer R, Geiger H, Baer PC. Short-term preconditioning enhances the therapeutic potential of adipose-derived stromal/stem cell-conditioned medium in cisplatin-induced acute kidney injury. Exp Cell Res. 2016;342(2):175–83.

Hu X, Xu Y, Zhong Z, Wu Y, Zhao J, Wang Y, Cheng H, Kong M, Zhang F, Chen Q, et al. A large-scale investigation of hypoxia-preconditioned allogeneic mesenchymal stem cells for myocardial repair in nonhuman primates: paracrine activity without remuscularization. Circ Res. 2016;118(6):970–83.

Lee SC, Jeong HJ, Lee SK, Kim SJ. Hypoxic conditioned medium from human adipose-derived stem cells promotes mouse liver regeneration through JAK/STAT3 signaling. Stem Cells Transl Med. 2016;5(6):816–25.

Christy BA, Herzig MC, Montgomery RK, Delavan C, Bynum JA, Reddoch KM, Cap AP. Procoagulant activity of human mesenchymal stem cells. J Trauma Acute Care Surg. 2017;83(1 Suppl 1):S164–s169.

Tatsumi K, Ohashi K, Matsubara Y, Kohori A, Ohno T, Kakidachi H, Horii A, Kanegae K, Utoh R, Iwata T, et al. Tissue factor triggers procoagulation in transplanted mesenchymal stem cells leading to thromboembolism. Biochem Biophys Res Commun. 2013;431(2):203–9.

Gleeson BM, Martin K, Ali MT, Kumar AH, Pillai MG, Kumar SP, O'Sullivan JF, Whelan D, Stocca A, Khider W, et al. Bone marrow-derived mesenchymal stem cells have innate procoagulant activity and cause microvascular obstruction following intracoronary delivery: amelioration by antithrombin therapy. Stem Cells. 2015;33(9):2726–37.

Lavrentieva A, Majore I, Kasper C, Hass R. Effects of hypoxic culture conditions on umbilical cord-derived human mesenchymal stem cells. Cell Commun Signal. 2010;8:18.

Ejtehadifar M, Shamsasenjan K, Movassaghpour A, Akbarzadehlaleh P, Dehdilani N, Abbasi P, Molaeipour Z, Saleh M. The effect of hypoxia on mesenchymal stem cell biology. Adv Pharm Bull. 2015;5(2):141–9.

Michiels C. Physiological and pathological responses to hypoxia. Am J Pathol. 2004;164(6):1875–82.

Chang EI, Loh SA, Ceradini DJ, Chang EI, Lin SE, Bastidas N, Aarabi S, Chan DA, Freedman ML, Giaccia AJ, et al. Age decreases endothelial progenitor cell recruitment through decreases in hypoxia-inducible factor 1alpha stabilization during ischemia. Circulation. 2007;116(24):2818–29.

Xue C, Shen Y, Li X, Li B, Zhao S, Gu J, Chen Y, Ma B, Wei J, Han Q, et al. Exosomes derived from hypoxia-treated human adipose mesenchymal stem cells enhance angiogenesis through the PKA signaling pathway. Stem Cells Dev. 2018;27(7):456–65.

Han KH, Kim AK, Kim MH, Kim DH, Go HN, Kang D, Chang JW, Choi SW, Kang KS, Kim DI. Protein profiling and angiogenic effect of hypoxia-cultured human umbilical cord blood-derived mesenchymal stem cells in hindlimb ischemia. Tissue Cell. 2017;49(6):680–90.

Liu J, Hao H, Xia L, Ti D, Huang H, Dong L, Tong C, Hou Q, Zhao Y, Liu H, et al. Hypoxia pretreatment of bone marrow mesenchymal stem cells facilitates angiogenesis by improving the function of endothelial cells in diabetic rats with lower ischemia. PLoS One. 2015;10(5):e0126715.

Thebaud B, Ladha F, Michelakis ED, Sawicka M, Thurston G, Eaton F, Hashimoto K, Harry G, Haromy A, Korbutt G, et al. Vascular endothelial growth factor gene therapy increases survival, promotes lung angiogenesis, and prevents alveolar damage in hyperoxia-induced lung injury: evidence that angiogenesis participates in alveolarization. Circulation. 2005;112(16):2477–86.

Yang Y, Hu S, Xu X, Li J, Liu A, Han J, Liu S, Liu L, Qiu H. The vascular endothelial growth factors-expressing character of mesenchymal stem cells plays a positive role in treatment of acute lung injury in vivo. Mediat Inflamm. 2016;2016:2347938.

