chemical-reversion-conventional-human-pluripotent-stem-cells-to-nave

Chemical Reversion of Conventional Human Pluripotent Stem Cells to a Na&#239;ve-like State with Improved Multilineage Differentiation Potency

Na&#239;ve human pluripotent stem cells (N-hPSC) with improved functionality may have a wide impact in regenerative medicine. The goal of this protocol is ...

defined-xenofree-reprogramming-cord-blood-progenitors-to-induced

Defined Xenofree Reprogramming of Cord Blood Progenitors to Induced Pluripotent and Blastomere-Like Stem Cells

Human cord blood (CB) myeloid progenitor reprogramming to a high-fidelity human induced pluripotent stem cell (hiPSC) state can be&#160;achieved using ...

Johns Hopkins School of Medicine

The Johns Hopkins University School of Medicine

&#x8840;&#x7BA1;&#x5468;&#x56F4;&#x591A;&#x80FD;&#x5E72;&#x95F4;&#x5145;&#x8D28;&#x7956;&#x7EC6;&#x80DE;&#x5B58;&#x5728;&#x4E8E;&#x5404;&#x79CD;&#x7EC4;&#x7EC7;&#xFF0C;&#x5305;&#x62EC;&#x80CE;&#x76D8;&#x3002;&#x5728;&#x8FD9;&#x91CC;&#xFF0C;&#x6211;&#x4EEC;&#x5EFA;&#x8BAE;&#x672C;&#x80CE;&#x76D8;&#x7EC4;&#x7EC7;&#x4E2D;&#x7684;&#x4E30;&#x5BCC;&#x8840;&#x7BA1;&#x53EF;&#x4EE5;&#x4F5C;&#x4E3A;&#x6E90;&#x7684;&#x6210;&#x808C;&#x7EC6;&#x80DE;&#x518D;&#x751F;&#x9AA8;&#x9ABC;&#x808C;&#x3002;&#x5165; SCID/mdx &#x9F20;&#xFF0C;&#x5176;&#x4E2D;&#x4ED6;&#x4EEC;&#x53C2;&#x52A0;&#x808C;&#x8089;&#x518D;&#x751F;&#x7684;&#x751F;&#x4EA7; myofibers &#x8868;&#x793A;&#x4EBA;&#x7C7B;&#x6297;&#x808C;&#x840E;&#x7F29;&#x86CB;&#x767D;&#x548C;&#x8840;&#x5F71;&#x7684;&#x8153;&#x80A0;&#x808C;&#x808C;&#x8089;&#x9996;&#x5148;&#x539F;&#x5C01;&#x4E0D;&#x52A8;&#x5730;&#x79FB;&#x690D;&#x89E3;&#x5256;&#x4ECE; mid-gestation &#x4EBA;&#x7C7B;&#x80CE;&#x76D8;&#x7ED2;&#x6BDB;&#x3002;&#x5728;&#x4F53;&#x5916;&#x80CE;&#x76D8;&#x7ED2;&#x6BDB;&#x91CA;&#x653E;&#x8868;&#x793A;&#x9AA8;&#x9AD3;&#x95F4;&#x5145;&#x8D28;&#x5E72;&#x7EC6;&#x80DE;&#x6807;&#x8BB0;&#x7269;&#x7684;&#x5047;&#x5B9A;&#x5468;&#x56F4;&#x8D77;&#x6E90; CD146 + CD34&#x207B;CD45&#x207B;CD56&#x207B; &#x7EC6;&#x80DE;&#x8FC5;&#x901F;&#x575A;&#x6301;&#x4E0E;&#x6D04;&#x6E38;&#x3002;CD146 + CD34&#x207B;CD45&#x207B;CD56&#x207B; &#x8840;&#x7BA1;&#x5468;&#x56F4;&#x7EC6;&#x80DE;&#x5206;&#x79BB;&#x548C;&#x51C0;&#x5316;&#x4ECE;&#x80CE;&#x76D8;&#x7ED2;&#x6BDB;&#x7684;&#x6D41;&#x6D41;&#x5F0F;&#x7EC6;&#x80DE;&#x4EEA;&#x662F;&#x5728;&#x6587;&#x5316;&#x4E2D;&#xFF0C;&#x786E;&#x5B9E;&#x975E;&#x5E38;&#x808C;&#x548C;&#x751F;&#x6210;&#x6297;&#x808C;&#x840E;&#x7F29;&#x86CB;&#x767D;&#x6297;&#x4F53;&#x9633;&#x6027; myofibers&#xFF0C;&#x4ED6;&#x4EEC;&#x664B;&#x5347;&#x5230; SCID/mdx &#x9F20;&#x6807;&#x808C;&#x8089;&#x79FB;&#x690D;&#x672F;&#x540E;&#x8840;&#x7BA1;&#x751F;&#x6210;&#x3002;&#x8FD9;&#x4E9B;&#x610F;&#x89C1;&#x786E;&#x8BA4;&#x95F4;&#x5145;&#x8D28;&#x7956;&#x7EC6;&#x80DE;&#x5728;&#x4EBA;&#x4F53;&#x8840;&#x7BA1;&#x58C1;&#x5185;&#x7684;&#x5B58;&#x5728;&#xFF0C;&#x5E76;&#x8868;&#x660E;&#x4E30;&#x5BCC;&#x5E26;&#x8840;&#x7BA1;&#x8482;&#x7684;&#x4EBA;&#x7C7B;&#x80CE;&#x76D8;&#x8840;&#x7BA1;&#x5468;&#x56F4;&#x808C;&#x7EC6;&#x80DE;&#x80FD;&#x591F;&#x5728;&#x8425;&#x517B;&#x4E0D;&#x826F;&#x6027;&#x808C;&#x5185;&#x8FC1;&#x79FB;&#xFF0C;&#x5E76;&#x91CD;&#x65B0;&#x751F;&#x6210; myofibers &#x7684;&#x4E30;&#x5BCC;&#x6765;&#x6E90;&#x3002;

