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

Chendong Pan, Matthew S. Nelson, Morayma Reyes Gil, Lisa Koodie, Joseph J. Brazil, Elliot J. Stephenson, Robert C. Zhao, Charles Peters, Scott B. Selleck, Sally E. Stringer, Pankaj Gupta

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

In mucopolysaccharidosis-I (MPS-I), α-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 recentiy 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 FQF-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.

Original languageEnglish (US)
Pages (from-to)1956-1964
Number of pages9
JournalBlood
Volume106
Issue number6
DOIs
StatePublished - Sep 15 2005
Externally publishedYes

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Mucopolysaccharidosis I
Heparitin Sulfate
Fibroblast Growth Factor 2
Stem Cells
Iduronidase
Cytokines
Dermatan Sulfate
Cytokine Receptors
Survival
Fibroblast Growth Factors
Cell proliferation
Glycosaminoglycans
Stem cells
Morphogenesis
Cell Survival
Healthy Volunteers
Bone
Substitution reactions
Bone Marrow
Cell Proliferation

ASJC Scopus subject areas

  • Hematology

Cite this

Functional abnormalities of heparan sulfate in mucopolysaccharidosis-I are associated with defective biologic activity of FGF-2 on human multipotent progenitor cells. / Pan, Chendong; Nelson, Matthew S.; Reyes Gil, Morayma; Koodie, Lisa; Brazil, Joseph J.; Stephenson, Elliot J.; Zhao, Robert C.; Peters, Charles; Selleck, Scott B.; Stringer, Sally E.; Gupta, Pankaj.

In: Blood, Vol. 106, No. 6, 15.09.2005, p. 1956-1964.

Research output: Contribution to journalArticle

Pan, C, Nelson, MS, Reyes Gil, M, Koodie, L, Brazil, JJ, Stephenson, EJ, Zhao, RC, Peters, C, Selleck, SB, Stringer, SE & Gupta, P 2005, 'Functional abnormalities of heparan sulfate in mucopolysaccharidosis-I are associated with defective biologic activity of FGF-2 on human multipotent progenitor cells', Blood, vol. 106, no. 6, pp. 1956-1964. https://doi.org/10.1182/blood-2005-02-0657
Pan, Chendong ; Nelson, Matthew S. ; Reyes Gil, Morayma ; Koodie, Lisa ; Brazil, Joseph J. ; Stephenson, Elliot J. ; Zhao, Robert C. ; Peters, Charles ; Selleck, Scott B. ; Stringer, Sally E. ; Gupta, Pankaj. / Functional abnormalities of heparan sulfate in mucopolysaccharidosis-I are associated with defective biologic activity of FGF-2 on human multipotent progenitor cells. In: Blood. 2005 ; Vol. 106, No. 6. pp. 1956-1964.
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