Proangiogenic Hypoxia-Mimicking Agents Attenuate Osteogenic Potential of Adipose Stem/Stromal Cells

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http://hdl.handle.net/10138/318880

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Abu-Shahba , A , Gebraad , A , Kaur , S , Paananen , R O , Peltoniemi , H , Seppänen-Kaijansinkko , R & Mannerström , B 2020 , ' Proangiogenic Hypoxia-Mimicking Agents Attenuate Osteogenic Potential of Adipose Stem/Stromal Cells ' , Tissue Engineering and Regenerative Medicine , vol. 17 , no. 4 , pp. 477-493 . https://doi.org/10.1007/s13770-020-00259-3

Title: Proangiogenic Hypoxia-Mimicking Agents Attenuate Osteogenic Potential of Adipose Stem/Stromal Cells
Author: Abu-Shahba, Ahmed; Gebraad, Arjen; Kaur, Sippy; Paananen, Riku O.; Peltoniemi, Hilkka; Seppänen-Kaijansinkko, Riitta; Mannerström, Bettina
Contributor: University of Helsinki, Clinicum
University of Helsinki, HUS Head and Neck Center
University of Helsinki, Department of Oral and Maxillofacial Diseases
University of Helsinki, Silmäklinikka
University of Helsinki, HUS Head and Neck Center
University of Helsinki, HUS Head and Neck Center
Date: 2020-08
Language: eng
Number of pages: 17
Belongs to series: Tissue Engineering and Regenerative Medicine
ISSN: 1738-2696
URI: http://hdl.handle.net/10138/318880
Abstract: BACKGROUND: Insufficient vascularization hampers bone tissue engineering strategies for reconstructing large bone defects. Delivery of prolyl-hydroxylase inhibitors (PHIs) is an interesting approach to upregulate vascular endothelial growth factor (VEGF) by mimicking hypoxic stabilization of hypoxia-inducible factor-1alpha (HIF-1α). This study assessed two PHIs: dimethyloxalylglycine (DMOG) and baicalein for their effects on human adipose tissue-derived mesenchymal stem/stromal cells (AT-MSCs). METHODS: Isolated AT-MSCs were characterized and treated with PHIs to assess the cellular proliferation response. Immunostaining and western-blots served to verify the HIF-1α stabilization response. The optimized concentrations for long-term treatment were tested for their effects on the cell cycle, apoptosis, cytokine secretion, and osteogenic differentiation of AT-MSCs. Gene expression levels were evaluated for alkaline phosphatase (ALPL), bone morphogenetic protein 2 (BMP2), runt-related transcription factor 2 (RUNX2), vascular endothelial growth factor A (VEGFA), secreted phosphoprotein 1 (SPP1), and collagen type I alpha 1 (COL1A1). In addition, stemness-related genes Kruppel-like factor 4 (KLF4), Nanog homeobox (NANOG), and octamer-binding transcription factor 4 (OCT4) were assessed. RESULTS: PHIs stabilized HIF-1α in a dose-dependent manner and showed evident dose- and time dependent antiproliferative effects. With doses maintaining proliferation, DMOG and baicalein diminished the effect of osteogenic induction on the expression of RUNX2, ALPL, and COL1A1, and suppressed the formation of mineralized matrix. Suppressed osteogenic response of AT-MSCs was accompanied by an upregulation of stemness-related genes. CONCLUSION: PHIs significantly reduced the osteogenic differentiation of AT-MSCs and rather upregulated stemness-related genes. PHIs proangiogenic potential should be weighed against their longterm direct inhibitory effects on the osteogenic differentiation of AT-MSCs.
Subject: ANGIOGENESIS
Adipose tissue-derived mesenchymal stem
Baicalein
DELIVERY
DIFFERENTIATION
Dimethyloxalylglycine
EXPRESSION
Hypoxia-inducible factor-1alpha
INDUCIBLE FACTOR
INTERNATIONAL-SOCIETY
LOW-OXYGEN TENSION
MESENCHYMAL STEM-CELLS
Osteogenesis
PROLIFERATION
STROMAL CELLS
stromal cells
1182 Biochemistry, cell and molecular biology
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