&#x4EBA;&#x4F53;&#x808C;&#x8089;&#x518D;&#x751F;&#x7684;&#x80CE;&#x76D8;&#x8840;&#x7BA1;&#x5468;&#x56F4;&#x7EC6;&#x80DE;&#x3002;

Perivascular multipotent mesenchymal progenitors exist in a variety of tissues, including the placenta. Here, we suggest that the abundant vasculature present in the human placenta can serve as a source of myogenic cells to regenerate skeletal muscle. Chorionic villi dissected from the mid-gestation human placenta were first transplanted intact into the gastrocnemius muscles of SCID/mdx mice, where they participated in muscle regeneration by producing myofibers expressing human dystrophin and spectrin. In vitro-cultured placental villi released rapidly adhering and migratory CD146+CD34â»CD45â»CD56â» cells of putative perivascular origin that expressed mesenchymal stem cell markers. CD146+CD34â»CD45â»CD56â» perivascular cells isolated and purified from the placental villi by flow cytometry were indeed highly myogenic in culture, and generated dystrophin-positive myofibers, and they promoted angiogenesis after transplantation into SCID/mdx mouse muscles. These observations confirm the existence of mesenchymal progenitor cells within the walls of human blood vessels, and suggest that the richly vascularized human placenta is an abundant source of perivascular myogenic cells able to migrate within dystrophic muscle and regenerate myofibers.

Placental perivascular cells for human muscle regeneration.

P&#xE9;rivasculaires multipotentes m&#xE9;senchymateuses prog&#xE9;nitrices existent dans une vari&#xE9;t&#xE9; de tissus, y compris le placenta. Ici, nous sugg&#xE9;rons que le pr&#xE9;sent syst&#xE8;me vasculaire abondante dans le placenta humain peut servir comme une source de cellules myog&#xE9;niques pour r&#xE9;g&#xE9;n&#xE9;rer le muscle squelettique. Villosit&#xE9;s choriales diss&#xE9;qu&#xE9;s &#xE0; partir du placenta &#xE0; mi-gestation humaine ont d&#x26;#39;abord &#xE9;t&#xE9; transplant&#xE9; intact dans les muscles jumeaux de SCID / mdx souris, o&#xF9; ils ont particip&#xE9; &#xE0; la r&#xE9;g&#xE9;n&#xE9;ration du muscle par myofibres producteurs exprimant la dystrophine humaine et la spectrine. In vitro-culture villosit&#xE9;s placentaires lib&#xE9;r&#xE9; rapidement adh&#xE9;rents et migrateurs CD146 + CD34 CD45 &#x207B; &#x207B; &#x207B; CD56 des cellules d&#x26;#39;origine p&#xE9;rivasculaire putatif qui a exprim&#xE9; marqueurs des cellules souches m&#xE9;senchymateuses. CD146 + CD34 CD45 &#x207B; &#x207B; &#x207B; CD56 des cellules p&#xE9;rivasculaires isol&#xE9;s et purifi&#xE9;s &#xE0; partir des villosit&#xE9;s placentaires par cytom&#xE9;trie de flux ont &#xE9;t&#xE9; en effet tr&#xE8;s myog&#xE9;nique dans la culture, et a g&#xE9;n&#xE9;r&#xE9; la dystrophine-positives myofibres, et ils ont favoris&#xE9; l&#x26;#39;angiogen&#xE8;se apr&#xE8;s la transplantation dans les muscles de souris SCID / mdx. Ces observations confirment l&#x26;#39;existence de cellules souches m&#xE9;senchymateuses dans les parois des vaisseaux sanguins de l&#x26;#39;homme, et sugg&#xE8;rent que le placenta humain richement vascularis&#xE9;e est une source abondante de cellules myog&#xE9;niques p&#xE9;rivasculaires capables de migrer &#xE0; l&#x26;#39;int&#xE9;rieur du muscle dystrophique et la r&#xE9;g&#xE9;n&#xE9;ration des fibres musculaires.

