Cell-based therapy in Alzheimer's disease: Current knowledge and perspective
Liyan Qiao1, Hongyun Huang2,3, Lin Chen4
1 Department of Neurology, Tsinghua University Yuquan Hospital, Beijing 100040, China;
2 Institute of Neurorestoratology, General Hospital of Armed Police Forces, Beijing 100039, China;
3 Beijing Hongtianji Neuroscience Academy, Lingxiu Building, Beijing 100043, China;
4 Department of Neurosurgery, Tsinghua University Yuquan Hospital, Beijing 100040, China
Cell-based therapy in Alzheimer's disease: Current knowledge and perspective
Liyan Qiao1, Hongyun Huang2,3, Lin Chen4
1 Department of Neurology, Tsinghua University Yuquan Hospital, Beijing 100040, China;
2 Institute of Neurorestoratology, General Hospital of Armed Police Forces, Beijing 100039, China;
3 Beijing Hongtianji Neuroscience Academy, Lingxiu Building, Beijing 100043, China;
4 Department of Neurosurgery, Tsinghua University Yuquan Hospital, Beijing 100040, China
摘要 Alzheimer's disease (AD) is the most prevalent type of dementia, and its neuropathology is characterized by the deposition of insoluble β-amyloid (Aβ) peptides, intracellular neurofibrillary tangles, amyloid angiopathy, age-related brain atrophy, synaptic pathology, white matter rarefaction, granulovacuolar degeneration, neuron loss, and neuroinflammation. Although much is known about the neurobiology of AD, very few conventional therapies are available to arrest or slow the disease. There is an urgent need for novel therapeutic approaches for AD. AD subjects have significantly fewer viable precursor cells in the hippocampus compared with age-matched healthy control subjects. However, the viable precursor cells that remain in AD and age-matched healthy control brain specimens can be induced to differentiate. To facilitate or mimic the natural compensatory effect in AD, cell therapy, including endogenous and exogenous stem cells, has been considered in AD. In this review, we focus on the history and development of cell therapy in AD, and consider the role of cell therapy as a potential treatment for AD.
Abstract: Alzheimer's disease (AD) is the most prevalent type of dementia, and its neuropathology is characterized by the deposition of insoluble β-amyloid (Aβ) peptides, intracellular neurofibrillary tangles, amyloid angiopathy, age-related brain atrophy, synaptic pathology, white matter rarefaction, granulovacuolar degeneration, neuron loss, and neuroinflammation. Although much is known about the neurobiology of AD, very few conventional therapies are available to arrest or slow the disease. There is an urgent need for novel therapeutic approaches for AD. AD subjects have significantly fewer viable precursor cells in the hippocampus compared with age-matched healthy control subjects. However, the viable precursor cells that remain in AD and age-matched healthy control brain specimens can be induced to differentiate. To facilitate or mimic the natural compensatory effect in AD, cell therapy, including endogenous and exogenous stem cells, has been considered in AD. In this review, we focus on the history and development of cell therapy in AD, and consider the role of cell therapy as a potential treatment for AD.
Liyan Qiao, Hongyun Huang, Lin Chen. Cell-based therapy in Alzheimer's disease: Current knowledge and perspective[J]. 临床转化神经科学, 2016, 2(1): 50-58.
Liyan Qiao, Hongyun Huang, Lin Chen. Cell-based therapy in Alzheimer's disease: Current knowledge and perspective. Translational Neuroscience and Clinics, 2016, 2(1): 50-58.
[1] Alzheimer's Association. 2015 Alzheimer's disease facts and figures. Alzheimers Dement 2015, 11(3): 332-384.
[2] Drachman DA. The amyloid hypothesis, time to move on: Amyloid is the downstream result, not cause, of Alzheimer's disease. Alzheimers Dement 2014, 10(3): 372-380.
[3] Hyman BT, Phelps CH, Beach TG, Bigio EH, Cairns NJ, Carrillo MC, Dickson DW, Duyckaerts C, Frosch MP, Masliah E, et al. National Institute on Aging-Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease. Alzheimers Dement 2012, 8(1): 1-13.
[4] Nelson PT, Alafuzoff I, Bigio EH, Bouras C, Braak H, Cairns NJ, Castellani RJ, Crain BJ, Davies P, Del Tredici K, et al. Correlation of Alzheimer disease neuropathologic changes with cognitive status: A review of the literature. J Neuropathol Exp Neurol 2012, 71(5): 362-381.
