Oligodendrocyte generation during iron deficiency

描述（由申请人提供）：世界上最普遍的营养缺乏症是缺铁。据估计，35%到58%的女性都有不同程度的缺铁。缺铁在怀孕期间尤为普遍。据报道，2岁以下儿童缺铁的发生率估计为25%。虽然已知儿童缺铁与许多神经缺陷有关，包括行为影响、血脑屏障改变、脂肪酸组成改变和髓鞘形成不足，但导致这些缺陷的细胞机制尚不清楚。例如，有人假设缺铁会导致少突胶质细胞成熟或存活失败。另一种已经讨论过的可能性是由于缺铁导致前体细胞产生少突胶质细胞的失败。这些假设是基于以下观察：体内铁可用性的峰值与髓鞘形成的高峰期恰好吻合，而正常的髓鞘形成在缺乏足够铁的情况下不会发生。绝大多数试图破译铁在胶质瘤发生中的特定作用的研究都集中在出生后的发育阶段，当少突胶质细胞在体内形成功能性髓磷脂时。然而，我们自己的研究表明，铁的缺乏对胚胎脊髓的早期胶质前体细胞有严重的影响。在低铁环境中生长的胚胎胶质前体细胞的分裂和分化能力似乎受到损害。因此，我们现在提出，与缺铁有关的髓鞘退化很可能是胚胎发生期间已经发生的损伤的晚期后果。我们认为铁干扰了起源于少突胶质细胞生成的最早发育步骤，因此破坏了正常的进行性谱系限制序列，而这是这些髓磷脂生成细胞正常生成所必需的。

DESCRIPTION (provided by applicant): The most prevalent nutrient deficiency in the world is a lack of iron. It has been estimated that 35 to 58% of women have some degree of iron deficiency. The occurrence of iron deficiency is particularly prevalent during pregnancy. It has been reported that for children under 2 years of age, the estimated prevalence of iron deficiency is 25%. While it is known that iron deficiency in children is associated with a number of neural defects including behavioral effects, alterations to the blood brain barrier, changes in fatty acid composition, and hypo-myelination, the cellular mechanisms leading to such defects are not well understood. For example, it has been hypothesized that iron deficiency leads to a failure of oligodendrocyte maturation or survival. Another possibility that has been discussed is a failure in the generation of oligodendrocytes from the precursor cells that give rise to them due to iron deficiency. These hypotheses are based on observations that there is a peak of iron availability in vivo that coincides precisely with peak periods of myelination and that normal myelination does not occur in the absence of sufficient iron. The vast majority of studies that try to decipher the specific role of iron in gliogenesis have focused on the postnatal stage of development, when oligodendrocytes form functional myelin in vivo. Our own studies, however, have indicated that a lack of iron has a severe impact on the very early glial precursor cells of the embryonic spinal cord. Embryonic glial precursor cells that grow in low iron seem to be impaired in their ability to divide and to differentiate. Thus, we now propose that the hypomyelination that is associated with iron deficiency is likely to be a late consequence of damage that occurred already during embryogenesis. We propose that iron interferes with the earliest developmental steps ancestral to oligodendrocyte generation and therefore disrupts the normal sequence of progressive lineage restriction that is required for proper generation of these myelin-producing cells.