Placentaires cellules p&#xE9;rivasculaires pour la r&#xE9;g&#xE9;n&#xE9;ration des muscles humains

Perivaskul&auml;ren multipotenten Mesenchymale Vorl&auml;uferzellen vorhanden in einer Vielzahl von Geweben, einschlie&szlig;lich der Plazenta. Hier empfehlen wir die reichlich Gef&auml;&szlig;system in der menschlichen Plazenta vorhanden als eine Quelle von myogener Zellen Regenerieren der Skelettmuskulatur dienen kann. Chorionzotten, die von der mid-gestation menschlichen Plazenta seziert wurden zun&auml;chst intakt in die Gastrocnemius Muskeln SCID/Mdx-M&auml;use, transplantiert wo sie bei Muskel-Regeneration nahmen durch die Herstellung von Myofibers, die menschliche Dystrophin und Spektrin auszudr&uuml;cken. In Vitro kultiviert Plazenta Zotten ver&ouml;ffentlicht rasch haftende und wandernde CD146 + CD34&#x207B;CD45&#x207B;CD56&#x207B; Zellen vermeintliche perivaskul&auml;ren Ursprungs, die mesenchymalen Stammzell-Marker ausgedr&uuml;ckt. CD146 + CD34&#x207B;CD45&#x207B;CD56&#x207B; perivaskul&auml;ren Zellen isoliert und gereinigt aus der Plazenta Zotten von Flow Cytometry waren in der Tat sehr myogener in Kultur, generiert Dystrophin-Positive Myofibers und f&ouml;rderten sie Angiogenesis nach der Transplantation in SCID/Mdx Maus Muskeln. Diese Beobachtungen best&auml;tigen die Existenz von mesenchymalen Vorl&auml;uferzellen innerhalb der Mauern der menschlichen Blutgef&auml;&szlig;e, und schlagen vor, da&szlig; die reich gef&auml;&szlig;reichen menschliche Plazenta ist eine reiche Quelle der perivaskul&auml;ren myogener Zellen migrieren innerhalb dystrophische Muskeln und Myofibers zu regenerieren k&ouml;nnen.

Plazenta perivaskul&auml;ren Zellen menschlichen Muskel-Regeneration.

Progenitori mesenchimali multipotenti perivascolare esistono in una variet&agrave; di tessuti, tra cui la placenta. Qui, suggeriamo che la vascolarizzazione abbondante presente nella placenta umana pu&ograve; servire come fonte di cellule miogena rigenerare i muscoli scheletrici. Villi coriali sezionati da placenta umana mid-gestation in primo luogo sono stati trapiantati intatto in muscoli gastrocnemio di topi SCID/mdx, dove hanno partecipato nella rigenerazione muscolare producendo myofibers esprimendo spettrina e distrofina umana. Nei villi placentari coltivate in vitro rilasciato rapidamente aderente e migratorie CD146 + CD34&#x207B;CD45&#x207B;CD56&#x207B; cellule di origine putativo perivascolare che espressi marcatori delle cellule staminali mesenchimali. CD146 + CD34&#x207B;CD45&#x207B;CD56&#x207B; perivascolari cellule isolate e purificate dalle villi placentari di flusso cytometry erano infatti altamente miogena nella cultura e generato myofibers distrofina-positivi, e hanno promosso l&#39;angiogenesi dopo trapianto in muscoli topo SCID/mdx. Queste osservazioni confermano l&#39;esistenza di cellule progenitrici mesenchimali entro le pareti dei vasi sanguigni umani e suggeriscono che la placenta umana riccamente vascolarizzata &egrave; un&#39;abbondante fonte di perivascolare miogena cellule in grado di migrare all&#39;interno distrofica muscolare e rigenerare myofibers.

Cellule perivascolari placentare per rigenerazione muscolare umana.

