Functional abnormalities of heparan sulfate in mucopolysaccharidosis-I are associated with defective biologic activity of FGF-2 on human multipotent progenitor cells.

In mucopolysaccharidosis-I (MPS-I), alpha-L-iduronidase deficiency leads to progressive heparan sulfate (HS) and dermatan sulfate (DS) glycosaminoglycan (GAG) accumulation. The functional consequences of these accumulated molecules are unknown. HS critically influences tissue morphogenesis by binding to and modulating the activity of several cytokines (eg, fibroblast growth factors [FGFs]) involved in developmental patterning. We recently isolated a multipotent progenitor cell from postnatal human bone marrow, which differentiates into cells of all 3 embryonic lineages. The availability of multipotent progenitor cells from healthy volunteers and patients with MPS-I (Hurler syndrome) provides a unique opportunity to directly examine the functional effects of abnormal HS on cytokine-mediated stem-cell proliferation and survival. We demonstrate here that abnormally sulfated HS in Hurler multipotent progenitor cells perturb critical FGF-2-FGFR1-HS interactions, resulting in defective FGF-2-induced proliferation and survival of Hurler multipotent progenitor cells. Both the mitogenic and survival-promoting activities of FGF-2 were restored by substitution of Hurler HS by normal HS. This perturbation of critical HS-cytokine receptor interactions may represent a mechanism by which accumulated HS contributes to the developmental pathophysiology of Hurler syndrome. Similar mechanisms may operate in the pathogenesis of other diseases where structurally abnormal GAGs accumulate.

Constitutive expression of the Fas receptor and its ligand in adult human bone marrow: a regulatory feedback loop for the homeostatic control of hematopoiesis.

Fas ligand (FasL) mediated apoptosis in the bone marrow may contribute to suppression of hematopoiesis in myelodysplastic syndromes (MDS) and in aplastic anemia, and also to the regulation of normal erythropoiesis. To identify potential effector and target cells in this regulatory pathway, we examined the constitutive expression of Fas receptor (Fas) and FasL (total and cell-surface) in myeloid and lymphoid cells and subsets of CD34+ cells in normal healthy adult human bone marrow using multiparameter flow cytometry. A high proportion of CD34+ cells constitutively expressed cell-surface FasL. However, none of the CD34+ cells expressed Fas alone. A reciprocal gradient of expression of FasL and Fas was observed in subsets of CD34+ cells: as compared to primitive CD34+/HLA-DR(-) (DR(-)) cells, a higher proportion of committed CD34+/HLA-DR(++) (DR(++)) cells expressed FasL but fewer expressed Fas; the expression of both molecules was intermediate in CD34+/HLA-DR(dim) cells. Also, the intensity of FasL expression was higher in DR(++) than in DR(-) cells. These results suggest that the homeostatic regulation of myelopoiesis in normal bone marrow is mediated via an autoregulatory feedback loop by myeloid cells and progenitors themselves, at least partly via the Fas-FasL pathway. This notion is also consistent with our recent observation that overexpression of FasL by myeloid cells in MDS correlates directly with anemia, transfusion requirements, and shorter survival, an example of dysregulation of this pathway.