Hyaluronan content of Wharton's jelly in healthy and Down syndrome fetuses.

The mechanisms by which the excess genetic material of chromosome 21 results in the dysmorphologic features of Down syndrome (DS) are largely unknown. It has been found that the extracellular matrix of nuchal skin of DS fetuses exhibits an higher content of hyaluronan (HA) compared to that of euploid fetuses. Since HA plays a central role in many morphogenetic processes during embryogenesis, an alteration in its metabolism could be involved in the pathogenesis of several structural defects of DS. The extracellular matrix of umbilical cord (UC) is the mammalian tissue with one of the highest content of HA. Therefore we sought to explore the quantitative HA modifications during gestation, tissue distribution and HA metabolism in euploid and DS UCs. Euploid UCs (n=28) and UCs from DS fetuses (n=13) were obtained after termination of pregnancy, spontaneous abortion, or at delivery. Quantitative and molecular size analysis were performed using HPLC and FPLC. Tissue distribution was visualized by immunohistochemistry. Gene expression for HA synthases (HAS) and hyaluronidases (HYAL) were quantified by real-time PCR techniques and HYAL activity was detected by zymography. In euploid UC only HA of a molecular weight of 1700 kDA was present while in DS UC an additional lower weight HA molecule of 1100 kDA was found. Immunohistochemistry showed a larger amount of Wharton's jelly HA in DS UCs than in euploid UC. Real-time PCR analysis showed that HAS 2 and HYAL 2 were expressed at significant levels in all specimens. A higher expression of HAS 2 and a lower expression of HYAL 2 was found in the Wharton's jelly of DS fetuses compared to that of euploid fetuses at 14 weeks of gestation. On the contrary, at term HYAL 2 expression was higher in DS specimens than in those from euploid fetuses. Zymographic studies showed a similar behavior with a lower HYAL activity at early gestation and a higher HYAL activity at term gestation in DS UCs compared to euploid specimens. Therefore we can conclude that HA is more represented in DS UCs than in euploid UCs. A complex alteration of the HA metabolism characterized by an increased synthesis of lower weight HA molecules is a peculiarity of DS UCs.