&#x8840;&#x7BA1;&#x5468;&#x56F2;&#x306E;&#x591A;&#x80FD;&#x6027;&#x9593;&#x8449;&#x7CFB;&#x524D;&#x99C6;&#x7D30;&#x80DE;&#x306F;&#x3001;&#x80CE;&#x76E4;&#x3092;&#x542B;&#x3080;&#x69D8;&#x3005;&#x306A;&#x7D44;&#x7E54;&#x306B;&#x5B58;&#x5728;&#x3057;&#x3066;&#x3044;&#x307E;&#x3059;&#x3002;&#x3053;&#x3053;&#x3067;&#x306F;&#x3001;&#x30D2;&#x30C8;&#x80CE;&#x76E4;&#x306B;&#x8C4A;&#x5BCC;&#x306A;&#x8840;&#x7BA1;&#x304C;&#x5B58;&#x5728;&#x3059;&#x308B;&#x9AA8;&#x683C;&#x7B4B;&#x3092;&#x518D;&#x751F;&#x3059;&#x308B;&#x305F;&#x3081;&#x306B;&#x7B4B;&#x7D30;&#x80DE;&#x306E;&#x4F9B;&#x7D66;&#x6E90;&#x3068;&#x3057;&#x3066;&#x6A5F;&#x80FD;&#x3059;&#x308B;&#x3053;&#x3068;&#x3092;&#x793A;&#x5506;&#x3057;&#x3066;&#x3044;&#x308B;&#x3002;&#x598A;&#x5A20;&#x4E2D;&#x671F;&#x30D2;&#x30C8;&#x80CE;&#x76E4;&#x304B;&#x3089;&#x89E3;&#x5256;&#x7D68;&#x6BDB;&#x306F;&#x3001;&#x6700;&#x521D;&#x306B;&#x3001;&#x5F7C;&#x3089;&#x304C;&#x4EBA;&#x9593;&#x306E;&#x30B8;&#x30B9;&#x30C8;&#x30ED;&#x30D5;&#x30A3;&#x30F3;&#x3068;&#x30B9;&#x30DA;&#x30AF;&#x30C8;&#x30EA;&#x30F3;&#x3092;&#x767A;&#x73FE;&#x3057;&#x3066;&#x751F;&#x6210;&#x3059;&#x308B;&#x7DDA;&#x7DAD;&#x306B;&#x3088;&#x3063;&#x3066;&#x7B4B;&#x8089;&#x306E;&#x518D;&#x751F;&#x306B;&#x53C2;&#x52A0;&#x3057;&#x305F;SCID / mdx&#x30DE;&#x30A6;&#x30B9;&#x306E;&#x8153;&#x8179;&#x7B4B;&#x306B;&#x305D;&#x306E;&#x307E;&#x307E;&#x79FB;&#x690D;&#x3057;&#x305F;&#x3002; in vitro&#x3067;&#x57F9;&#x990A;&#x3057;&#x305F;&#x80CE;&#x76E4;&#x306E;&#x7D68;&#x6BDB;&#x306F;&#x3001;&#x6025;&#x901F;&#x306B;&#x4ED8;&#x7740;&#x3057;&#x3001;&#x6E21;&#x308A;&#x9CE5;&#x306E;CD146 + CD34 CD45&#x207B;&#x207B;&#x207B;CD56&#x9593;&#x8449;&#x7CFB;&#x5E79;&#x7D30;&#x80DE;&#x30DE;&#x30FC;&#x30AB;&#x30FC;&#x3092;&#x767A;&#x73FE;&#x63A8;&#x5B9A;&#x8840;&#x7BA1;&#x7531;&#x6765;&#x306E;&#x7D30;&#x80DE;&#x3002;&#x30EA;&#x30EA;&#x30FC;&#x30B9;&#x30D5;&#x30ED;&#x30FC;&#x30B5;&#x30A4;&#x30C8;&#x30E1;&#x30C8;&#x30EA;&#x30FC;&#x306B;&#x3088;&#x308B;&#x80CE;&#x76E4;&#x7D68;&#x6BDB;&#x304B;&#x3089;&#x5358;&#x96E2;&#x3055;&#x308C;&#x3001;&#x7CBE;&#x88FD;&#x3055;&#x308C;&#x305F;CD146 + CD34&#x207B;CD45&#x207B;CD56&#x207B;&#x8840;&#x7BA1;&#x5468;&#x56F2;&#x7D30;&#x80DE;&#x306F;&#x3001;&#x57F9;&#x990A;&#x4E2D;&#x306E;&#x5B9F;&#x969B;&#x306B;&#x975E;&#x5E38;&#x306B;&#x7B4B;&#x305F;&#x3057;&#x3001;&#x30B8;&#x30B9;&#x30C8;&#x30ED;&#x30D5;&#x30A3;&#x30F3;&#x967D;&#x6027;&#x7DDA;&#x7DAD;&#x3092;&#x751F;&#x6210;&#x3057;&#x3001;&#x305D;&#x3057;&#x3066;&#x3001;&#x5F7C;&#x3089;&#x306F;SCID / mdx&#x30DE;&#x30A6;&#x30B9;&#x306E;&#x7B4B;&#x8089;&#x306B;&#x79FB;&#x690D;&#x5F8C;&#x306E;&#x8840;&#x7BA1;&#x65B0;&#x751F;&#x3092;&#x4FC3;&#x9032;&#x3057;&#x305F;&#x3002;&#x3053;&#x308C;&#x3089;&#x306E;&#x89B3;&#x200B;&#x200B;&#x5BDF;&#x306F;&#x3001;&#x4EBA;&#x9593;&#x306E;&#x8840;&#x7BA1;&#x306E;&#x58C1;&#x5185;&#x306E;&#x9593;&#x8449;&#x7CFB;&#x524D;&#x99C6;&#x7D30;&#x80DE;&#x306E;&#x5B58;&#x5728;&#x3092;&#x78BA;&#x8A8D;&#x3057;&#x3001;&#x8C4A;&#x304B;&#x306A;&#x8840;&#x7BA1;&#x30D2;&#x30C8;&#x80CE;&#x76E4;&#x304C;&#x30B8;&#x30B9;&#x30C8;&#x30ED;&#x30D5;&#x30A3;&#x30FC;&#x7B4B;&#x304A;&#x3088;&#x3073;&#x518D;&#x751F;&#x6210;&#x306E;&#x7B4B;&#x7DDA;&#x7DAD;&#x5185;&#x306B;&#x79FB;&#x884C;&#x3059;&#x308B;&#x3053;&#x3068;&#x304C;&#x3067;&#x304D;&#x8840;&#x7BA1;&#x7B4B;&#x7D30;&#x80DE;&#x306E;&#x8C4A;&#x5BCC;&#x306A;&#x4F9B;&#x7D66;&#x6E90;&#x3067;&#x3042;&#x308B;&#x3053;&#x3068;&#x3092;&#x793A;&#x5506;&#x3057;&#x3066;&#x3044;&#x308B;&#x3002;

&#x4EBA;&#x9593;&#x306E;&#x7B4B;&#x8089;&#x306E;&#x518D;&#x751F;&#x306E;&#x305F;&#x3081;&#x306B;&#x80CE;&#x76E4;&#x306E;&#x8840;&#x7BA1;&#x5468;&#x56F2;&#x7D30;&#x80DE;

