上世紀(jì) 90年代以來,，干細(xì)胞移植技術(shù)得到飛速發(fā)展。研究人員利用干細(xì)胞形成特定組織器官用于移植,。胚胎干細(xì)胞能夠形成各種各樣的身體組織,。很多研究人員相信利用這種細(xì)胞使組織再生，從而能夠起到治療多種疾病的作用,。用胚胎干細(xì)胞修復(fù)動(dòng)物組織器官的成功實(shí)例也時(shí)有報(bào)道,。

Memorial Sloan-kettering癌癥中心的研究人員，Diego Fraidenraich和同事,，在10月8日的Science上,，公布了他們的一項(xiàng)新研究的結(jié)果，胚胎干細(xì)胞還能夠分泌出治愈性的分子，這些分泌物足以逆轉(zhuǎn)小鼠的致死性的先天缺陷,。這個(gè)新研究則揭示出胚胎干細(xì)胞的另外的一個(gè)功能,。

在這項(xiàng)新的研究中，研究人員把胚胎干細(xì)胞注射到有致命心臟缺陷的小鼠胚胎（這些胚胎必定會(huì)出現(xiàn)嚴(yán)重的心臟缺陷,，并且使得小鼠可能會(huì)在子宮中死亡）中后,，但出乎意料的是，干細(xì)胞分泌的信號(hào)分子使小鼠心臟的缺陷沒有發(fā)展,，有一半的新生小鼠有一個(gè)健康的心臟,。同時(shí)，將干細(xì)胞注射給沒有妊娠的母鼠,，部分地改正了它們后代的遺傳性心臟缺陷,，避免了胚胎的死亡。盡管很少有干細(xì)胞真的長成了健康的心臟組織,，但研究人員發(fā)現(xiàn)干細(xì)胞能夠分泌出特殊的分子,，長程信號(hào)分子IGF1和短程信號(hào)分子WNT5a，這些分子在改正這些缺陷和挽救小鼠胚胎上起了作用,。研究的領(lǐng)導(dǎo)者Fraidenraich將這些分泌物叫做“拯救因子”,。當(dāng)科學(xué)家把干細(xì)胞注射到成熟的母鼠身上時(shí)，來自干細(xì)胞的IGF1 似乎能穿過胎盤到達(dá)小鼠胚胎,，但是WNT5a不能,。當(dāng)把干細(xì)胞直接注射給早期的小鼠胚胎時(shí)，兩種信號(hào)分子都到達(dá)了有缺陷的心臟組織,。

這個(gè)新發(fā)現(xiàn)拓寬了胚胎干細(xì)胞治療疾病的方式,。許多干細(xì)胞研究專家對(duì)這個(gè)發(fā)現(xiàn)也給予了高度的評(píng)價(jià)。胚胎干細(xì)胞分泌的因子也許有朝一日能用來治療成年人的心臟病,。

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Rescue of cardiac malformations in mutant mouse embryos by ES cells. (A) Embryos lacking the Id1, Id2, and Id3 genes display multiple cardiac abnormalities and die around embryonic day 13.5. The complex cardiac phenotype includes ventricular septal defects (VSD), thinning of the myocardial wall, outflow tract atresia, and endocardial cushion defects. Additionally, these hearts display reduced cell proliferation by disorganized sheets of myocytes and a discontinuous endocardial lining. (B) Injection of a small number of wild-type (wt) ES cells carrying a lacZ marker into Id mutant blastocysts resulted in about 20% chimerism of heart tissue and complete rescue of the Id mutant phenotype. Intraperitoneal injection of wild-type ES cells into female mice (Id1-/-, Id3+/-) prior to conception that were mated with males (Id1-/-, Id3+/-) partially rescued the cardiac phenotype of Id mutant embryos without incorporation of ES cells into the fetal heart tissue. Short- and long-range signals emanating from the ES cells reversed the myocardial defect in a non-cell autonomous manner. Two signaling molecules secreted by ES cells--Wnt5a, a locally secreted factor, and IGF-1, a bloodstream factor that promotes myocyte proliferation--were identified as potential candidates involved in the rescue process.

Fig. 1. Cardiac defects in Id KO embryos are rescued by injection of 15 ES cells. [(A) to (O)] A WT (A, D, G, J, and M), Id1–/–Id3–/– (B, E, H, K, and N), or Id1–/–Id3–/–:R26 (C, F, I, L, and O) E11.5 embryo was X-Gal stained [(A) to (C)] or transversely sectioned at the ventricle [(D) to (L)] or OT level [(M) to (O)]. (D) to (F) are magnified by 50x and (M) to (O) are magnified by 80x, desmin immunodetection. (G) to (I) show CD31 immunodetection at 200x. (J) to (L) show BrdU immunodetection at 100x. The inset in (L) shows the percentage of BrdU from (J) to (L). [(P) and (Q)] A WT (P), ROSA+/– [(P), inset], or Id1–/–Id3–/–:R26 (Q) E17.5 embryo was X-Gal and eosin stained (magnified by 50x). [(R) to (Z2)] A WT (R and S), WT:R26 (V and W), Id1–/– Id2+/– Id3–/–:R26 (T and U), or Id1–/–Id3–/–:R26 (X and Y) P7 [(R) to (U)] or P120 [(V) to (Z2)] heart was sectioned (dashed lines), X-Gal and eosin stained [(S) and (U), 25x; (W) and (Y), 15x) or CD31 immunostained [(Z1) and (Z2), 50x). He, heart; FB, forebrain; VS, ventricular septum; Tr, trabeculae; End, endocardium; Myo, myocardium; Th, thymus; LV, left ventricle; RV, right ventricle; blue arrow, outflow tract EC; KO, Id KO; red bar in (J) to (L), myocardial wall thickness; red bar in (M) to (O), luminal thickness; black arrowhead in (Z1) and (Z2), CD31+ cells. Scale bar, 500 µm [(A) to (C)]; 2 mm [(R), (T), (V), and (X)].

