Formicola Luigi, Marazzi Giovanna, Sassoon David A
UMRS 1166 INSERM, Stem Cells and Regenerative Medicine, Institute of Cardiometabolism and Nutrition (ICAN), University of Pierre and Marie Curie Paris VI Paris, France.
Front Aging Neurosci. 2014 Dec 1;6:328. doi: 10.3389/fnagi.2014.00328. eCollection 2014.
Specific muscles are spared in many degenerative myopathies. Most notably, the extraocular muscles (EOMs) do not show clinical signs of late stage myopathies including the accumulation of fibrosis and fat. It has been proposed that an altered stem cell niche underlies the resistance of EOMs in these pathologies, however, to date, no reports have provided a detailed characterization of the EOM stem cell niche. PW1/Peg3 is expressed in progenitor cells in all adult tissues including satellite cells and a subset of interstitial non-satellite cell progenitors in muscle. These PW1-positive interstitial cells (PICs) include a fibroadipogenic progenitor population (FAP) that give rise to fat and fibrosis in late stage myopathies. PICs/FAPs are mobilized following injury and FAPs exert a promyogenic role upon myoblasts in vitro but require the presence of a minimal population of satellite cells in vivo. We and others recently described that FAPs express promyogenic factors while satellite cells express antimyogenic factors suggesting that PICs/FAPs act as support niche cells in skeletal muscle through paracrine interactions. We analyzed the EOM stem cell niche in young adult and aged wild-type mice and found that the balance between PICs and satellite cells within the EOM stem cell niche is maintained throughout life. Moreover, in the adult mdx mouse model for Duchenne muscular dystrophy (DMD), the EOM stem cell niche is unperturbed compared to normal mice, in contrast to Tibialis Anterior (TA) muscle, which displays signs of ongoing degeneration/regeneration. Regenerating mdx TA shows increased levels of both PICs and satellite cells, comparable to normal unaffected EOMs. We propose that the increase in PICs that we observe in normal EOMs contributes to preserving the integrity of the myofibers and satellite cells. Our data suggest that molecular cues regulating muscle regeneration are intrinsic properties of EOMs.
在许多退行性肌病中，特定的肌肉得以幸免。最显著的是，眼外肌（EOMs）不会出现晚期肌病的临床症状，包括纤维化和脂肪堆积。有人提出，干细胞生态位的改变是这些病症中眼外肌具有抗性的基础，然而，迄今为止，尚无报告对眼外肌干细胞生态位进行详细的特征描述。PW1/Peg3在所有成体组织的祖细胞中表达，包括卫星细胞以及肌肉中的一部分间质非卫星细胞祖细胞。这些PW1阳性间质细胞（PICs）包括一个纤维脂肪生成祖细胞群体（FAP），该群体在晚期肌病中会导致脂肪和纤维化。PICs/FAPs在损伤后被动员，FAPs在体外对成肌细胞发挥促肌生成作用，但在体内需要最少数量的卫星细胞存在。我们和其他人最近描述了FAPs表达促肌生成因子，而卫星细胞表达抗肌生成因子，这表明PICs/FAPs通过旁分泌相互作用在骨骼肌中充当支持性生态位细胞。我们分析了年轻成年和老年野生型小鼠的眼外肌干细胞生态位，发现眼外肌干细胞生态位内PICs和卫星细胞之间的平衡在整个生命过程中得以维持。此外，在杜兴肌营养不良症（DMD）的成年mdx小鼠模型中，与正常小鼠相比，眼外肌干细胞生态位未受干扰，而胫前肌（TA）则显示出持续退变/再生的迹象。再生的mdx TA中PICs和卫星细胞的水平均升高，与正常未受影响的眼外肌相当。我们提出，我们在正常眼外肌中观察到的PICs增加有助于维持肌纤维和卫星细胞的完整性。我们的数据表明，调节肌肉再生的分子信号是眼外肌的内在特性。
