Hypoxia Promotes Osteogenesis but Suppresses Adipogenesis of Human Mesenchymal Stromal Cells in a Hypoxia-Inducible Factor-1 Dependent Manner

Wagegg, Markus; Gaber, Timo; Lohanatha, Ferenz Leonard; Hahne, M.; Strehl, Cindy; Fangradt, Monique; Tran, Cam Loan; Schönbeck, K; Hoff, Paula; Ode, Andrea; Perka, Carsten; Duda, Georg N.; Buttgereit, Frank

doi:10.1371/journal.pone.0046483

Cited by 168 publications

(134 citation statements)

References 34 publications

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“…Previous studies have indicated that MSCs can be recruited by osteocytes under hypoxia, and genetic activation of the HIF-1α pathway increases neoangiogenesis and promotes bone regeneration (13). The present study identified that CoCl 2 was able to significantly increase the expression of Runx2, ALP and OC.…”

Section: Discussionsupporting

confidence: 60%

Effect of CoCl2 on fracture repair in a rat model of bone fracture

Huang

Liu

Feng

et al. 2015

Molecular Medicine Reports

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Abstract. Low oxygen availability is known to activate the hypoxia-inducible factor-1α (HIF-1α) pathway, which is involved in the impairment of fracture healing. However, the role of low oxygen in fracture healing remains to be fully elucidated. In the present study, rats were divided into two groups and treated with CoCl 2 or saline, respectively. Rats with tibial fractures were sacrificed at 14, 28 and 42 days subsequent to fracture. Autoradiography was performed to measure healing of the bone tissue. In addition, the effects of cobalt chloride (CoCl 2 ) on the expression of two major angiogenic mediators, HIF-1α and vascular endothelial growth factor (VEGF), as well as the osteoblast markers runt-related transcription factor 2 (Runx2), alkaline phosphatase (ALP) and osteocalcin (OC) were determined at mRNA and protein levels by reverse transcription-quantitative polymerase chain reaction, western blot analysis and immunohistochemistry. Systemic administration of CoCl 2 (15 mg/ kg/day intraperitoneally) significantly promoted fracture healing and mechanical strength. The present study demonstrated that in rats treated with CoCl 2 , the expression of HIF-1α, VEGF, Runx2, ALP and OC was significantly increased at mRNA and protein levels, and that CoCl 2 treatment enhances fracture repair in vivo. IntroductionTraumatic fractures are the most common type of injury in daily life. In the majority of clinical cases, the most simple fractures heal with minimal intervention; however, in severe fractures and in certain patient populations, including diabetics and patients with splintered fractures, impaired fracture healing and bone defects occur (1,2). In spite of numerous advances in every discipline of medicine, patients with complex bone injuries of the upper and lower extremities and are required to undergo prolonged reconstructive procedures for retrieval of their limb functions (2,3).It has been reported that the hypoxia-inducible factor (HIF) pathway is the central pathway for sensing and responding to alterations in local oxygen levels in a wide variety of organisms (4). Activation of the HIF-1α pathway can act as a critical mediator of neoangiogenesis, which is required for skeletal regeneration; thus, it is suggested that the application of HIF activators may be used as therapies to improve bone healing (4). An increasing number of studies suggested that hypoxia may be a powerful stimulus for bone cells via the mediation of angiogenesis [vascular endothelial growth factor (VEGF)], cellular metabolism (glucose transporter) and the recruitment of mesenchymal cells (MSCs) to areas of matrix damage (5-7). A more thorough understanding of hypoxia in bone healing will lead to the elucidation of cellular and molecular mechanisms that may aid in the development of protective therapies. CoCl 2 , a mimic of hypoxia, directly enhances HIF-1α stabilization and downstream target genes by inhibiting prolyl hydroxylase enzymes (8). An improved understanding of the alterations in gene expression that occur during fracture he...

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Section: Discussionsupporting

confidence: 60%

Effect of CoCl2 on fracture repair in a rat model of bone fracture

Huang

Liu

Feng

et al. 2015

Molecular Medicine Reports

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“…(109)]. Moreover, osteoblast differentiation at the expense of adipocyte differentiation was shown to be HIF-1a mediated in human stromal precursors (110). Taken together, we suggest the following: In the BM, immature stromal cells are able to retain their undifferentiated state and maintain their role in supporting primitive hematopoietic cells due to low ROS levels (also in the hematopoietic cells).…”

Section: Ros Mediates Proliferation and Differentiation Of Bm Mesenchmentioning

confidence: 73%

Reactive Oxygen Species Regulate Hematopoietic Stem Cell Self-Renewal, Migration and Development, As Well As Their Bone Marrow Microenvironment

Ludin

Gur-Cohen²,

Golan³

et al. 2014

Antioxidants & Redox Signaling

271

240

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Significance: Blood forming, hematopoietic stem cells (HSCs) mostly reside in the bone marrow in a quiescent, nonmotile state via adhesion interactions with stromal cells and macrophages. Quiescent, proliferating, and differentiating stem cells have different metabolism, and accordingly different amounts of intracellular reactive oxygen species (ROS). Importantly, ROS is not just a byproduct of metabolism, but also plays a role in stem cell state and function. Recent Advances: ROS levels are dynamic and reversibly dictate enhanced cycling and myeloid bias in ROS high short-term repopulating stem cells, and ROS low quiescent long-term repopulating stem cells. Low levels of ROS, regulated by intrinsic factors such as cell respiration or nicotinamide adenine dinucleotide phosphate-oxidase (NADPH oxidase) activity, or extrinsic factors such as stem cell factor or prostaglandin E2 are required for maintaining stem cell self-renewal. High ROS levels, due to stress and inflammation, induce stem cell differentiation and enhanced motility. Critical Issues: Stem cells need to be protected from high ROS levels to avoid stem cell exhaustion, insufficient host immunity, and leukemic transformation that may occur during chronic inflammation. However, continuous low ROS production will lead to lack of stem cell function and opportunistic infections. Ultimately, balanced ROS levels are crucial for maintaining the small stem cell pool and host immunity, both in homeostasis and during stress situations. Future Directions: Deciphering the signaling pathway of ROS in HSC will provide a better understanding of ROS roles in switching HSC from quiescence to activation and vice versa, and will also shed light on the possible roles of ROS in leukemia initiation and development. Antioxid. Redox Signal. 21, 1605-1619.

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“…Note that VEGF, GLUT1, LDHA, PGK1 genes are target genes of HIF-1a. 81 Previous data showed an increase in PDK1 gene expression. These data confirm that reduced cell respiration under hypoxic conditions is an outcome of the reduction of mitochondrial oxygen consumption.…”

Section: 83mentioning

confidence: 97%