Huang ZW, Liu N, Li D, Zhang HY, Wang Y, Liu Y, Zhang LL, Ju XL. Angiopoietin-1 modified human umbilical cord mesenchymal stem cell therapy for endotoxin-induced acute lung injury in rats. Yonsei Med J. 2017;58(1):206–16.

McCarter SD, Mei SH, Lai PF, Zhang QW, Parker CH, Suen RS, Hood RD, Zhao YD, Deng Y, Han RN, et al. Cell-based angiopoietin-1 gene therapy for acute lung injury. Am J Respir Crit Care Med. 2007;175(10):1014–26.

Luan ZG, Zhang XJ, Yin XH, Ma XC, Zhang H, Zhang C, Guo RX. Downregulation of HMGB1 protects against the development of acute lung injury after severe acute pancreatitis. Immunobiology. 2013;218(10):1261–70.

Zhang X, Luan Z, Liang Y, Liu Y, Ma X. Downregulation of high mobility group box 1 attenuates the severity of acute lung injury in endotoxemic mice. Mol Med Rep. 2015;11(6):4513–7.

Allen TC, Kurdowska A. Interleukin 8 and acute lung injury. Arch Pathol Lab Med. 2014;138(2):266–9.

Chada M, Nogel S, Schmidt AM, Ruckel A, Bosselmann S, Walther J, Papadopoulos T, von der Hardt K, Dotsch J, Rascher W, et al. Anakinra (IL-1R antagonist) lowers pulmonary artery pressure in a neonatal surfactant depleted piglet model. Pediatr Pulmonol. 2008;43(9):851–7.

Liu XW, Ma T, Cai Q, Wang L, Song HW, Liu Z. Elevation of serum PARK7 and IL-8 levels is associated with acute lung injury in patients with severe sepsis/septic shock. J Intensive Care Med. 2017;885066617709689.

Miller EJ, Cohen AB, Nagao S, Griffith D, Maunder RJ, Martin TR, Weiner-Kronish JP, Sticherling M, Christophers E, Matthay MA. Elevated levels of NAP-1/interleukin-8 are present in the airspaces of patients with the adult respiratory distress syndrome and are associated with increased mortality. Am Rev Respir Dis. 1992;146(2):427–32.

Kurdowska AK, Geiser TK, Alden SM, Dziadek BR, Noble JM, Nuckton TJ, Matthay MA. Activity of pulmonary edema fluid interleukin-8 bound to alpha(2)-macroglobulin in patients with acute lung injury. Am J Physiol Lung Cell Mol Physiol. 2002;282(5):L1092–8.

Bustos ML, Huleihel L, Meyer EM, Donnenberg AD, Donnenberg VS, Sciurba JD, Mroz L, McVerry BJ, Ellis BM, Kaminski N, et al. Activation of human mesenchymal stem cells impacts their therapeutic abilities in lung injury by increasing interleukin (IL)-10 and IL-1RN levels. Stem Cells Transl Med. 2013;2(11):884–95.

Parsons PE, Moss M, Vannice JL, Moore EE, Moore FA, Repine JE. Circulating IL-1ra and IL-10 levels are increased but do not predict the development of acute respiratory distress syndrome in at-risk patients. Am J Respir Crit Care Med. 1997;155(4):1469–73.

Rosler B, Herold S. Lung epithelial GM-CSF improves host defense function and epithelial repair in influenza virus pneumonia-a new therapeutic strategy? Mole Cell Pediatr. 2016;3(1):29.

Overgaard CE, Schlingmann B, Dorsainvil White S, Ward C, Fan X, Swarnakar S, Brown LA, Guidot DM, Koval M. The relative balance of GM-CSF and TGF-beta1 regulates lung epithelial barrier function. Am J Physiol Lung Cell Mol Physiol. 2015;308(12):L1212–23.

Swaroopa D, Bhaskar K, Mahathi T, Katkam S, Raju YS, Chandra N, Kutala VK. Association of serum interleukin-6, interleukin-8, and Acute Physiology and Chronic Health Evaluation II score with clinical outcome in patients with acute respiratory distress syndrome. Indian J Crit Care Med. 2016;20(9):518–25.

Aisiku IP, Yamal JM, Doshi P, Benoit JS, Gopinath S, Goodman JC, Robertson CS. Plasma cytokines IL-6, IL-8, and IL-10 are associated with the development of acute respiratory distress syndrome in patients with severe traumatic brain injury. Crit Care (London, England). 2016;20:288.

Ware LB, Koyama T, Billheimer DD, Wu W, Bernard GR, Thompson BT, Brower RG, Standiford TJ, Martin TR, Matthay MA. Prognostic and pathogenetic value of combining clinical and biochemical indices in patients with acute lung injury. Chest. 2010;137(2):288–96.