Human bone marrow derived mesodermal progenitor cells (mpc) in vitro correct the biochemical abnormality in hurler syndrome

Pankaj Gupta, Joseph J. Brazil, Morayma Reyes, Catherine M. Verfaillie

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Abstract

Deficiency of a-L-iduronidase enzyme in Hurler syndrome leads to abnormal glycosaminoglycan (GAG) accumulation, progressive multisystem dysfunction and death in the first decade. Hematopoietic stem cell (HSC) transplantation provides a source of enzyme and prolongs life, but does not adequately correct neurological or skeletal abnormalities. We have recently cultured a multipotent, non-hematopoietic stem cell (MPC) from post-natal human bone marrow (Reyes M et al, ASH 1999). MPC have enormous expansion potential and can differentiate into neurons, glia, osteoblasts. chondrocytes, cardiac, smooth and skeletal muscle, and endothelial cells. We cultured MPC from Hurler bone marrow and analyzed the structure and metabolism of abnormal GAGs, using HPLC purification, followed by size, sulfation pattern and oligosaccharide domain analysis. Hurler MPC GAGs were markedly abnormal. Abnormal intracellular heparan sulfate (HS) GAGs resolved on HPLC as a distinct peak (60% of total GAGs) comprised of small (5 kD) highly sulfated (65%) oligosaccharides having abnormal oligosaccharide domains. In contrast, HS from normal MPC comprised only 19% of the total GAGs, were large (42kD) and less sulfated (22%). Since the biological activities of HS are mediated by optimal binding to various cytokines (Gupta P et al. Blood 2000; 95: 147-55), we examined the binding properties of Hurler HS using affinity co-electrophoresis. Normal MPC HS bound strongly to the stem cell homing inducing chemokines SDP-1 a and -β but Hurler HS did not, suggesting that Hurler HS is functionally abnormal. Normal MPC expressed high levels of a-L-iduronidase enzyme both at the mRNA (14 U by Clonetech 1.211 array) and functional protein levels. When cultured either in contact with or separated from Hurler MPC by a Transwell membrane, normal MPC completely cross-corrected the abnormal GAGs in Hurler MPC in a dose- and time-dependent manner. The metabolism of newly synthesized GAGs was completely corrected in 24 h, and 50% of previously accumulated GAGs were cleared by 7 days of co-culture. Following coculture, the size distribution of GAGs in Hurler cells was also normalized. Our data suggest that engraftment of normal MPC may correct the biochemical abnormality in host Hurler cells located at a distance from donor cells. Since MPC can differentiate into diverse lineages, transplantation of such cells may correct abnormalities even in organ systems that are not adequately corrected by HSC transplantation alone.

Original languageEnglish (US)
Pages (from-to)279a
JournalBlood
Volume96
Issue number11 PART I
StatePublished - Dec 1 2000

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