Perivascular multipotent &#xC5FD; progenitors &#xC870;&#xC9C1;, &#xD0DC; &#xBC18; &#xB4F1;&#xC758; &#xB2E4;&#xC591; &#xD55C; &#xC874;&#xC7AC;. &#xC5EC;&#xAE30;, &#xC778;&#xAC04;&#xC758; &#xD0DC; &#xBC18;&#xC5D0; &#xD48D;&#xBD80;&#xD55C; &#xD608;&#xAD00; &#xACE8;&#xACA9; &#xADFC;&#xC721; &#xC7AC;&#xC0DD;&#xC131; myogenic &#xC140;&#xC758; &#xC6D0;&#xBCF8;&#xC73C;&#xB85C; &#xC0AC;&#xC6A9;&#xD560; &#xC218; &#xC788;&#xC2B5;&#xB2C8;&#xB2E4; &#xD558;&#xB294; &#xAC83;&#xC774; &#xC88B;&#xC2B5;&#xB2C8;&#xB2E4;. Mid-gestation &#xC778;&#xAC04;&#xC758; &#xD0DC; &#xBC18;&#xC5D0;&#xC11C; &#xD574; &#xBD80; &#xC735; villi &#xCC98;&#xC74C; SCID/mdx &#xC950;, &#xADF8;&#xB4E4;&#xC740; &#xC778;&#xAC04;&#xC758; dystrophin spectrin &#xD45C;&#xD604; myofibers&#xB97C; &#xC0DD;&#xC0B0; &#xD558; &#xC5EC; &#xADFC;&#xC721; &#xC7AC;&#xC0DD;&#xC131;&#xC5D0; &#xCC38;&#xAC00; gastrocnemius &#xADFC;&#xC721;&#xC5D0; &#xADF8;&#xB300;&#xB85C; &#xC774;&#xC2DD; &#xD588;&#xB2E4;. Placental villi &#xCCB4; &#xC678; &#xBC30;&#xC591; &#xC911;&#xAC04; &#xC5FD; &#xC904;&#xAE30; &#xC138;&#xD3EC; &#xD45C;&#xC2DD; &#xD45C;&#xC2DC; &#xC0C1; perivascular &#xAE30;&#xC6D0;&#xC758; &#xC2E0;&#xC18D; &#xD558; &#xAC8C; &#xC811;&#xCC29; &#xD558; &#xACE0; &#xCCA0;&#xC0C8; CD146 + CD34&#x207B;CD45&#x207B;CD56&#x207B; &#xC140;&#xC744; &#xBC1C;&#xD45C; &#xD588;&#xB2E4;. CD146 + CD34&#x207B;CD45&#x207B;CD56&#x207B; perivascular &#xC138;&#xD3EC; &#xACA9;&#xB9AC; &#xADF8;&#xB9AC;&#xACE0; &#xC815;&#xD654; &#xD750;&#xB984;&#xC5D0; &#xC758;&#xD574; placental villi&#xC5D0;&#xC11C; cytometry &#xD588;&#xB2E4; &#xC2E4;&#xC81C;&#xB85C; &#xB192;&#xC740; &#xBB38;&#xD654;, myogenic&#xC640; dystrophin &#xC591;&#xC131; myofibers &#xC0DD;&#xC131; SCID/mdx &#xB9C8;&#xC6B0;&#xC2A4; &#xADFC;&#xC721;&#xC5D0; &#xC774;&#xC2DD; &#xD6C4; &#xC2E0;&#xC0DD;&#xC744; &#xC2B9;&#xC9C4;. &#xC774;&#xB7EC;&#xD55C; &#xAD00;&#xCE21; &#xC778;&#xAC04;&#xC758; &#xD608;&#xAD00; &#xBCBD; &#xB0B4; &#xC5FD; &#xC870;&#xC0C1; &#xC138;&#xD3EC;&#xC758; &#xC874;&#xC7AC;&#xB97C; &#xD655;&#xC778; &#xD558; &#xACE0; &#xD48D;&#xBD80;&#xD55C; vascularized &#xC778;&#xAC04;&#xC758; &#xD0DC; &#xBC18; &#xD48D;&#xBD80;&#xD55C; &#xC6D0;&#xCC9C;&#xC774; perivascular myogenic &#xC140; dystrophic &#xADFC;&#xC721; &#xB0B4;&#xC5D0;&#xC11C; &#xB9C8;&#xC774;&#xADF8;&#xB808;&#xC774;&#xC158;&#xD560; myofibers&#xB97C; &#xB2E4;&#xC2DC; &#xC0DD;&#xC131; &#xD558;&#xB294; &#xAC83;&#xC774; &#xC88B;&#xC2B5;&#xB2C8;&#xB2E4;.

&#xC778;&#xAC04;&#xC758; &#xADFC;&#xC721; &#xC7AC;&#xC0DD; &#xD0DC; &#xBC18; perivascular &#xC140;&#xC785;&#xB2C8;&#xB2E4;.

