Umbilical Cord Mesenchymal Stem Cells Conditioned Medium Promotes Aβ25-35 phagocytosis by Modulating Autophagy and Aβ-Degrading Enzymes in BV2 Cells
Mesenchymal stem cell (MSC) therapy is a promising prospect for the treatment of Alzheimer’s disease (AD); however, the underlying mechanisms by which MSCs mediate positive effects are still unclear. We speculated that MSCs mediate microglial autophagy and enhance the clearance of Aβ. To test this hypothesis, we cultured BV2 microglial cells with umbilical cord mesenchymal stem cells conditioned medium (ucMSCs-CM) in the presence or absence of Aβ25–35 oligomers. We investigated BV2 cell proliferation, cell death, and Aβ25–35 phagocytosis as well as protein expression levels of LC3, Beclin-1, p62, insulin-degrading enzyme (IDE), and neprilysin (Nep) with western blotting. The results showed that ucMSCs-CM inhibited the proliferation and decreased cell death of BV2 cells induced by Aβ25–35. ucMSCs-CM also promoted the phagocytosis of Aβ25–35 by BV2 cells and changed the expression of autophagy-related proteins LC3, Beclin-1, and p62. Treatment also upregulated the expression of Aβ-degrading enzymes IDE and Nep. Furthermore, the culture medium in BV2 cells with Aβ25–35 and ucMSCs-CM prevented neuronal cell SH-SY5Y from cell death compared to control medium without ucMSCs-CM. Altogether, these data suggested that ucMSCs-CM protect microglial and neuronal cells from Aβ25–35-induced cell death and promote Aβ phagocytosis by modulating autophagy and enhancing the expression of Aβ-degrading enzymes in microglia.
KeywordsMesenchymal stem cells Conditioned medium Microglia Aβ Autophagy
We would like to thank Editage [www.editage.cn] for English language editing. This study was supported by the Doctoral Research Start-up Fund of Xinxiang Medical University, Scientific Research Fund of Xinxiang Medical University (2013QN122), Postdoctoral Research Fund of Henan Province (2013041), Project of Science and Technology Department of Henan Province (162102310493), Key Project of Science and Technology Research of Henan Provincial Education Department (14B180027), National Natural Science Foundation of China (131600791, 81771226), Xinxiang City Foundation (CXRC16003 and ZD17008), Xinxiang Medical University Foundation (20172DCG-03), and National Training Program of Innovation and Entrepreneurship for Undergraduates of China (201610472051).
Compliance with Ethical Standards
Disclosure of Potential Conflicts of Interest
All authors have no conflict of interest to declare.
- Alzheimer's Disease International (2016) World Alzheimer Report. Alzheimer's Disease International, LondonGoogle Scholar
- Cantinieaux D, Quertainmont R, Blacher S, Rossi L, Wanet T, Noel A, Brook G, Schoenen J, Franzen R (2013) Conditioned medium from bone marrow-derived mesenchymal stem cells improves recovery after spinal cord injury in rats: an original strategy to avoid cell transplantation. PLoS One 8(8):e69515CrossRefPubMedCentralGoogle Scholar
- Cui Y, Ma S, Zhang C, Cao W, Liu M, Li D, Lv P, Xing Q, Qu R, Yao N, Yang B, Guan F (2017) Human umbilical cord mesenchymal stem cells transplantation improves cognitive function in Alzheimer's disease mice by decreasing oxidative stress and promoting hippocampal neurogenesis. Behav Brain Res 320:291–301CrossRefGoogle Scholar