[5] Parsons CG, Danysz W, Dekundy A, Pulte I. Memantine and cholinesterase inhibitors: Complementary mechanisms in the treatment of Alzheimer's disease. Neurotox Res 2013, 24(3): 358-369.
[6] Muoio V, Persson PB, Sendeski MM. The neurovascular unitconcept review. Acta Physiol (Oxf) 2014, 210(4): 790-798.
[7] Baloyannis SJ, Baloyannis IS. The vascular factor in Alzheimer's disease: A study in Golgi technique and electron microscopy. J Neurol Sci 2012, 322(1-2): 117-121.
[8] Bell RD, Zlokovic BV. Neurovascular mechanisms and blood-brain barrier disorder in Alzheimer's disease. Acta Neuropathol 2009, 118(1): 103-113.
[9] Terry AV Jr., Buccafusco JJ. The cholinergic hypothesis of age and Alzheimer's disease-related cognitive deficits: Recent challenges and their implications for novel drug development. J Pharmacol Exp Ther 2003, 306(3): 821-827.
[10] Altman J. Are new neurons formed in the brains of adult mammals? Science 1962, 135(3509): 1127-1128.
[11] Altman J. Autoradiographic investigation of cell proliferation in the brains of rats and cats. Anat Rec 1963, 145: 573-591.
[12] Altman J, Das GD. Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats. J Comp Neurol 1965, 124(3): 319-335.
[13] Altman J. Autoradiographic and histological studies of postnatal neurogenesis. IV. Cell proliferation and migration in the anterior forebrain, with special reference to persisting neurogenesis in the olfactory bulb. J Comp Neurol 1969, 137(4): 433-457.
[14] Eriksson PS, Perfilieva E, Bjork-Eriksson T, Alborn AM, Nordborg C, Peterson DA, Gage FH. Neurogenesis in the adult human hippocampus. Nat Med 1998, 4(11): 1313-1317.
[15] Lovell MA, Geiger H, Van Zant GE, Lynn BC, Markesbery WR. Isolation of neural precursor cells from Alzheimer's disease and aged control postmortem brain. Neurobiol Aging 2006, 27(7): 909-917.
[16] Kakimura J, Kitamura Y, Takata K, Umeki M, Suzuki S, Shibagaki K, Taniguchi T, Nomura Y, Gebicke-Haerter PJ, Smith MA, et al. Microglial activation and amyloid-beta clearance induced by exogenous heat-shock proteins. FASEB J 2002, 16(6): 601-603.
[17] Koren J, 3rd, Jinwal UK, Lee DC, Jones JR, Shults CL, Johnson AG, Anderson LJ, Dickey CA. Chaperone signalling complexes in Alzheimer's disease. J Cell Mol Med 2009, 13(4): 619-630.
[18] Choi SS, Lee SR, Kim SU, Lee HJ. Alzheimer's disease and stem cell therapy. Exp Neurobiol 2014, 23(1): 45-52.
[19] Wilhelmus MM, de Waal RM, Verbeek MM. Heat shock proteins and amateur chaperones in amyloid-Beta accumulation and clearance in Alzheimer's disease. Mol Neurobiol 2007, 35(3): 203-216.
[20] Sahara N, Murayama M, Mizoroki T, Urushitani M, Imai Y, Takahashi R, Murata S, Tanaka K, Takashima A. In vivo evidence of CHIP up-regulation attenuating tau aggregation. J Neurochem 2005, 94(5): 1254-1263.
[21] Jinwal UK, O'Leary JC, Borysov SI, Jones JR, Li Q, Koren J, Abisambra JF, Vestal GD, Lawson LY, Johnson AG, Blair LJ, Jin Y, Miyata Y, Gestwicki JE, Dickey CA. Hsc70 rapidly engages tau after microtubule destabilization. J Biol Chem 2010, 285(22): 16798-16805.
[22] Ridwan S, Bauer H, Frauenknecht K, Hefti K, von Pein H, Sommer CJ. Distribution of the hematopoietic growth factor G-CSF and its receptor in the adult human brain with specific reference to Alzheimer's disease. J Anat 2014, 224(4): 377-391.
