Myostatin genetic inactivation inhibits myogenesis by muscle-derived stem cells in vitro but not when implanted in the mdx mouse muscle.
Myostatin genetic inactivation inhibits myogenesis by muscle-derived stem cells in vitro but not when implanted in the mdx mouse muscle.
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DOI：
10.1186/scrt152
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发表时间：
2013-01-07
影响因子：
7.5
通讯作者：
Gonzalez-Cadavid NF
中科院分区：
文献类型：
--
作者：
Tsao J;Vernet DA;Gelfand R;Kovanecz I;Nolazco G;Bruhn KW;Gonzalez-Cadavid NF
刺激植入的dystrophin+肌源性干细胞(MDSCs)进入肌源性而不是脂肪纤维性谱系，是治疗Duchenne肌营养不良(DMD)的一种有前景的治疗策略。为了验证对抗肌肉质量的负调控因子和促脂肪纤维化因子myostatin是否有助于这一过程，我们比较了野生型(WT)和肌肉抑制素基因敲除(MST KO)小鼠的MDSCs在不同调节剂下的体外成肌和成纤维能力，关键干细胞和生肌基因的表达，以及这些MDSCs修复老年营养不良MDX小鼠脂肪纤维化恶化的腓肠肌的能力。令人惊讶的是，WT MDSCs在体外形成肌管的能力对myostatin表达或活性的调节剂是无效的，而MST KO MDSCs在各种条件下都未能形成肌管，尽管MDSC表达Oct4和各种干细胞基因并分化为非肌源性谱系。MDSCs中Myostatin的基因失活与早期肌肉发生的关键基因(Actc1、Acta1和MyoD)的沉默有关。将WT MDSCs移植到老年MDX小鼠受损的腓肠肌中，显著改善了肌纤维修复，减少了脂肪沉积，并在较小程度上减少了纤维化。与它们的体外行为相比，体内的MST KO MDSCs也显著地促进了肌纤维的修复，但对脂纤维变性的影响很小。虽然WT MDSCs在培养中非常成肌，并刺激老年MDX小鼠损伤后的肌肉修复，但myostatin基因失活在体外阻止了肌管的形成，但在体内，在myostatin+宿主组织环境的影响下，成肌能力可恢复，可能是通过重新激活最初在MST KO MDSCs中沉默的关键基因。
Stimulating the commitment of implanted dystrophin+ muscle-derived stem cells (MDSCs) into myogenic, as opposed to lipofibrogenic lineages, is a promising therapeutic strategy for Duchenne muscular dystrophy (DMD). To examine whether counteracting myostatin, a negative regulator of muscle mass and a pro-lipofibrotic factor, would help this process, we compared the in vitro myogenic and fibrogenic capacity of MDSCs from wild-type (WT) and myostatin knockout (Mst KO) mice under various modulators, the expression of key stem cell and myogenic genes, and the capacity of these MDSCs to repair the injured gastrocnemius in aged dystrophic mdx mice with exacerbated lipofibrosis. Surprisingly, the potent in vitro myotube formation by WT MDSCs was refractory to modulators of myostatin expression or activity, and the Mst KO MDSCs failed to form myotubes under various conditions, despite both MDSC expressing Oct 4 and various stem cell genes and differentiating into nonmyogenic lineages. The genetic inactivation of myostatin in MDSCs was associated with silencing of critical genes for early myogenesis (Actc1, Acta1, and MyoD). WT MDSCs implanted into the injured gastrocnemius of aged mdx mice significantly improved myofiber repair and reduced fat deposition and, to a lesser extent, fibrosis. In contrast to their in vitro behavior, Mst KO MDSCs in vivo also significantly improved myofiber repair, but had few effects on lipofibrotic degeneration. Although WT MDSCs are very myogenic in culture and stimulate muscle repair after injury in the aged mdx mouse, myostatin genetic inactivation blocks myotube formation in vitro, but the myogenic capacity is recovered in vivo under the influence of the myostatin+ host-tissue environment, presumably by reactivation of key genes originally silenced in the Mst KO MDSCs.
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影响因子：
7.5
作者：
Gharaibeh B;Lavasani M;Cummins JH;Huard J
通讯作者：
Huard J
DOI：
10.1152/ajpendo.00656.2010
发表时间：
2011-06-01
影响因子：
5.1
作者：
Choi, Sun Ju;Yablonka-Reuveni, Zipora;Wisse, Brent E.
通讯作者：
Wisse, Brent E.
影响因子：
7.2
作者：
Ho MH;Heydarkhan S;Vernet D;Kovanecz I;Ferrini MG;Bhatia NN;Gonzalez-Cadavid NF
通讯作者：
Gonzalez-Cadavid NF
影响因子：
4.1
作者：
Hsiao, Sheng Pin;Chen, Shen Liang
通讯作者：
Chen, Shen Liang
DOI：
10.1073/pnas.95.25.14938
发表时间：
1998-12-08
影响因子：
11.1
作者：
Gonzalez-Cadavid, NF;Taylor, WE;Bhasin, S
通讯作者：
Bhasin, S