Perivasculares progenitores mesenquimales multipotentes existir en una variedad de tejidos, incluyendo la placenta. Aqu&#xED;, se sugiere que la presente vasculatura abundante en la placenta humana puede servir como una fuente de c&#xE9;lulas miog&#xE9;nicas para regenerar el m&#xFA;sculo esquel&#xE9;tico. Las vellosidades cori&#xF3;nicas disecados de la placenta humana mitad de la gestaci&#xF3;n fueron trasplantados primera intacto en los m&#xFA;sculos gemelos de SCID / MDX ratones, en los que participaron en la regeneraci&#xF3;n del m&#xFA;sculo por la producci&#xF3;n de fibras musculares que expresan humana distrofina y espectrina. In vitro, cultivo de vellosidades placentarias libera r&#xE1;pidamente adherentes y migratorias CD146 + CD34 CD45 &#x207B; &#x207B; CD56 &#x207B; c&#xE9;lulas de origen supuesta perivascular que expresa marcadores de c&#xE9;lulas madre mesenquimales. CD146 + CD34 &#x207B; CD45 CD56 &#x207B; &#x207B; de las c&#xE9;lulas perivasculares aislados y purificados a partir de las vellosidades placentarias por citometr&#xED;a de flujo eran en realidad altamente miog&#xE9;nica en la cultura, y ha generado positivas de distrofina fibras musculares, y se promueve la angiog&#xE9;nesis tras el trasplante en los m&#xFA;sculos de ratones SCID / MDX. Estas observaciones confirman la existencia de c&#xE9;lulas progenitoras mesenquimales dentro de las paredes de los vasos sangu&#xED;neos humanos, y sugieren que el ricamente vascularizado de la placenta humana es una fuente abundante de c&#xE9;lulas perivasculares miog&#xE9;nicas capaces de migrar dentro del m&#xFA;sculo distr&#xF3;fico y regenerar fibras musculares.

Placenta c&#xE9;lulas perivasculares para la regeneraci&#xF3;n del m&#xFA;sculo humano

Cancer treatment generally relies on tumor ablative techniques that can lead to major functional or disfiguring defects. These post-therapy impairments require the development of safe regenerative therapy strategies during cancer remission. Many current tissue repair approaches exploit paracrine (immunomodulatory, pro-angiogenic, anti-apoptotic and pro-survival effects) or restoring (functional or structural tissue repair) properties of mesenchymal stem/stromal cells (MSC). Yet, a major concern in the application of regenerative therapies during cancer remission remains the possible triggering of cancer recurrence. Tumor relapse implies the persistence of rare subsets of tumor-initiating cancer cells which can escape anti-cancer therapies and lie dormant in specific niches awaiting reactivation via unknown stimuli. Many of the components required for successful regenerative therapy (revascularization, immunosuppression, cellular homing, tissue growth promotion) are also critical for tumor progression and metastasis. While bi-directional crosstalk between tumorigenic cells (especially aggressive cancer cell lines) and MSC (including tumor stroma-resident populations) has been demonstrated in a variety of cancers, the effects of local or systemic MSC delivery for regenerative purposes on persisting cancer cells during remission remain controversial. Both pro- and anti-tumorigenic effects of MSC have been reported in the literature. Our own data using breast cancer clinical isolates have suggested that dormant-like tumor-initiating cells do not respond to MSC signals, unlike actively dividing cancer cells which benefited from the presence of supportive MSC. The secretome of MSC isolated from various tissues may partially diverge, but it includes a core of cytokines (i.e. CCL2, CCL5, IL-6, TGFβ, VEGF), which have been implicated in tumor growth and/or metastasis. This article reviews published models for studying interactions between MSC and cancer cells with a focus on the impact of MSC secretome on cancer cell activity, and discusses the implications for regenerative therapy after cancer. 

Mesenchymal stem cell secretome and regenerative therapy after cancer.

The generation of vascular progenitors (VPs) from human induced pluripotent stem cells (hiPSCs) has great potential for treating vascular disorders such as ischemic retinopathies. However, long-term in vivo engraftment of hiPSC-derived VPs into the retina has not yet been reported. This goal may be limited by the low differentiation yield, greater senescence, and poor proliferation of hiPSC-derived vascular cells. To evaluate the potential of hiPSCs for treating ischemic retinopathies, we generated VPs from a repertoire of viral-integrated and nonintegrated fibroblast and cord blood (CB)-derived hiPSC lines and tested their capacity for homing and engrafting into murine retina in an ischemia-reperfusion model.

Vascular progenitors from cord blood-derived induced pluripotent stem cells possess augmented capacity for regenerating ischemic retinal vasculature.

