Transcript
Page 1: St. Marianna University School of Medicineigakukai.marianna-u.ac.jp/idaishi/www/353/05-35-03Manae Kurokawa.pdfstem cells transfected with IGFII gene in a mouse model of muscle injury

� � ����������Vol. 35, pp. 143�149, 2007

���������� ��������������

���

���

��

��

�1 �

��

��1 �

��

���1

��

��

���

��1

��

��

����

1�2

�� :�� 19� 8� 27��

�������� �����

���� ����� ����� ����� !"#$%&'()� ��*+,)-���.�,�/.��0123.�456$� 7��689'�:;4<=�� �>�/+?@A�.B�$CD�:�<=9� E�� -���. !*+,)� �/FG"HI$#4F �embryonic stem, ES� G"�3JK� �LM$�L��.G"# N%&89O'(P)QLR2� 7*$+S.TU<V+SWXHI$Y,'()Z[2\\=9�123. N%&R2I]^�/G"Q_`�/

*ab*�-(� c LA�.T#89I&*$�_`�/*+,)]^�/G"*c /.d0#ef89dgh�Q�:i<=9� bj*$� ES G"�31(.�/G"k. N%&#ZlUm*$2n*dg34G"k. N#5l1'$�o6&9� (�( N%&#�,p7<ZlUm*$c Lh�dgQ%&R2q� _`�/k.�-7�r.st'L9� 1.uv4#B889I&*� 1(.�/G"'$9* in vitro <dg#%&(� 1(.�/G"'m[w)]^891'<]^�/G"Q:;'89d0/#<xRw91'Q:�*L9� dg34G"# N%&(]^89I&*� :;L]^G"y#z&={4*>|� -�Rw9dg./0}?83=@:�'~�329� in vitro<dg34G"# N%&89Um� �. ��A

�(LA�#�B891'Q:;'L9Q� 12$2n* N%&#C�9t�*\,).D�V:;'L9� 1.1'$� �E�4G". N%&LM;*dgh�#FHL�2�,�L,Um*� �.�����#D�(� +S�Gk'�@\�9�V:�'L9���$� ���+?@������. ES G"�3JKG"� �G"� �EG"� d�G"LM# N%&(� 56������*]^891'*?��HA�I�[2IA�QB�891'#J�()�I1�7�� K*JKG"���"���.%&*+,)$� y�L.MN< Np7#P)(),9Q� O����� ES G"#�� ��¡¢D891'< N%&(IJKG"*P£� JK N*¤;LQ¥t� Mash1 ¦R�#&S891'< N%&(IJKG"<$� �H��"��.§T7$�oL9Q;*dg.h�$�oL91'Q �¨),91�2����$123.JKG"#TUV������*]^(� P©Wª'()XY<=9�D«¬­.|#ZS(ITUV���''V*Kn(*UV[.�HA�#P)(IKXQ=9� JKG"]^���<$Wª���*P©()\®*�HA�QB�(� ]^¯ 1��]<^o_°L���.�HA�. 50�]`H<B�(I� (�(±^*B�89*$,I3L,1�3�� 1.]^���.�d0#functional MRI <²³(I� ´µ[��a�<$�¶Wª���?�d0$<x(),9V..� _°���?�$d0/Q�r(),93�� 1.I&�JKG"'dg#}�89G"'#9�* N%&(m[w)]^891'*?�� dgh�#b·(

1 ���������� c¸��dµHA�2 ������������¹ ef��º»¼g-���º»*h

143

17

Page 2: St. Marianna University School of Medicineigakukai.marianna-u.ac.jp/idaishi/www/353/05-35-03Manae Kurokawa.pdfstem cells transfected with IGFII gene in a mouse model of muscle injury

������������� ���� ����������������������������� ES!�"#$%�&� IGFII'%���(� �()*+,!�� -�*,���(�./(),��012�� �345�6� ���7�8�()9:���;<����=�>�?@5�=� AB<�����CDB��(E�5�� F�GH �IJ"!��K�34(���LM5NO� ;<���PQ����=&��RS��012�� �TU� Mash1��!�34()GH � VW�XY�B�IZ[=\E]� ��?@��^���F6=_��4��`�NO� �IA�I��!a� ��b���cde�B� ��Ofghig�Ajkl�k,mn� o�B��pED�B� ES !qo�r �()�I��!a� �=s�t����&��

ES ������������

�u!6�IJ"!Bvw�x!�&��y�Iz! �hemangioblast� qo�r5�8�10���I�{"B�I{" �vasculogenesis�� �IZ[ �angiogenesis�� a(���{"�|}�I�"~6�01��� �arteriogenesis� � 3 �����oN�11� 12�� ���B�[ 17 ��������� �!"����� F��y�Iz!=�H()�#���=7oN� ���!B�uz!6E<� ���!=�I��!6E�� F��I��!=$H(���I��{"5���=� ����I{"���6E�� a���IZ[����B%zA���;<;<�Q!qE�I&={"N� ����01�������B�����'�"~�I�{"=��N�� F�;c��I��!B�I%[�����qo�(�E5!�&

� 1 �� ES !���2 2¡g ¢)�;£ OP9!6v*+()!�{�A, B ��2 2¡g ¢)� 4���¤¡¥g�¦5� *+§�,¨(�-©.�/E!=L[(�ª0«�� *+y��1¬{�!=�N��20«��C, D ��2 2¡g ¢) 4�� OP9!6v*+�­�( 24K®��¤¡¥g�{��¦5�1¬{�!�20«���/E!=¯<°}�ª0«�{�¤¡¥g=±²³oN� �C�� F��/E!B3E¤¡¥g��/E!64´�µH(�I¶�{"5�·¸�5Q) �D�� �BOP9!�¹�¦5�

ªº»6¼ 7%8% o144

18

Page 3: St. Marianna University School of Medicineigakukai.marianna-u.ac.jp/idaishi/www/353/05-35-03Manae Kurokawa.pdfstem cells transfected with IGFII gene in a mouse model of muscle injury

�� ��������� ��� ������������������������ ��!"#$�%&'(&)�&*+,-�� .�/012�3456 ES ��7, Flk-1 89��':;-� ������<=��6"#� >?@� ����A�!6���B'CD-@��13�15�� E�FG ES ��7,H� ��!�������=��6"#'CD-@��16�17�� ?7? ES ��7,"#?�I6��&��JK5LM�NO?��PQR�S�TU�VWXY-@�)��

ES ����������� ����������������������� �!"

Z[5\5]^1 �MC��_��`ab;cde�� ��f6��6"#�gh_�,-@���

i��/01 ES ���Z[5\5]^1j�@cd$�%&���� �k��l��2�3������6"#��m�� n:;��op?@qrspcd?�/01 ES ���� 0�8�Z[5\5]^1�tucv!cd�wx$�&� 3yz{��|}96��'~�?� 4yz�� 1�2�6��7,)��^G�6�]�^�b�$��# 1 A, B�����cvjE��%6|}��6�����b!� ��b6��':;?��?@h�6'� ,-� %-'��f�:;?���&*+,-�7��%-� op�op /01��6��1G]^/��!�� OP9���! 24���cd$�&� ��]�^6��6��'��;$����� � ��b6�����;?���'�u���)�]�^6b�'� ,-��# 1C�� FG!� � 17 y�

# 2 �k��l��2�3�������¡�):¢/^£^6��A, B Z[5\5]^1¤¥¦ 4yz �A� 2�3>6¦ OP9��&�cd 24��¦ �B� 6�]�^�2�@� �k��l��6/^£^!�� Flk-16���� ��C, D OP9 ��&�cd 24 ��¦6�]�^�2�@� ������6/^£^!�� CD31 �C� & VE-cadherin �D� 6���� �� VE-cadherin ����]�^§�6��)��<�¨�b�?����©h��$����� ��

/01ª9«����������2�3=��6:;"# 145

19

Page 4: St. Marianna University School of Medicineigakukai.marianna-u.ac.jp/idaishi/www/353/05-35-03Manae Kurokawa.pdfstem cells transfected with IGFII gene in a mouse model of muscle injury

