体外扩增后干细胞移植可形成恶性肿瘤（附原文）

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' ^" G1 ?4 t" X8 j  Q" t/ GCirculation Research. 2011% Z: N( y5 u3 _
Published online before print April 14, 2011, doi: 10.1161/CIRCRESAHA.110.239848' Q' z) V* |. r9 s0 C6 F6 Y$ D
  PubMed Citation   Articles by Jeong, J.-O.   Articles by Yoon, Y.-S.  
# x" a8 V8 B9 G7 o© 2011 American Heart Association, Inc. % f# s2 V1 n" |
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Malignant Tumor Formation After Transplantation of Short-Term Cultured Bone Marrow Mesenchymal Stem Cells in Experimental Myocardial Infarction and Diabetic Neuropathy1 U- _& }4 k# P& n7 k! B
经过短期培养的骨髓间充质干细胞移植治疗实验性心肌梗死和糖尿病神经形成恶性肿瘤病变9 l: I9 G. q$ @+ g! u
Jin-Ok Jeong, Ji Woong Han, Jin-Man Kim, Hyun-Jai Cho, Changwon Park, Namho Lee, Dong-Wook Kim Young-Sup Yoon
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, G* n4 U6 @! E4 ?, F* E+ L( Z$ TFrom the Division of Cardiovascular Research, Caritas St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, MA (J.-O.J., H.-J.C., N.L., Y.-S.Y.); Department of Internal Medicine (J.-O.J.) and Department of Pathology (J.K.), College of Medicine, Chungnam National University, Daejeon, Korea; Department of Internal Medicine, Seoul National University Hospital, Chongno-Gu, Yongon-Dong, Seoul, Korea (H.-J.C.); Division of Cardiology, Kangnam Sacred Heart Hospital, Hallym University School of Medicine, Seoul, Korea (N.L.); Department of Pharmacology, University of Illinois at Chicago, Chicago, IL (C.P.); Stem Cell Research Center, 21C R&D Program of Ministry of Education, Science, and Technology, Yonsei University Medical Center, Seoul, Korea (D.-W.K.); and Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, GA (J.W.H., C.P., Y.-S.Y.). ( Q5 i0 i% x! ^% N; u

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Correspondence to Young-Sup Yoon, MD, PhD, Division of Cardiology, Department of Medicine, Emory University School of Medicine, 1639 Pierce Drive, WMB 3009, Atlanta, GA 30322. E-mail yyoon5@emory.edu: l1 w+ n5 B- h6 e4 y, {* O
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Abstract
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! I8 g" {' [. CRationale:Bone marrow (BM)–derived mesenchymal stem cells (MSCs) hold great promise for cardiovascular cell therapy owing to their multipotency and culture expandability. 3 h: U& g" U  C( K

$ M3 K; v9 f5 M1 M) i9 Y0 vObjective:The aim of the study was to investigate whether MSCs can treat experimental acute myocardial infarction (MI) and diabetic neuropathy. 9 @9 p% r4 D/ \& m- L
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Methods and Results:We isolated mononuclear cells from mouse BM and cultured MSCs in a conventional manner. Flow cytometry analyses of these cultured cells at passage 4 showed expression of typical MSC markers such as CD44 and CD29, but not hematopoietic markers such as c-kit, flk1, and CD34. To determine the therapeutic effects of MSCs, we injected MSCs into the peri-infarct area after ligation of the left anterior descending coronary arteries of mice and, as separate experiments, injected the same batch of MSCs into hindlimb muscles of mice with diabetic neuropathy. During the follow-up at 4 to 8 weeks after cell transplantation, growing tumors were observed in 30% of hearts in the MI model, and in 46% of hindlimbs in the diabetic neuropathy model. Histological examination of the tumors revealed hypercelluarity, pleomorphic nucleoli, cytological atypia and necrosis, and positive staining for α-smooth muscle actin, indicative of malignant sarcoma with myogenic differentiation. Chromosomal analysis of these MSCs showed multiple chromosomal aberrations including fusion, fragmentation, and ring formation.   v5 `( ?4 J( s" y. U
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Conclusions:Genetically unmodified MSCs can undergo chromosomal abnormalities even at early passages and form malignant tumors when transplanted in vivo. These results suggest that careful monitoring of chromosomal status is warranted when in vitro expanded MSCs are used for cell therapy such as for MI.
$ B0 i! Z. N' [1 D7 @2 ~( z结论：未经基因修饰的干细胞在早期传代过程中可发生染色体异常，并且移植后会在体内形成恶性肿瘤。这些结果表明，体外扩增间充质干细胞用于心肌梗死治疗等疾病的细胞治疗时必须严格考察染色体的状态。5 K$ `" P0 Y8 Z, g
Key Words: bone marrow • mesenchymal stem cells • malignant tumors • transplantation • ischemia5 C7 c( K) j, n6 h  R, U# ^
http://circres.ahajournals.org/c ... RESAHA.110.239848v1( L: r6 L! K: A2 h+ d/ X" E( q7 |