Fig. 2. R26 cells rescue Id1–/–Id3–/– cells non–cell autonomously. (A to C and I to K) A WT [(A) and (I)], Id1–/–Id3–/– [(B) and (J)], or Id1–/–Id3–/–:R26 [(C) and (K)] E11.5 embryo was subjected to ISH for Stra13 (100x). (D) Adjacent section of (C), X-Gal stained. (L) An Id1–/–Id3–/–:R26 E14.5 embryo was X-Gal and CD31 immunostained (100x). [(E) to (G)] A WT (E), Id1–/–Id3+/– (F), or Id1–/–Id2+/–Id3–/–:R26 (G) P7 heart was subjected to ISH for skMLC (50x). (H) Adjacent section of (G), X-Gal stained. [(E), inset] Northern blot from a WT or Id1–/–Id3+/– E13.5 heart probed for skMLC. Insets in (I) to (K) show bright field. V, ventricle; At, atrium; GE, ganglionic eminence; black arrowhead in (J) inset, hemorrhage; white arrowheads (L), CD31+ cells.

Fig. 3. Conditioned medium from Id KO:R26 epicardial cells (epiCM) corrects myocardial proliferation defects in Id KO hearts. (A to C) A WT, Id1–/–Id3+/–, or Id1–/–Id3+/–:R26 E17.5 embryo was sectioned at heart level and Ki67 immunostained. (D) Percentage of Ki67+ cells of (A) to (C). Error bars show mean + SD. (E to G and I to K) An Id1–/–Id3+/– E17.5 [(E) to (G)] or Id1–/–Id3–/– E12.5 [(I) to (K)] heart was cultured with BrdU and WT [(E) and (I)], Id1–/–Id3+/– [(F) and (J)], or Id1–/–Id3+/–:R26 [(G) and (K)] epiCM, sectioned, and Ki67 [(E) to (G)] or BrdU [(E) to (G), insets] immunostained or subjected to ISH for skMLC [(I) to (K)]. (H) Percentage of Ki67+ cells of (E) to (G) and control with no epiCM. Error bars show mean + SD. (L) RT-PCR [cardiac actin (ca), epicardin (epi), and pecam (pec)] of Id1–/–Id3+/–:R26 epicardial-derived cells (lane 1) or E13.5 heart (lane 2). [(L), inset] Id1–/–Id3+/–:R26 epicardial-derived cells were X-Gal stained. KO, Id1–/–Id3+/–. Magnification: 630x in (A) to (C) and (E) to (G); 400x in (I) to (K). CZ, myocardial compact zone; M, markers.

Fig. 4. Id1/Id3 double KO pups are born from mice intraperitoneally injected with ES cells or IGF-1. (A to C) An Id1–/–Id3–/– E11.5 embryo from an ES-injected female was sectioned at heart [(A) to (C)] or brain [(B), inset] level and Desmin [(A), 50x], CD31 [(B), 200x and (B), inset, 100x] or BrdU [(C), 100x] immunostained. [(D) to (L)] A WT (D to F), an Id1–/–Id3–/– from an ES-injected female (G to I), or an Id1–/–Id3–/– from an IGF-1–injected female (J to L) P1 heart was transversely sectioned and stained with X-Gal and eosin [(D), (G), and (J), 25x], CD31 [(E), (H), and (K), 200x], or Ki67 [(F), (I), and (L), 50x]. [(F) and (I), insets] A WT [(F), inset, 400x] or an Id1–/–Id3+/– E18.5 heart from a noninjected or from an R26 injected female [(I), insets, 400x] was sectioned and Ki67 immunostained. KO(R26), Id KO embryos (pups) from R26-injected females; KO (IGF-1), Id KO pups from IGF-1–injected females; End, endocardium; Myo, myocardium; RV, right ventricle; LV, left ventricle; VS, ventricular septum; GE, ganglionic eminence; arrowhead (A), VS defect; red bar (C), thickness of compact myocardium; white arrowhead (G), VS defect; black arrowheads (E), CD31+ endocardial cells; white arrowheads (E), CD31+ endothelial cells; white arrowheads [(H) and (K)], disorganized

Fig. 5. IGF-1 is down-regulated in Id1/Id3 KO embryos. [(A) to (F)] A WT (A, C, and E) or an Id1–/–Id3–/– (B, D, and F) E11.5 heart was sagittally sectioned and desmin immunostained [(A) and (B)] or IGF-1 in situ stained [(C) to (F)]. [(E) and (F), insets] Desmin immunostaining of (E) and (F). (A) to (D), 100x; (E) and (F), 200x. (G) RNA from a WT or an Id1–/–Id3–/– E11.5 liver was hybridized with IGF-1, IGFBP4, or glyceraldehyde-3-phosphate dehydrogenase (GAPDH). At, atrium; Ve, ventricle; end, endocardium; epi, epicardium. White arrowheads [(C) and (D)], EC+ cells; gray arrowheads [(C) and (D)], endocardial+ cells; gray arrowheads [(E) and (F)], end+ cells; blue arrowheads [(E) and (F)], epi+ cells.

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http://intl.sciencemag.org/cgi/content/full/306/5694/239

http://www.eurekalert.org/pub_releases/2004-10/mscc-esc100404.php