����������� ��� ���������������� ����������� !�"#$%&� '()� !&�*+,-��./ !��0� .)123�� !&��� !����4��56,7 !�"#$%&� ���������"#$%189,7�:;�����<=>7� ?7���*+,7 !�@)&� AB1CD1-EF,�GHI;��,7�� 1D�� JKLM1NB-��./ !&AB1OF,-PQ��R;������ ��LM1S>756�TU�.VW�-B��XYZ�7�<+56,7 !1��./?7&[ !1\]^�<_`%a%�Jb,-B�=� RT-PCR cNdefghi1-jk,7� ����� !�`%a%�XYZ�� Flk-1&18�� `lm ES !&Jb,-NZn� opqrq#%mst !Ndeopqrq#%mstu OP9�vwxu,7 !1Jb;yz7�� 1�� {|� ES !&opqrq#%m�wx��������� !1<+56������}~��7�I�� !���./ !Jb��� CD34

& ES !�opqrq#%mstu� !� OP9�vwxu� !1Jb;yz7� ��./�`%a%&� VE-cadherin& Flk-1����Jb;},7�� CD31& ES !=ZJb;yz7�$"p���rpq"����� �nicotinicacethylcholine receptor, nAChR� & a� a� b� g ?7& e� d ����$��=Z�� 5 ���0���./ !1NB- a7;�� nAChR ���1d0���K�������������719��nAChR �Jb; a1�7� b1�4������1�B-jk,7���� a2Nde b1�Jb;opqrq#%mst !Ndeopqrq#%mstuOP9 !�vwx,7 !1yz7� ���K;���� Est-120�� Vezf-121�����K;����Hex22��Jb  Flk-1 ���1yz7�� Est-1 &OP9 ! Jb;yz7�¡¢�£¢;¤¥��<_¦H�,-� ���§p#¨�©ª%«�� erythropoietin producing

human hepatocellular carcinoma�Eph� �¬��­�®� Ephrin �Eph-receptor-interacting protein��¨m¯°�±²��� EphrinB2 &¡¢./ !1Jb,-N023�� @³£¢./ !1& EphB4

� 1 ��H� !\]^�<_� mRNA �Jb

´µ¶·¸ ¹_º_ Z146

20

Page 5: St. Marianna University School of Medicineigakukai.marianna-u.ac.jp/idaishi/www/353/05-35-03Manae Kurokawa.pdfstem cells transfected with IGFII gene in a mouse model of muscle injury

���������24�� �� � �� �������������� ��������� !��� "�#�$%�&�� �'()*$+,-25�� .���/�&0��1 EphrinB2� EphB4 2�34�,� �� ��� 5,�670���/+,�82�����-9&� ��670����+,�0���:�;��<=� Tie2 1�ES 0�� >?@A@BCDE�0�� >?@A@BCDE�F OP90�2GH�&0�����34�,&� 670�I��J+,� PDGF1$%�&��K$�L��0�!MN��:O�PQ!�R�� 8� PDGF � B S�>?@A@BCDE�0�� >?@A@BCDE�F OP90�2GH�&0�T���34�,&� ���UV0��WCXC2-� aSMA ���1� OP90�!YZ[�0��\���34�,&� >?@A@BCDE��]^�_��0���/+,Q�82�`a+,�� bcde@���!f���T ghi!j9&�� >?@A@BCDE�0�� Flk-1���!34� >?@A@BCDE�F OP90�2GH�&0����670��WCXCTk� VE-cadherin� CD31����34�,&�� 2��8,��$l��� >?@A@BCDE�\mnOP9 0�2�GH�mo�p��q0�\mn��670���0���/TQ�82�`a+,&� rF8�0�s�R� +��tuvw�<O�x�yzt*I!;{O�2G�� 8,��0�!|}� ~1 3��H�mo��!*����������� �6T����*�vtu!���Q&� �� ES 0����/�&��0�v��V0�2G���@�����O�82�mo� ��������������� ������K$+,�����2��m'->X���T��O���� � ����de@(T���-�9&tu����M��mo�tu���O��!��O���Tk��

