Ye Ran1, Yankai Dong2,3, Yuejiao Li2,3, Jundong Xie2,4, Shubin Zeng2,4, Chuanlei Liang2,4, Wei Dai1, Wenjing Tang1, Yaojiong Wu5,6, Shengyuan Yu7. 1. Department of Neurology, The Chinese PLA General Hospital, Medical School of Chinese PLA, Beijing, 100853, China. 2. State Key Laboratory of Chemical Oncogenomics, Shenzhen Key Laboratory of Health Sciences and Technology, Institute of Biopharmaceutical and Health Engineering (iBHE), Shenzhen International Graduate School, Tsinghua University, Shenzhen, 518055, China. 3. School of Life Sciences, Tsinghua University, Beijing, 100084, China. 4. Tsinghua-Berkeley Shenzhen Institute (TBSI), Tsinghua University, Shenzhen, 518055, China. 5. State Key Laboratory of Chemical Oncogenomics, Shenzhen Key Laboratory of Health Sciences and Technology, Institute of Biopharmaceutical and Health Engineering (iBHE), Shenzhen International Graduate School, Tsinghua University, Shenzhen, 518055, China. wu.yaojiong@sz.tsinghua.edu.cn. 6. Tsinghua-Berkeley Shenzhen Institute (TBSI), Tsinghua University, Shenzhen, 518055, China. wu.yaojiong@sz.tsinghua.edu.cn. 7. Department of Neurology, The Chinese PLA General Hospital, Medical School of Chinese PLA, Beijing, 100853, China. yusy1963@126.com.
Abstract
BACKGROUND: Mesenchymal stem cells (MSCs) have shown immense therapeutic potential for various brain diseases. Intrathecal administration of MSCs may enhance their recruitment to lesions in the central nervous system, but any impact on cerebrospinal fluid (CSF) flow remains unclear. METHODS: Rats with or without middle cerebral artery occlusion (MCAO) received intrathecal injections of 2D cultured MSCs, 3D cultured MSCs or an equal volume of artificial cerebrospinal fluid (ACSF). Ventricle volume was assessed by MRI on Days 2 and 14 post-MCAO surgery. A beam walking test was used to assess fine motor coordination and balance. Aggregation of MSCs was evaluated in CSF and frozen brain tissue. Differential expression of cell adhesion molecules was evaluated by RNA-Seq, flow cytometry and immunofluorescence analyses. The influence of VCAM-1 blockade in mediating the aggregation of 2D MSCs was investigated in vitro by counting cells that passed through a strainer and in vivo by evaluating ventricular dilation. RESULTS: MSC expanded in 2D culture formed aggregates in the CSF and caused ventricular enlargement in both MCAO and normal rats. Aggregates were associated with impaired motor function. 2D MSCs expressed higher levels of integrin α4 and VCAM-1 than 3D MSCs. Blockade of VCAM-1 in 2D MSCs reduced their aggregation in vitro and reduced lateral ventricular enlargement after intrathecal infusion. 3D MSCs exhibited lower cell aggregation and reduced cerebral ventricular dilation after intrathecal transplantation CONCLUSIONS: The aggregation of 2D MSCs, mediated by the interaction of integrin α4 and VCAM-1, is a potential risk for obstruction of CSF flow after intrathecal transplantation.
BACKGROUND: Mesenchymal stem cells (MSCs) have shown immense therapeutic potential for various brain diseases. Intrathecal administration of MSCs may enhance their recruitment to lesions in the central nervous system, but any impact on cerebrospinal fluid (CSF) flow remains unclear. METHODS: Rats with or without middle cerebral artery occlusion (MCAO) received intrathecal injections of 2D cultured MSCs, 3D cultured MSCs or an equal volume of artificial cerebrospinal fluid (ACSF). Ventricle volume was assessed by MRI on Days 2 and 14 post-MCAO surgery. A beam walking test was used to assess fine motor coordination and balance. Aggregation of MSCs was evaluated in CSF and frozen brain tissue. Differential expression of cell adhesion molecules was evaluated by RNA-Seq, flow cytometry and immunofluorescence analyses. The influence of VCAM-1 blockade in mediating the aggregation of 2D MSCs was investigated in vitro by counting cells that passed through a strainer and in vivo by evaluating ventricular dilation. RESULTS: MSC expanded in 2D culture formed aggregates in the CSF and caused ventricular enlargement in both MCAO and normal rats. Aggregates were associated with impaired motor function. 2D MSCs expressed higher levels of integrin α4 and VCAM-1 than 3D MSCs. Blockade of VCAM-1 in 2D MSCs reduced their aggregation in vitro and reduced lateral ventricular enlargement after intrathecal infusion. 3D MSCs exhibited lower cell aggregation and reduced cerebral ventricular dilation after intrathecal transplantation CONCLUSIONS: The aggregation of 2D MSCs, mediated by the interaction of integrin α4 and VCAM-1, is a potential risk for obstruction of CSF flow after intrathecal transplantation.