- s( J0 s7 R: B6 v6 `' J5楼原文 感谢longer 提供

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回复 biohacker 的帖子
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恐怕还是不行，肿瘤和干细胞的关系十分复杂，人们的认识还处在十分初级的阶段：
! b* F1 f7 _9 l$ I1. 干细胞具有向肿瘤组织的定向归巢作用；
+ I+ N2 ^8 D$ O2. 干细胞是众多肿瘤的起源细胞？9 y! z  V  ]' T$ s0 a$ D
3. 干细胞帮助肿瘤形成伴生血管；
$ r. h: M8 N4 y0 J0 ~# x4. 干细胞可被肿瘤“说服”而同流合污；
8 q0 K2 b6 e4 z: y; x5 L5. 干细胞为肿瘤生长提供微环境（营养因子）；
' q* p) |. m( O* t6. 干细胞个别基因变异就可以转变为肿瘤；
- p9 S+ z' K! V5 n7. 干细胞免疫抑制作用是肿瘤的帮凶；
6 j! W' I$ w6 r* e# H9 Y( r8.  干细胞疗法可造成移植性肿瘤；
8 O0 y: I0 t, \* Z; d/ G# T9. 干细胞携带肿瘤病毒可传播肿瘤；6 Y: m  Z* F1 {- l1 J* c
10. 干细胞规模化应用后将引发前所未有的肿瘤及其他怪异疾病发生.....
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老狼以为干细胞是一群没有明确定义标准的动态混合细胞，首先应该考虑从表观遗传特征入手结合安全性研究建立干细胞的新的控制手段。

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; f: e8 f  A6 u6 u# M人们对于干细胞治疗渴望的心情是可以理解的，但是，人类已经和疾病抗争中已经等待了千万年，如果继续再等个10年20年要求并不算过分，我们的科学家、工程师、医生需要携起手尽最大努力去避免新技术带来的灾难性后果，大家对干细胞真的了解还太少...例如目前最为接近临床应用条件间充质干细胞（MSC）尚且有许多基础工作需要弄明白，如干细胞移植后的行为和命运：$ D3 T( b4 }% W! L: O8 ]/ m
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1. MSC在宿主体内的分布、定植、分化、转归规律?( C! F/ E9 B. ]

9 F% E+ ^+ k* s2.关于MSC组织归巢、病理归巢的规律，对非目标组织器官的影响?) `  B+ Y. I" r/ Z9 V- y2 f4 w
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3. 同种异基因MSC与自体MSC在体内的行为区别？9 ?7 C$ `8 W/ C" s; L% E6 C. h5 B

3 w$ ]' o% O& c4.MSC与肿瘤的关系，是哪些肿瘤的帮凶，对那类肿瘤具有抑制作用？8 q; h7 |/ t, G4 O5 t+ b  R" }2 @
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5.相合、半相合、不相合情况下MSC体内行为与组织配型（HLA）的关系？
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6. 组织来源、年龄、体外过程等对MSC体内行为的影响？0 r; G. L6 c; K/ C
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7.MSC移植后持续不良后果的终止方案？4 J. K. l8 r; c# V
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8. MSC移植后引起远期免疫学后果？$ U0 G9 I2 Q& }1 Z0 z

# `2 c* `) b4 }. \! f5 m5 p9. 通过对niche的干预或内源性MSC动员是否有可能够最终替代MSC移植？3 T7 A" `2 Y; b
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目前ESC在国外也仅仅是临床研究阶段距离应用任重而道远。另一方面，我国法律体系和美国是不一样，美国临床研究企业自己承担风险，而我国政府一旦批准就意味着风险是可控的....关于干细胞的法规、标准、评价体系以及相关资源均未到位，曾试着和官员沟通过MSC临床研究受众人群选择问题，给出的基本观点是：
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# n6 H* b# v. l' b1. 无生育机会的人群；
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5 P5 L, x+ Q$ c2. 无治疗手段的疾病；7 I$ i3 ~( n) H
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3. 非肿瘤疾病患者；" R: b9 Z+ t0 ]
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4. 能够HLA配型的；. d2 P0 {4 `! a0 a; Y' ^. ^) g! E# H
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5. 能够长期随访的；2 N' l7 V$ P7 P& Z
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果真这样的话，完成I/II/III/IV期临床观察恐怕要历时数十年，耗资数十亿....