����

.��8,(T�W�D!�&����� ES0���w�/�&���0�����8,(T��-����� ¡�¢���Tk�82�`+,&� 82���tuv��V�tu���1£ ���Tk9&� ���-��� ES 0��1¤

K¥��!1�4� �¦§�!�¨O©�� ªo«¬j�-­,®-�-¯°�±� ���-¯°��²�O�³��k��.�1´���¦§�!�¨�� rF�³�-µ¶���!·¸¹º)��Tk��

� �

1� Chiba S, Ikeda R, Kurokawa MS, YoshikawaH, Takeno M, Nagafuchi H, Tadokoro M,

Sekino H, Hashimoto T and Suzuki N. Ana-

tomical and functional recovery by embryonic

stem cell-derived neural tissue of a mouse

model of brain damage. J Neurol Sci 2004; 219:

107�117.2� Ikeda R, Kurokawa MS, Chiba S, YoshikawaH, Hashimoto T, Tadokoro M and Suzuki N.

Transplantation of motoneurons derived from

MASH1-transfected mouse ES cells reconsti-

tutes neural networks and improves motor

function in hemiplegic mice. Exp neurol 2004;

189: 280�292.3� Ikeda R, Kurokawa MS, Chiba S, YoshikawaH, Ide M, Tadokoro M, Nito S, Nakatsuji N,

Kondoh Y, Nagata K, Hashimoto T and

Suzuki N. Transplantation of neural cells de-

rived from retinoic acid-treated cynomolgus

monkey embryonic stem cells successfully im-

proved motor function of hemiplegic mice with

experimental brain injury. Neurobiol Dis 2005;

20: 38�48.4� Hamada M, Yoshikawa H, Ueda Y, Kuro-kawa MS, Watanabe K, Sakakibara M, Ta-

dokoro M, Akashi K, Aoki H and Suzuki N.

Introduction of the MASH1 gene into mouse

embryonic stem cells leads to di#erentiation of

motoneuron precursors lacking Nogo receptor

expression that can be applicable for transplan-

tation to spinal cord injury. Neurobiol Dis

2006; 22: 509�522.5� Kamochi H, Kurokawa MS, Yoshikawa H,Ueda Y, Masuda C, Takada E, Watanabe K,

Sakakibara M, Natuki Y, Kimura K, Beppu

M, Aoki H and Suzuki N. Transplantation of

myocyte precursors derived from embryonic

W�D�»¼0�����670�\mn�0��w�/ 147

21

Page 6: St. Marianna University School of Medicineigakukai.marianna-u.ac.jp/idaishi/www/353/05-35-03Manae Kurokawa.pdfstem cells transfected with IGFII gene in a mouse model of muscle injury

stem cells transfected with IGFII gene in a

mouse model of muscle injury. Transplanta-

tion 2006; 82: 516�526.6� Homma R, Yoshikawa H, Takeno M, Kuro-kawa MS, Masuda C, Takada E, Tsubota K,

Ueno S and Suzuki N. Induction of epithelial

progenitors in vitro from mouse embryonic

stem cells and application for reconstruction of

damaged cornea in mice. Invest Pohthalmol

Vis Sci 2004; 45: 4320�4326.7� Miyagi T, Takeno M, Nagafuchi H, TakahashiM and Suzuki N. Flk1� cells derived frommouse embryonic stem cells reconstitute hema-

topoiesis in vivo in SCID mice. Exp Hematol

2002; 30: 1444�1453.8� Keller G, Kennedy M, Papayannopoulou Tand Wiles MV. Hematopoietic commitment

during embryonic stem cell di#erentiation in

culture. Mol Cell Biol 1993; 13: 473�486.9� Kennedy M, Firpo M, Choi K, Wall C, Rob-ertson S, Kabrun N and Keller G. A common

precursor for primitive erythropoiesis and de-

finitive haematopoiesis. Nature 1997; 386: 488�493.