Authors: Valery L Feigin; Grant Nguyen; Kelly Cercy; Catherine O Johnson; Tahiya Alam; Priyakumari G Parmar; Amanuel A Abajobir; Kalkidan H Abate; Foad Abd-Allah; Ayenew N Abejie; Gebre Y Abyu; Zanfina Ademi; Gina Agarwal; Muktar B Ahmed; Rufus O Akinyemi; Rajaa Al-Raddadi; Leopold N Aminde; Catherine Amlie-Lefond; Hossein Ansari; Hamid Asayesh; Solomon W Asgedom; Tesfay M Atey; Henok T Ayele; Maciej Banach; Amitava Banerjee; Aleksandra Barac; Suzanne L Barker-Collo; Till Bärnighausen; Lars Barregard; Sanjay Basu; Neeraj Bedi; Masoud Behzadifar; Yannick Béjot; Derrick A Bennett; Isabela M Bensenor; Derbew F Berhe; Dube J Boneya; Michael Brainin; Ismael R Campos-Nonato; Valeria Caso; Carlos A Castañeda-Orjuela; Jacquelin C Rivas; Ferrán Catalá-López; Hanne Christensen; Michael H Criqui; Albertino Damasceno; Lalit Dandona; Rakhi Dandona; Kairat Davletov; Barbora de Courten; Gabrielle deVeber; Klara Dokova; Dumessa Edessa; Matthias Endres; Emerito J A Faraon; Maryam S Farvid; Florian Fischer; Kyle Foreman; Mohammad H Forouzanfar; Seana L Gall; Tsegaye T Gebrehiwot; Johanna M Geleijnse; Richard F Gillum; Maurice Giroud; Alessandra C Goulart; Rahul Gupta; Rajeev Gupta; Vladimir Hachinski; Randah R Hamadeh; Graeme J Hankey; Habtamu A Hareri; Rasmus Havmoeller; Simon I Hay; Mohamed I Hegazy; Desalegn T Hibstu; Spencer L James; Panniyammakal Jeemon; Denny John; Jost B Jonas; Jacek Jóźwiak; Rizwan Kalani; Amit Kandel; Amir Kasaeian; Andre P Kengne; Yousef S Khader; Abdur R Khan; Young-Ho Khang; Jagdish Khubchandani; Daniel Kim; Yun J Kim; Mika Kivimaki; Yoshihiro Kokubo; Dhaval Kolte; Jacek A Kopec; Soewarta Kosen; Michael Kravchenko; Rita Krishnamurthi; G Anil Kumar; Alessandra Lafranconi; Pablo M Lavados; Yirga Legesse; Yongmei Li; Xiaofeng Liang; Warren D Lo; Stefan Lorkowski; Paulo A Lotufo; Clement T Loy; Mark T Mackay; Hassan Magdy Abd El Razek; Mahdi Mahdavi; Azeem Majeed; Reza Malekzadeh; Deborah C Malta; Abdullah A Mamun; Lorenzo G Mantovani; Sheila C O Martins; Kedar K Mate; Mohsen Mazidi; Suresh Mehata; Toni Meier; Yohannes A Melaku; Walter Mendoza; George A Mensah; Atte Meretoja; Haftay B Mezgebe; Tomasz Miazgowski; Ted R Miller; Norlinah M Ibrahim; Shafiu Mohammed; Ali H Mokdad; Mahmood Moosazadeh; Andrew E Moran; Kamarul I Musa; Ruxandra I Negoi; Minh Nguyen; Quyen L Nguyen; Trang H Nguyen; Tung T Tran; Thanh T Nguyen; Dina Nur Anggraini Ningrum; Bo Norrving; Jean J Noubiap; Martin J O’Donnell; Andrew T Olagunju; Oyere K Onuma; Mayowa O Owolabi; Mahboubeh Parsaeian; George C Patton; Michael Piradov; Martin A Pletcher; Farshad Pourmalek; V Prakash; Mostafa Qorbani; Mahfuzar Rahman; Muhammad A Rahman; Rajesh K Rai; Annemarei Ranta; David Rawaf; Salman Rawaf; Andre MN Renzaho; Stephen R Robinson; Ramesh Sahathevan; Amirhossein Sahebkar; Joshua A Salomon; Paola Santalucia; Itamar S Santos; Benn Sartorius; Aletta E Schutte; Sadaf G Sepanlou; Azadeh Shafieesabet; Masood A Shaikh; Morteza Shamsizadeh; Kevin N Sheth; Mekonnen Sisay; Min-Jeong Shin; Ivy Shiue; Diego A S Silva; Eugene Sobngwi; Michael Soljak; Reed J D Sorensen; Luciano A Sposato; Saverio Stranges; Rizwan A Suliankatchi; Rafael Tabarés-Seisdedos; David Tanne; Cuong Tat Nguyen; J S Thakur; Amanda G Thrift; David L Tirschwell; Roman Topor-Madry; Bach X Tran; Luong T Nguyen; Thomas Truelsen; Nikolaos Tsilimparis; Stefanos Tyrovolas; Kingsley N Ukwaja; Olalekan A Uthman; Yuri Varakin; Tommi Vasankari; Narayanaswamy Venketasubramanian; Vasiliy V Vlassov; Wenzhi Wang; Andrea Werdecker; Charles D A Wolfe; Gelin Xu; Yuichiro Yano; Naohiro Yonemoto; Chuanhua Yu; Zoubida Zaidi; Maysaa El Sayed Zaki; Maigeng Zhou; Boback Ziaeian; Ben Zipkin; Theo Vos; Mohsen Naghavi; Christopher J L Murray; Gregory A Roth Journal: N Engl J Med Date: 2018-12-20 Impact factor: 91.245