The hematopoietic and vascular lineages are intimately entwined as they arise together from bipotent hemangioblasts and hemogenic endothelial precursors during human embryonic development. In vitro differentiation of human pluripotent stem cells toward these lineages provides opportunities for elucidating the mechanisms of hematopoietic genesis. We previously demonstrated the stepwise in vitro differentiation of human embryonic stem cells (hESC) to definitive erythromyelopoiesis through clonogenic bipotent primitive hemangioblasts. This system recapitulates an orderly hematopoiesis similar to human yolk sac development via the generation of mesodermal-hematoendothelial progenitor cells that give rise to endothelium followed by embryonic primitive and definitive hematopoietic cells. Here, we report that under modified feeder-free endothelial culture conditions, multipotent CD34⁺ CD45⁺ hematopoietic progenitors arise in mass quantities from differentiated hESC and human induced pluripotent stem cells (hiPSC). These hematopoietic progenitors arose directly from adherent endothelial/stromal cell layers in a manner resembling in vivo hematopoiesis from embryonic hemogenic endothelium. Although fibroblast-derived hiPSC lines were previously found inefficient in hemato-endothelial differentiation capacity, our culture system also supported robust hiPSC hemato-vascular differentiation at levels comparable to hESC. We present comparative differentiation results for simultaneously generating hematopoietic and vascular progenitors from both hESC and fibroblast-hiPSC. This defined, optimized, and low-density differentiation system will be ideal for direct single-cell time course studies of the earliest hematopoietic events using time-lapse videography, or bulk kinetics using flow cytometry analyses on emerging hematopoietic progenitors.

Efficient and simultaneous generation of hematopoietic and vascular progenitors from human induced pluripotent stem cells.

The stromal-vascular fraction (SVF) of adipose tissue is a rich source of multipotent stem cells. We and others have described three major populations of stem/progenitor cells in this fraction, all closely associated with small blood vessels: endothelial progenitor cells (EPC, CD45-/CD31+/CD34+), pericytes (CD45-/CD31-/CD146+), and supra-adventitial adipose stromal cells (SA-ASC, CD45-/CD31-/CD146-/CD34+). EPC are luminal, pericytes are adventitial, and SA-ASC surround the vessel like a sheath. The multipotency of the pericytes and SA-ASC compartments is strikingly similar to that of CD45-/CD34-/CD73+/CD105+/CD90+ bone marrow-derived mesenchymal stem cells (BM-MSC). Here, we determine the extent to which this mesenchymal pattern is expressed on the three adipose stem/progenitor populations. Eight independent adipose tissue samples were analyzed in a single tube (CD105-FITC/CD73-PE/CD146-PETXR/CD14-PECY5/CD33-PECY5/CD235A-PECY5/CD31-PECY7/CD90-APC/CD34-A700/CD45-APCCY7/DAPI). Adipose EPC were highly proliferative with (14.3 ± 2.8)% (mean ± SEM) having >2N DNA. About half (53.1 ± 7.6)% coexpressed CD73 and CD105, and (71.9 ± 7.4)% expressed CD90. Pericytes were less proliferative [(8.2 ± 3.4)% >2N DNA)] with a smaller proportion [(29.6 ± 6.9)% CD73+/CD105+, (60.5 ± 10.2)% CD90+] expressing mesenchymal associated markers. However, the CD34+ subset of CD146+ pericytes were both highly proliferative [(15.1 ± 3.6)% with >2N DNA] and of uniform mesenchymal phenotype [(93.3 ± 3.7)% CD73+/CD105+, (97.8 ± 0.7)% CD90+], suggesting transit amplifying progenitor cells. SA-ASC were the least proliferative [(3.7 ± 0.8)%>2N DNA] but were also highly mesenchymal in phenotype [(94.4 ± 3.2)% CD73+/CD105+, (95.5 ± 1.2)% CD90+]. These data imply a progenitor/progeny relationship between pericytes and SA-ASC, the most mesenchymal of SVF cells. Despite phenotypic and functional similarities to BM-MSC, SA-ASC are distinguished by CD34 expression.

Mesenchymal markers on human adipose stem/progenitor cells.

The cancer stem cell (CSC) paradigm presumes the existence of self-renewing cancer cells capable of regenerating all tumor compartments and exhibiting stem cell-associated phenotypes. Recent interpretations of the CSC hypothesis envision stemness as a dynamic trait of tumor-initiating cells rather than a defined and unique cell type. Bidirectional crosstalk between the tumor microenvironment and the cancer bulk is well described in the literature and the tumor-associated stroma, vasculature and immune infiltrate have all been implicated as direct contributors to tumor development. These non-neoplastic cell types have also been shown to organize specific niches within the tumor bulk where they can control the intra-tumor CSC content and alter the fate of CSCs and tumor progenitors during tumorigenesis to acquire phenotypic features for invasion, metastasis and dormancy. Despite the complexity of the tumor-stroma interactome, novel therapeutic approaches envision combining tumor-ablative treatment with manipulation of the tumor microenvironment. We will review the currently available literature that provides clues about the complex cellular network that regulate the CSC phenotype and its niches during tumor progression.

Dynamic Interactions Between Cancer Stem Cells And Their Stromal Partners.

Tankyrase 1 (TNKS1; PARP-5a) and Tankyrase 2 (TNKS2; PARP-5b) are poly-ADP-ribosyl-polymerase (PARP)-domain-containing proteins that regulate the activities of a wide repertoire of target proteins via post-translational addition of poly-ADP-ribose polymers (PARylation). Although tankyrases were first identified as regulators of human telomere elongation, important and expansive roles of tankyrase activity have recently emerged in the development and maintenance of stem cell states. Herein, we summarize the current state of knowledge of the various tankyrase-mediated activities that may promote human naïve and 'extended' pluripotency'. We review the putative role of tankyrase and PARP inhibition in trophectoderm specification, telomere elongation, DNA repair and chromosomal segregation, metabolism, and PTEN-mediated apoptosis. Importantly, tankyrases possess PARP-independent activities that include regulation of MDC1-associated DNA repair by homologous recombination (HR) and autophagy/pexophagy, which is an essential mechanism of protein synthesis in the preimplantation embryo. Additionally, tankyrases auto-regulate themselves via auto-PARylation which augments their cellular protein levels and potentiates their non-PARP tankyrase functions. We propose that these non-PARP-related activities of tankyrase proteins may further independently affect both naïve and extended pluripotency via mechanisms that remain undetermined. We broadly outline a hypothetical framework for how inclusion of a tankyrase/PARP inhibitor in small molecule cocktails may stabilize and potentiate naïve and extended pluripotency via pleiotropic routes and mechanisms.