10� Park C, Ma YD and Choi K. Evidence for thehemangioblast. Exp Hematol 2005; 33: 965�970.

11� Risau W. Mechanisms of angiogenesis. Nature1997; 386: 671�674.

12� Buschmann I and Schaper W. The pathophysi-ology of the collateral circulation �arteriogene-sis�. J Pathol 2000; 190: 338�342.

13� Hirashima M, Kataoka H, Nishikawa S, Mat-suyoshi N and Nishikawa S. Maturation of

embryonic stem cells into endothelial cells in an

in vitro model of vasculogenesis. Blood 1999;

93: 1253�1263.14� Yamashita J, Itoh H, Hirashima M, Ogawa M,

Nishikawa S, Yurugi T, Naito M, Nakao K

and Nishikawa S. Flk1-positive cells derived

from embryonic stem cells serve as vascular

progenitors. Nature 2000; 408: 92�96.15� Sone M, Itoh H, Yamashita J, Yurugi-

Kobayashi T, Suzuki Y, Kondo Y, Nonoguchi

A, Sawada N, Yamahara K, Miyashita K,

Park K, Shibuya M, Nito S, Nishikawa S and

Nakao K. Di#erent di#erentiation kinetics of

vascular progenitor cells in primate and mouse

embryonic stem cells. Circulation 2003; 107:

2085�2088.16� Levenberg S, Golub JS, Amit M, Itskovitz-Eldor J and Langer R. Endothelial cells de-

rived from human embryonic stem cells. Proc

Natl Acad Sci USA 2002; 99: 4391�4396.17� Gerecht-Nir S, Ziskind A, Cohen S and Itsko-

vitz-Eldor J. Human embryonic stem cells as

an in vitro model for human vascular develop-

ment and the induction of vascular di#erenti-

ation. Lab Invest 2003; 83: 1811�1820.18� Lugus JJ, Park C and Choi K. Developmentalrelationship between hematopoietic and endo-

thelial cells. Immunol Res 2005; 32: 57�74.19� Heeschen C, Weis M, Aicher A, Dimmeler S

and Cooke JP. A novel angiogenic pathway

mediated by non-neuronal nicotinic acetylcho-

line receptors. J Clin Invest 2002; 110: 527�536.20� Sato Y. Role of ETS family transcription fac-tors in vascular development and angiogenesis.

Cell Struct Funct 2001; 26: 19�24.21� Miyashita H, Kanemura M, Yamazaki T, AbeM and Sato Y. Vascular endothelial zinc finger

1 is involved in the regulation of angiogenesis:

possible contribution of stathmin�OP18 as adownstream target gene. Arterioscler Thromb

Vasc Biol 2004; 24: 878�884.22� Minami T, Murakami T, Horiuchi K, MiuraM, Noguchi T, Miyazaki J, Hamakubo T, Aird

WC and Kodama T. Interaction between hex

and GATA transcription factors in vascular

endothelial cells inhibits flk-1�KDR-mediatedvascular endothelial growth factor signaling. J

Biol Chem 2004; 279: 20626�29635.23� Gerety SS, Wang HU, Chen ZF and Anderson

DJ. Symmetrical mutant phenotypes of the re-

ceptor EphB4 and its specific transmembrane

ligand ephrin-B 2 in cardiovascular develop-

ment. Mol Cell 1999; 4: 403�414.24� Wang HU, Chen ZF and Anderson DJ. Mo-

����� ���� 148

22

Page 7: St. Marianna University School of Medicineigakukai.marianna-u.ac.jp/idaishi/www/353/05-35-03Manae Kurokawa.pdfstem cells transfected with IGFII gene in a mouse model of muscle injury

lecular distinction and angiogenic interaction

between embryonic arteries and veins revealed

by ephrin-B2 and its receptor Eph-B4. Cell

1998; 93: 741�753�

25� Zhong TP, Childs S, Leu JP and Fishman MC.Gridlock signalling pathway fashions the first

embryonic artery. Nature 2001; 414: 216�220.

���������� �������������� 149

23


Top Related