[23] Prakash A, Medhi B, Chopra K. Granulocyte colony stimulating factor (GCSF) improves memory and neurobehavior in an amyloid-beta induced experimental model of Alzheimer's disease. Pharmacol Biochem Behav 2013, 110: 46-57.
[24] Tsai KJ, Tsai YC, Shen CK. G-CSF rescues the memory impairment of animal models of Alzheimer's disease. J Exp Med 2007, 204(6): 1273-1280.
[25] Sanchez-Ramos J, Song S, Sava V, Catlow B, Lin X, Mori T, Cao C, Arendash GW. Granulocyte colony stimulating factor decreases brain amyloid burden and reverses cognitive impairment in Alzheimer's mice. Neuroscience 2009, 163(1): 55-72.
[26] Shin JW, Lee JK, Lee JE, Min WK, Schuchman EH, Jin HK, Bae JS. Combined effects of hematopoietic progenitor cell mobilization from bone marrow by granulocyte colony stimulating factor and AMD3100 and chemotaxis into the brain using stromal cell-derived factor-1alpha in an Alzheimer's disease mouse model. Stem Cells 2011, 29(7): 1075-1089.
[27] Parthsarathy V, Holscher C. Chronic treatment with the GLP1 analogue liraglutide increases cell proliferation and differentiation into neurons in an AD mouse model. PLoS One 2013, 8(3): e58784.
[28] Chang KA, Kim JA, Kim S, Joo Y, Shin KY, Kim HS, Suh YH. Therapeutic potentials of neural stem cells treated with fluoxetine in Alzheimer's disease. Neurochem Int 2012, 61(6): 885-891.
[29] Chadwick W, Mitchell N, Caroll J, Zhou Y, Park SS, Wang L, Becker KG, Zhang Y, Lehrmann E, Wood WH, Martin B, Maudsley S. Amitriptyline-mediated cognitive enhancement in aged 3xTg Alzheimer's disease mice is associated with neurogenesis and neurotrophic activity. PLoS One 2011, 6(6): e21660.
[30] Kakio A, Nishimoto SI, Yanagisawa K, Kozutsumi Y, Matsuzaki K. Cholesterol-dependent formation of GM1 ganglioside-bound amyloid beta-protein, an endogenous seed for Alzheimer amyloid. J Biol Chem 2001, 276(27): 24985-24990.
[31] Moghadam FH, Alaie H, Karbalaie K, Tanhaei S, Nasr Esfahani MH, Baharvand H. Transplantation of primed or unprimed mouse embryonic stem cell-derived neural precursor cells improves cognitive function in Alzheimerian rats. Differentiation 2009, 78(2-3): 59-68.
[32] Friedenstein AJ, Chailakhyan RK, Latsinik NV, Panasyuk AF, Keiliss-Borok IV. Stromal cells responsible for transferring the microenvironment of the hemopoietic tissues. Cloning in vitro and retransplantation in vivo. Transplantation 1974, 17(4): 331-340.
[33] Oh SH, Kim HN, Park HJ, Shin JY, Lee PH. Mesenchymal stem cells increase hippocampal neurogenesis and neuronal differentiation by enhancing the wnt signaling pathway in an Alzheimer's disease model. Cell Transplant 2015, 24(6): 1097-1109.
[34] Zilka N, Zilkova M, Kazmerova Z, Sarissky M, Cigankova V, Novak M. Mesenchymal stem cells rescue the Alzheimer's disease cell model from cell death induced by misfolded truncated tau. Neuroscience 2011, 193:330-337.
[35] Khairallah MI, Kassem LA, Yassin NA, El Din MA, Zekri M, Attia M. The hematopoietic growth factor “erythropoietin” enhances the therapeutic effect of mesenchymal stem cells in Alzheimer's disease. Pak J Biol Sci 2014, 17(1): 9-21.
[36] Lee HJ, Lee JK, Lee H, Shin JW, Carter JE, Sakamoto T, Jin HK, Bae JS. The therapeutic potential of human umbilical cord blood-derived mesenchymal stem cells in Alzheimer's disease. Neurosci Lett 2010, 481(1): 30-35.
[37] Shin JY, Park HJ, Kim HN, Oh SH, Bae JS, Ha HJ, Lee PH. Mesenchymal stem cells enhance autophagy and increase betaamyloid clearance in Alzheimer disease models. Autophagy 2014, 10(1): 32-44.
