Increased stemness and migration of human mesenchymal stem cells in hypoxia is associated with altered integrin expression

Saller, Maximilian Michael; Prall, Wolf Christian; Docheva, Denitsa; Schönitzer, Veronika; Popov, Cvetan; Anz, David; Clausen‐Schaumann, Hauke; Mutschler, Wolf; Volkmer, Elias; Schieker, Matthias; Polzer, Hans

doi:10.1016/j.bbrc.2012.05.134

Cited by 76 publications

(59 citation statements)

References 22 publications

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“…However, further study is needed into the sequential gene expression pattern in normoxic/hypoxic conditions at various experimental time points to confirm the aforementioned hypothesis. The migration of MSCs was shown to increase under the influence of hypoxia [21]; similar results were obtained using the present in vitro assay, and hypoxic preconditioning of hBMSCs in the ectopic transplantation increased the distribution of newly formed mineralized tissues within the transplanted materials.…”

Section: Discussionsupporting

confidence: 87%

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Human bone marrow stem cells cultured under hypoxic conditions present altered characteristics and enhanced in vivo tissue regeneration

Lee

Park

Kim

et al. 2015

Bone

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Section: Discussionsupporting

confidence: 87%

“…4). This concurs with the previous finding that cell migration activity is enhanced in hypoxia [21]. Histological analysis revealed that the formation of blood vessels was greatly increased with hypoxia.…”

Section: Enhanced Migration Activity Of Hbmscs Cultured Under Hypoxiasupporting

confidence: 91%

Human bone marrow stem cells cultured under hypoxic conditions present altered characteristics and enhanced in vivo tissue regeneration

Lee

Park

Kim

et al. 2015

Bone

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“…Thus, culturing MSCs under hypoxia can mimic the natural microenvironment of stem cells and allow investigations of the proliferation, differentiation, senescence, metabolic balance, and other physiological aspects of these cells, which have potentially important clinical applications (Rosová et al 2008). Previous studies mainly reported the positive effects of hypoxia on the biological characteristics of human MSCs (Saller et al 2012;Lennon et al 2001;Hung et al 2007; Grayson On the other hand, several studies showed negative or no effects of hypoxia on MSCs (Holzwarth et al 2010;Roemeling-van Rhijn et al 2013;Raheja et al 2011;Salim et al 2004;Zhu et al 2006;Malladi et al 2006). These discrepancies may be due to the variation in the oxygen tension, the duration of hypoxic culture, comparison of a limited range of biological characteristics employing a low number of MSCs, and the variation in the system that was used in each study to control the oxygen level.…”

Section: Discussionmentioning

confidence: 99%

Effect of low oxygen tension on the biological characteristics of human bone marrow mesenchymal stem cells

Kim

Lee

et al. 2016

Cell Stress and Chaperones

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Culture of mesenchymal stem cells (MSCs) under ambient conditions does not replicate the low oxygen environment of normal physiological or pathological states and can result in cellular impairment during culture. To overcome these limitations, we explored the effect of hypoxia (1 % O 2 ) on the biological characteristics of MSCs over the course of different culture periods. The following biological characteristics were examined in human bone marrow-derived MSCs cultured under hypoxia for 8 weeks: proliferation rate, morphology, cell size, senescence, immunophenotypic characteristics, and the expression levels of stemness-associated factors and cytokine and chemokine genes. MSCs cultured under hypoxia for approximately 2 weeks showed increased proliferation and viability. During long-term culture, hypoxia delayed phenotypic changes in MSCs, such as increased cell volume, altered morphology, and the expression of senescence-associated-β-gal, without altering their characteristic immunophenotypic characteristics. Furthermore, hypoxia increased the expression of stemness and chemokine-related genes, including OCT4 and CXCR7, and did not decrease the expression of KLF4, C-MYC, CCL2, CXCL9, CXCL10, and CXCR4 compared with levels in cells cultured under normoxia. In conclusion, low oxygen tension improved the biological characteristics of MSCs during ex vivo expansion. These data suggest that hypoxic culture could be a useful method for increasing the efficacy of MSC cell therapies.

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“…HMSC were isolated from femoral heads of patients undergoing hip joint replacement due to a proximal femoral fracture as published previously [7,23,24]. Inclusion criteria were female gender, age >60 years and a T-Score of either >À1.0 SD for the healthy control group or <À2.5 SD for the osteoporosis group as measured by bone mineral density (DXA).…”

Section: Cells and Cell Culturementioning

confidence: 99%

Mesenchymal stem cells from osteoporotic patients reveal reduced migration and invasion upon stimulation with BMP-2 or BMP-7

Haasters

Docheva

Gassner

et al. 2014

Biochemical and Biophysical Research Communications

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Fractures to the osteoporotic bone feature a delay in callus formation and reduced enchondral ossification. Human mesenchymal stem cells (hMSC), the cellular source of fracture healing, are recruited to the fracture site by cytokines, such as BMP-2 and BMP-7. Aim of the study was to scrutinize hMSC for osteoporosis associated alterations in BMP mediated migration and invasion as well as in extracellular matrix (ECM) binding integrin expression. HMSC were isolated from 18 healthy or osteoporotic donors. Migration was assessed using a collagen IV coated micro-slide linear gradient chamber and time-lapse microscopy. Invasion was analyzed utilizing an ECM coated transmembrane invasion assay. Quantitative real-time RT PCR was performed for the ECM binding integrins α1, α2, α3, α4, α5, α11, αv and β1. HMSC from osteoporotic patients showed a significant increase of migration upon BMP-2 or FCS stimulation, as well as a significant increase of invasion upon BMP-2, BMP-7 or FCS stimulation. Nevertheless, the migration and invasion capacity was significantly decreased compared to healthy controls. Out of all integrins analyzed, collagen binding integrin α2 was significantly downregulated in hMSC from osteoporotic patients. In conclusion, we here demonstrate for the first time osteoporosis associated alterations in BMP mediated hMSC recruitment. These findings may underlie the reduced healing of osteoporotic fractures. Nevertheless, the maintained migration and invasion response upon BMP stimulation illustrates the therapeutic potential of these clinically approved substances in the treatment of osteoporotic fractures. Another therapeutic target may be the downregulation of the collagen binding integrin α2 in hMSC from osteoporotic patients.

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Increased stemness and migration of human mesenchymal stem cells in hypoxia is associated with altered integrin expression

Cited by 76 publications

References 22 publications

Human bone marrow stem cells cultured under hypoxic conditions present altered characteristics and enhanced in vivo tissue regeneration

Human bone marrow stem cells cultured under hypoxic conditions present altered characteristics and enhanced in vivo tissue regeneration

Effect of low oxygen tension on the biological characteristics of human bone marrow mesenchymal stem cells

Mesenchymal stem cells from osteoporotic patients reveal reduced migration and invasion upon stimulation with BMP-2 or BMP-7

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