- Frenkel D, Wilkinson K, Zhao L, Hickman SE, Means TK, Puckett L, Farfara D, Kingery ND, Weiner HL, El Khoury J (2013) Scara1 deficiency impairs clearance of soluble amyloid-beta by mononuclear phagocytes and accelerates Alzheimer's-like disease progression. Nat Commun 4:2030CrossRefPubMedCentralGoogle Scholar
- Godoy MA, Saraiva LM, Carvalho LRP, Vasconcelos-Dos-Santos A, Beiral HJV, Ramos AB, Silva LRP, Leal RB, Monteiro VHS, Braga CV, Araujo-Silva CA, Sinis LC, Santos VB, Brunswick THK, Alcantara CL, Lima A, Cunha ESNLD, Galina A, Vieyra A, De Felice FG, Mendez-Otero R, Ferreira ST (2017) Mesenchymal stem cells and cell-derived extracellular vesicles protect hippocampal neurons from oxidative stress and synapse damage induced by amyloid-beta oligomers. J Biol Chem 293(6):1957–1975CrossRefGoogle Scholar
- Janssen L, Dubbelaar ML, Holtman IR, de Boer-Bergsma J, Eggen BJ, Boddeke HW, De Deyn PP, Van Dam D (2017) Aging, microglia and cytoskeletal regulation are key factors in the pathological evolution of the APP23 mouse model for Alzheimer's disease. Biochim Biophys Acta 1863(2):395–405CrossRefGoogle Scholar
- Khabbal J, Kerkela E, Mitkari B, Raki M, Nystedt J, Mikkonen V, Bergstrom K, Laitinen S, Korhonen M, Jolkkonen J (2015) Differential clearance of rat and human bone marrow-derived mesenchymal stem cells from the brain after intra-arterial infusion in rats. Cell Transplant 24(5):819–828CrossRefGoogle Scholar
- Kim DH, Lee D, Chang EH, Kim JH, Hwang JW, Kim JY, Kyung JW, Kim SH, Oh JS, Shim SM, Na DL, Oh W, Chang JW (2015) GDF-15 secreted from human umbilical cord blood mesenchymal stem cells delivered through the cerebrospinal fluid promotes hippocampal neurogenesis and synaptic activity in an Alzheimer's disease model. Stem Cells Dev 24(20):2378–2390CrossRefPubMedCentralGoogle Scholar
- Kim JY, Kim DH, Kim JH, Lee D, Jeon HB, Kwon SJ, Kim SM, Yoo YJ, Lee EH, Choi SJ, Seo SW, Lee JI, Na DL, Yang YS, Oh W, Chang JW (2012) Soluble intracellular adhesion molecule-1 secreted by human umbilical cord blood-derived mesenchymal stem cell reduces amyloid-beta plaques. Cell Death Differ 19(4):680–691CrossRefGoogle Scholar
- Mallard C, Tremblay ME, Vexler ZS (2018) Microglia and neonatal brain injury. Neuroscience Jan 17 [Epub ahead of print]Google Scholar
- Menzies FM, Fleming A, Caricasole A, Bento CF, Andrews SP, Ashkenazi A, Fullgrabe J, Jackson A, Jimenez Sanchez M, Karabiyik C, Licitra F, Lopez Ramirez A, Pavel M, Puri C, Renna M, Ricketts T, Schlotawa L, Vicinanza M, Won H, Zhu Y, Skidmore J, Rubinsztein DC (2017) Autophagy and neurodegeneration: pathogenic mechanisms and therapeutic opportunities. Neuron 93(5):1015–1034CrossRefGoogle Scholar
- Plaza-Zabala A, Sierra-Torre V, Sierra A (2017) Autophagy and microglia: novel partners in neurodegeneration and aging. Int J Mol Sci 18(3):598Google Scholar
- Sun W, Xu Z, Liu R, Yuan Z, Feng H (2013) Comparison of different fetal bovine serums in cultivation of human umbilical cord stroma-derived mesenchymal stem cells. J Xinxiang Med Univ 30(10):787–789,793Google Scholar
- Yang DS, Stavrides P, Mohan PS, Kaushik S, Kumar A, Ohno M, Schmidt SD, Wesson D, Bandyopadhyay U, Jiang Y, Pawlik M, Peterhoff CM, Yang AJ, Wilson DA, St George-Hyslop P, Westaway D, Mathews PM, Levy E, Cuervo AM, Nixon RA (2011) Reversal of autophagy dysfunction in the TgCRND8 mouse model of Alzheimer's disease ameliorates amyloid pathologies and memory deficits. Brain 134(Pt 1):258–277CrossRefGoogle Scholar