[38] Naaldijk Y, Jager C, Fabian C, Leovsky C, Bluher A, Rudolph L, Hinze A, Stolzing A. Effect of systemic transplantation of bone marrow-derived mesenchymal stem cells on neuropathology markers in APP/PS1 Alzheimer mice. Neuropathol Appl Neurobiol 2016.
[39] Lee JK, Jin HK, Bae JS. Bone marrow-derived mesenchymal stem cells reduce brain amyloid-beta deposition and accelerate the activation of microglia in an acutely induced Alzheimer's disease mouse model. Neurosci Lett 2009, 450(2): 136-141.
[40] Bae JS, Jin HK, Lee JK, Richardson JC, Carter JE. Bone marrow-derived mesenchymal stem cells contribute to the reduction of amyloid-beta deposits and the improvement of synaptic transmission in a mouse model of pre-dementia Alzheimer's disease. Curr Alzheimer Res 2013, 10(5): 524- 531.
[41] Park D, Yang G, Bae DK, Lee SH, Yang YH, Kyung J, Kim D, Choi EK, Choi KC, Kim SU, Kang SK, Ra JC, Kim YB. Human adipose tissue-derived mesenchymal stem cells improve cognitive function and physical activity in ageing mice. J Neurosci Res 2013, 91(5): 660-670.
[42] Kim S, Chang KA, Kim J, Park HG, Ra JC, Kim HS, Suh YH. The preventive and therapeutic effects of intravenous human adipose-derived stem cells in Alzheimer's disease mice. PLoS One 2012, 7(9): e45757.
[43] Diaz-Moreno M, Hortiguela R, Goncalves A, Garcia-Carpio I, Manich G, Garcia-Bermudez E, Moreno-Estelles M, Eguiluz C, Vilaplana J, Pelegri C, Vilar M, Mira H. Abeta increases neural stem cell activity in senescence-accelerated SAMP8 mice. Neurobiol Aging 2013, 34(11): 2623-2638.
[44] Yamasaki TR, Blurton-Jones M, Morrissette DA, Kitazawa M, Oddo S, LaFerla FM. Neural stem cells improve memory in an inducible mouse model of neuronal loss. J Neurosci 2007, 27(44): 11925-11933.
[45] Ryu JK, Cho T, Wang YT, McLarnon JG. Neural progenitor cells attenuate inflammatory reactivity and neuronal loss in an animal model of inflamed AD brain. J Neuroinflammation 2009, 6: 39.
[46] Zhang W, Wang PJ, Sha HY, Ni J, Li MH, Gu GJ. Neural stem cell transplants improve cognitive function without altering amyloid pathology in an APP/PS1 double transgenic model of Alzheimer's disease. Mol Neurobiol 2014, 50(2): 423-437.
[47] Blurton-Jones M, Kitazawa M, Martinez-Coria H, Castello NA, Muller FJ, Loring JF, Yamasaki TR, Poon WW, Green KN, LaFerla FM. Neural stem cells improve cognition via BDNF in a transgenic model of Alzheimer disease. Proc Natl Acad Sci USA 2009, 106(32): 13594-13599.
[48] Xuan AG, Long DH, Gu HG, Yang DD, Hong LP, Leng SL. BDNF improves the effects of neural stem cells on the rat model of Alzheimer's disease with unilateral lesion of fimbria-fornix. Neurosci Lett 2008, 440(3): 331-335.
[49] Xuan AG, Luo M, Ji WD, Long DH. Effects of engrafted neural stem cells in Alzheimer's disease rats. Neurosci Lett 2009, 450(2): 167-171.
[50] Zhang W, Wang PJ, Gu GJ, Li MH, Gao XL. Effects of neural stem cells transplanted into an animal model of Alzheimer disease on Abeta plaques. Zhonghua Yi Xue Za Zhi 2013, 93(45): 3636-3639.
[51] Kern DS, Maclean KN, Jiang H, Synder EY, Sladek JR Jr., Bjugstad KB. Neural stem cells reduce hippocampal tau and reelin accumulation in aged Ts65Dn Down syndrome mice. Cell Transplant 2011, 20(3): 371-379.
[52] Wu S, Sasaki A, Yoshimoto R, Kawahara Y, Manabe T, Kataoka K, Asashima M, Yuge L. Neural stem cells improve learning and memory in rats with Alzheimer's disease. Pathobiology 2008, 75(3): 186-194.
