Abstract
BackgroundStem 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.ResultsIsolated 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.ConclusionsOur 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.
Highlights
Stem cell-fate is highly regulated by stem cell niche, which is composed of a distinct microenvironment, including neighboring cells, signals and extracellular matrix
The expression of HPSE1 by mouse Bone marrow-derived mesenchymal stem cells (BM-mesenchymal stem cells (MSCs)) and the enzymatic inhibition by OGT2115 To test our hypothesis that cell autonomous heparanase participated in the maintenance of stem cell niche, we first demonstrated that mouse BM-MSCs express HPSE1
To clarify whether heparanase expressed by isolated BM-MSCs is enzymatically active, cell lysates were harvested for western blot
Summary
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. We inhibited the enzymatic activity of cell-autonomous HPSE1 in BM-MSCs to clarify the physiological role of HPSE1 in BM-MSCs. Stem cells are featured by their asymmetric behaviors of self-renewal and multipotentiality that are controlled by intrinsic genetic networks, which are modulated in response to extrinsic signals from the stem cell niches [1,2]. The best understood niche is hematopoietic stem cells (HSCs) in the bone marrow in which the mesenchymal stem cells (MSCs) have been suggested to contribute to the HSCs niche [4,5,6]. The fact that transplanted bone marrow cells re-establish stem cell colony around sinusoids along with the formation of a miniature bone organ suggested that BM-MSCs share similar perivascular niche microenvironment [13]. The detailed composition of this microenvironment and how the niche of mouse BM-MSCs is maintained remain elusive
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