Oligodendrocyte generation during iron deficiency

描述(申请人提供)：世界上最普遍的营养缺乏症是缺铁。据估计，35%至58%的女性有不同程度的缺铁。缺铁的情况在怀孕期间尤为普遍。据报道，对于2岁以下的儿童，铁缺乏症的估计患病率为25%。虽然众所周知，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、脂肪酸组成变化和髓鞘功能低下，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。已经讨论过的另一种可能性是，由于缺铁，导致少突胶质细胞从前体细胞产生的失败。这些假说是基于这样的观察，即体内铁可利用性的峰值恰好与髓鞘形成的高峰期重合，并且在缺乏足够的铁的情况下，正常的髓鞘形成不会发生。绝大多数试图破译铁在胶质形成中的具体作用的研究都集中在出生后发育阶段，此时少突胶质细胞在体内形成功能髓鞘。然而，我们自己的研究表明，缺铁对胚胎脊髓的早期神经胶质前体细胞有严重影响。在低铁环境中生长的胚胎胶质前体细胞分裂和分化的能力似乎受到了损害。因此，我们现在提出，与缺铁相关的髓鞘过少很可能是胚胎发育过程中已经发生的损伤的晚期后果。我们认为，铁干扰了少突胶质细胞生成的祖先的最早发育步骤，因此扰乱了正常的进行性谱系限制序列，这是正确生成这些髓鞘生成细胞所必需的。

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.