[53] Lee JK, Jin HK, Endo S, Schuchman EH, Carter JE, Bae JS. Intracerebral transplantation of bone marrow-derived mesenchymal stem cells reduces amyloid-beta deposition and rescues memory deficits in Alzheimer's disease mice by modulation of immune responses. Stem Cells 2010, 28(2): 329-343.
[54] Yang H, Xie Z, Wei L, Yang S, Zhu Z, Wang P, Zhao C, Bi J. Human umbilical cord mesenchymal stem cell-derived neuron-like cells rescue memory deficits and reduce amyloidbeta deposition in an AbetaPP/PS1 transgenic mouse model. Stem Cell Res Ther 2013, 4(4):76.
[55] Lee HJ, Lim IJ, Park SW, Kim YB, Ko Y, Kim SU. Human neural stem cells genetically modified to express human nerve growth factor (NGF) gene restore cognition in the mouse with ibotenic acid-induced cognitive dysfunction. Cell Transplant 2012, 21(11): 2487-2496.
[56] Ende N, Chen R, Ende-Harris D. Human umbilical cord blood cells ameliorate Alzheimer's disease in transgenic mice. J Med 2001, 32(3-4): 241-247.
[57] Darlington D, Deng J, Giunta B, Hou H, Sanberg CD, Kuzmin-Nichols N, Zhou HD, Mori T, Ehrhart J, Sanberg PR, Tan J. Multiple low-dose infusions of human umbilical cord blood cells improve cognitive impairments and reduce amyloid-beta-associated neuropathology in Alzheimer mice. Stem Cells Dev 2013, 22(3): 412-421.
[58] Nikolic WV, Hou H, Town T, Zhu Y, Giunta B, Sanberg CD, Zeng J, Luo D, Ehrhart J, Mori T, Sanberg PR, Tan J. Peripherally administered human umbilical cord blood cells reduce parenchymal and vascular beta-amyloid deposits in Alzheimer mice. Stem Cells Dev 2008, 17(3): 423-439.
[59] Kim KS, Kim HS, Park JM, Kim HW, Park MK, Lee HS, Lim DS, Lee TH, Chopp M, Moon J. Long-term immunomodulatory effect of amniotic stem cells in an Alzheimer's disease model. Neurobiol Aging 2013, 34(10): 2408-2420.
[60] Fujiwara N, Shimizu J, Takai K, Arimitsu N, Saito A, Kono T, Umehara T, Ueda Y, Wakisaka S, Suzuki T, Suzuki N. Restoration of spatial memory dysfunction of human APP transgenic mice by transplantation of neuronal precursors derived from human iPS cells. Neurosci Lett 2013, 557 Pt B: 129-134.
[61] Ooi L, Sidhu K, Poljak A, Sutherland G, O'Connor MD, Sachdev P, Munch G. Induced pluripotent stem cells as tools for disease modelling and drug discovery in Alzheimer's disease. J Neural Transm 2013, 120(1): 103-111.
[62] Yagi T, Ito D, Okada Y, Akamatsu W, Nihei Y, Yoshizaki T, Yamanaka S, Okano H, Suzuki N. Modeling familial Alzheimer's disease with induced pluripotent stem cells. Hum Mol Genet 2011, 20(23): 4530-4539.
[63] Demars M, Hu YS, Gadadhar A, Lazarov O. Impaired neurogenesis is an early event in the etiology of familial Alzheimer's disease in transgenic mice. J Neurosci Res 2010, 88(10): 2103-2117.
[64] Rodriguez JJ, Jones VC, Verkhratsky A. Impaired cell proliferation in the subventricular zone in an Alzheimer's disease model. Neuroreport 2009, 20(10): 907-912.
[65] Haughey NJ, Nath A, Chan SL, Borchard AC, Rao MS, Mattson MP. Disruption of neurogenesis by amyloid betapeptide, and perturbed neural progenitor cell homeostasis, in models of Alzheimer's disease. J Neurochem 2002, 83(6): 1509-1524.
[66] Hayashi Y, Kashiwagi K, Ohta J, Nakajima M, Kawashima T, Yoshikawa K. Alzheimer amyloid protein precursor enhances proliferation of neural stem cells from fetal rat brain. Biochem Biophys Res Commun 1994, 205(1): 936-943.