Pleiotropic roles of tankyrase/PARP proteins in the establishment and maintenance of human naïve pluripotency.

Human pluripotent stem cells (hPSCs) can generate specialized cell lineages that have great potential for regenerative therapies and disease modeling. However, the developmental stage of the lineages generated from conventional hPSC cultures in vitro are embryonic in phenotype, and may not possess the cellular maturity necessary for corrective regenerative function in vivo in adult recipients. Here, we present the scientific evidence for how adult human tissues could generate human-animal interspecific chimeras to solve this problem. First, we review the phenotypes of the embryonic lineages differentiated from conventional hPSC in vitro and through organoid technologies and compare their functional relevance to the tissues generated during normal human in utero fetal and adult development. We hypothesize that the developmental incongruence of embryo-stage hPSC-differentiated cells transplanted into a recipient adult host niche is an important mechanism ultimately limiting their utility in cell therapies and adult disease modeling. We propose that this developmental obstacle can be overcome with optimized interspecies chimeras that permit the generation of adult-staged, patient-specific whole organs within animal hosts with human-compatible gestational time-frames. We suggest that achieving this goal may ultimately have to await the derivation of alternative, primitive totipotent-like stem cells with improved embryonic chimera capacities. We review the scientific challenges of deriving alternative human stem cell states with expanded embryonic potential, outline a path forward for conducting this emerging research with appropriate ethical and regulatory oversight, and defend the case of why current federal funding restrictions on this important category of biomedical research should be liberalized.

Running the full human developmental clock in interspecies chimeras using alternative human stem cells with expanded embryonic potential.

Tankyrase/PARP inhibitor-regulated naïve human pluripotent stem cells (TIRN-hPSC) represent a new class of human stem cells for regenerative medicine that can differentiate into multi-lineage progenitors with improved in vivo functionality. Chemical reversion of conventional, primed hPSC to a TIRN-hPSC state alleviates dysfunctional epigenetic donor cell memory, lineage-primed gene expression, and potentially disease-associated aberrations in their differentiated progeny. Here, we provide methods for the reversion of normal or diseased patient-specific primed hPSC to TIRN-hPSC and describe their subsequent differentiation into embryonic-like pericytic-endothelial "naïve" vascular progenitors (N-VP). N-VP possess improved vascular functionality, high epigenetic plasticity, maintain greater genomic stability, and are more efficient in migrating to and re-vascularizing ischemic tissues than those generated from primed isogenic hPSC. We also describe detailed methods for the ocular transplantation and quantitation of vascular engraftment of N-VP into the ischemia-damaged neural retina of a humanized mouse model of ischemic retinopathy. The application of TIRN-hPSC-derived N-VP will advance vascular cell therapies of ischemic retinopathy, myocardial infarction, and cerebral vascular stroke.

ArticleTotal : 2	Year
Publication title Cited by 16	2018
Publication title	2025

Article	Year
Placental perivascular cells for human muscle regeneration. Stem cells and development\| PubMed ID: 20923371	2011
Mesenchymal stem cell secretome and regenerative therapy after cancer. Biochimie\| PubMed ID: 23747841	2013
Vascular progenitors from cord blood-derived induced pluripotent stem cells possess augmented capacity for regenerating ischemic retinal vasculature. Circulation\| PubMed ID: 24163065	2014
Efficient and simultaneous generation of hematopoietic and vascular progenitors from human induced pluripotent stem cells. Cytometry. Part A : the journal of the International Society for Analytical Cytology\| PubMed ID: 22736485	2013
Mesenchymal markers on human adipose stem/progenitor cells. Cytometry. Part A : the journal of the International Society for Analytical Cytology\| PubMed ID: 23184564	2013
Dynamic Interactions Between Cancer Stem Cells And Their Stromal Partners. Current pathobiology reports\| PubMed ID: 24660130	2014
Pleiotropic roles of tankyrase/PARP proteins in the establishment and maintenance of human naïve pluripotency. Experimental cell research\| PubMed ID: 32151493	2020
Running the full human developmental clock in interspecies chimeras using alternative human stem cells with expanded embryonic potential. NPJ Regenerative medicine\| PubMed ID: 34001907	2021
Generation of Pericytic-Vascular Progenitors from Tankyrase/PARP-Inhibitor-Regulated Naïve (TIRN) Human Pluripotent Stem Cells. Methods in molecular biology (Clifton, N.J.)\| PubMed ID: 34870835	2022

Ludovic Zimmerlin

Biography

JoVE Journal Publications

Other Publications