title: Cell-autonomous heparanase modulates self-renewal and migration in bone marrow-derived mesenchymal stem cells.
abstract: BACKGROUND
  Stem cell-fate is highly regulated by stem cell niche, which is composed of a distinct microenvironment, including neighboring cells, signals and extracellular matrix. Bone marrow-derived mesenchymal stem cells (BM-MSCs) are multipotent stem cells and are potentially applicable in wide variety of pathological conditions. However, the niche microenvironment for BM-MSCs maintenance has not been clearly characterized. Accumulating evidence indicated that heparan sulfate glycosaminoglycans (HS-GAGs) modulate the self-renewal and differentiation of BM-MSCs, while overexpression of heparanase (HPSE1) resulted in the change of histological profile of bone marrow. Here, we inhibited the enzymatic activity of cell-autonomous HPSE1 in BM-MSCs to clarify the physiological role of HPSE1 in BM-MSCs.
  
  
  RESULTS
  Isolated mouse BM-MSCs express HPSE1 as indicated by the existence of its mRNA and protein, which includes latent form and enzymatically active HPSE1. During in vitro osteo-differentiations, although the expression levels of Hpse1 fluctuated, enzymatic inhibition did not affect osteogenic differentiation, which might due to increased expression level of matrix metalloproteinase 9 (Mmp9). However, cell proliferation and colony formation efficiency were decreased when HPSE1 was enzymatically inhibited. HPSE1 inhibition potentiated SDF-1/CXCR4 signaling axis and in turn augmented the migratory/anchoring behavior of BM-MSCs. We further demonstrated that inhibition of HPSE1 decreased the accumulation of acetylation marks on histone H4 lysine residues suggesting that HPSE1 also modulates the chromatin remodeling.
  
  
  CONCLUSIONS
  Our findings indicated cell-autonomous HPSE1 modulates clonogenicity, proliferative potential and migration of BM-MSCs and suggested the HS-GAGs may contribute to the niche microenvironment of BM-MSCs.
authors.forename: Chun-Chun
authors.initials: CC
authors.lastname: Cheng
authors.forename: Yen-Hua
authors.initials: YH
authors.lastname: Lee
authors.forename: Shau-Ping
authors.initials: SP
authors.lastname: Lin
authors.forename: Wei-Chun
authors.initials: WC
authors.lastname: Huangfu
authors.affiliation: Department of Animal Science and Technology, National Taiwan University, Taipei 106, Taiwan. ihliu@ntu.edu.tw.
authors.forename: I-Hsuan
authors.initials: IH
authors.lastname: Liu
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D054377:Chemokine CXCL12 / Q000096:biosynthesis; D005966:Glucuronidase / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D039902:Multipotent Stem Cells; D010012:Osteogenesis / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D055153:Stem Cell Niche / Q000235:genetics*; D000099175:Heparanase
chemical_list: D054377:Chemokine CXCL12; D005966:Glucuronidase; D000099175:Heparanase; C515256:Cxcl12 protein, mouse