[67] Chevallier NL, Soriano S, Kang DE, Masliah E, Hu G, Koo EH. Perturbed neurogenesis in the adult hippocampus associated with presenilin-1 A246E mutation. Am J Pathol 2005, 167(1): 151-159.
[68] Wen PH, Shao X, Shao ZP, Hof PR, Wisniewski T, Kelley K, Friedrich Jr. VL, Ho L, Pasinetti GM, Shioi JC, Robakisa NK, Eldera GA. Overexpression of wild type but not an FAD mutant presenilin-1 promotes neurogenesis in the hippocampus of adult mice. Neurobiol Dis 2002, 10(1): 8-19.
[69] Zhang X, Jin G, Tian M, Qin J, Huang Z. The denervated hippocampus provides proper microenvironment for the survival and differentiation of neural progenitors. Neurosci Lett 2007, 414(2): 115-120.
[70] Kuhn HG, Dickinson-Anson H, Gage FH. Neurogenesis in the dentate gyrus of the adult rat: age-related decrease of neuronal progenitor proliferation. J Neurosci 1996, 16(6): 2027-2033.
[71] Zhang Q, Wu HH, Wang Y, Gu GJ, Zhang W, Xia R. Neural stem cell transplantation decreases neuroinflammation in a transgenic mouse model of Alzheimer's disease. J Neurochem 2015.
[72] Ager RR, Davis JL, Agazaryan A, Benavente F, Poon WW, LaFerla FM, Blurton-Jones M. Human neural stem cells improve cognition and promote synaptic growth in two complementary transgenic models of Alzheimer's disease and neuronal loss. Hippocampus 2015, 25(7): 813-826.
[73] Lee JK, Jin HK, Bae JS. Bone marrow-derived mesenchymal stem cells attenuate amyloid beta-induced memory impairment and apoptosis by inhibiting neuronal cell death. Curr Alzheimer Res 2010, 7(6): 540-548.
[74] Laxton AW, Tang-Wai DF, McAndrews MP, Zumsteg D, Wennberg R, Keren R, Wherrett J, Naglie G, Hamani C, Smith GS, Lozano AM. A phase I trial of deep brain stimulation of memory circuits in Alzheimer's disease. Ann Neurol 2010, 68(4): 521-534.
[75] Calissano P, Matrone C, Amadoro G. Nerve growth factor as a paradigm of neurotrophins related to Alzheimer's disease. Dev Neurobiol 2010, 70(5): 372-383.
[76] Lee IS, Jung K, Kim IS, Lee H, Kim M, Yun S, Hwang K, Shin JE, Park KI. Human neural stem cells alleviate Alzheimer-like pathology in a mouse model. Mol Neurodegener 2015, 10: 38.
[77] Lilja AM, Malmsten L, Rojdner J, Voytenko L, Verkhratsky A, Ogren SO, Nordberg A, Marutle A. Neural stem cell transplant-induced effect on neurogenesis and cognition in Alzheimer Tg2576 mice is inhibited by concomitant treatment with amyloid-lowering or cholinergic alpha7 nicotinic receptor drugs. Neural Plast 2015, 2015: 370432.
[78] Kim JA, Ha S, Shin KY, Kim S, Lee KJ, Chong YH, Chang KA, Suh YH. Neural stem cell transplantation at critical period improves learning and memory through restoring synaptic impairment in Alzheimer's disease mouse model. Cell Death Dis 2015, 6: e1789.
[79] Tarczyluk MA, Nagel DA, Rhein Parri H, Tse EH, Brown JE, Coleman MD, Hill EJ. Amyloid beta 1-42 induces hypometabolism in human stem cell-derived neuron and astrocyte networks. J Cereb Blood Flow Metab 2015, 35(8): 1348-1357.
[80] Burke J, Kolhe R, Hunter M, Isales C, Hamrick M, Fulzele S. Stem cell-derived exosomes: A potential alternative therapeutic agent in orthopaedics. Stem Cells Int 2016, 2016:5802529.
[81] Zhang B, Yeo RW, Tan KH, Lim SK. Focus on extracellular vesicles: Therapeutic potential of stem cell-derived extracellular vesicles. Int J Mol Sci 2016, 17(2): 174.
2016, Vol. 2 
