Oxygen Tension Within the Neurogenic Niche Regulates Dopaminergic Neurogenesis in the Developing Midbrain

Abstract

Oxygen tension is an important factor controlling stem cell proliferation and maintenance in various stem cell populations with a particular relevance in midbrain dopaminergic progenitors. Further studies have shown that the oxygen-dependent transcription factor hypoxia-inducible factor 1a (HIF-1a) is involved in these processes. However, all available studies on oxygen effects in dopaminergic neuroprogenitors were performed in vitro and thus it remains unclear whether tissue oxygen tension in the embryonic midbrain is also relevant for the regulation of dopaminergic neurogenesis in vivo. We thus dissect here the effects of oxygen tension in combination with HIF-1a conditional knockout on dopaminergic neurogenesis by using a novel experimental design allowing for the control of oxygen tension within the microenvironment of the neurogenic niche of the murine fetal midbrain in vivo. The microenvironment of the midbrain dopaminergic neurogenic niche was detected as hypoxic with oxygen tensions below 1.1%. Maternal oxygen treatment of 10%, 21%, and 75% atmospheric oxygen tension for 48 h translates into robust changes in fetal midbrain oxygenation. Fetal midbrain hypoxia hampered the generation of dopaminergic neurons and is accompanied with restricted fetal midbrain development. In contrast, induced hyperoxia stimulated proliferation and differentiation of dopaminergic progenitors during early and late embryogenesis. Oxygen effects were not directly mediated through HIF-1a signaling. These data-in agreement with in vitro data-indicate that oxygen is a crucial regulator of developmental dopaminergic neurogenesis. Our study provides the initial framework for future studies on molecular mechanisms mediating oxygen regulation of dopaminergic neurogenesis within the fetal midbrain as its natural environment.

Hypoxic-Preconditioned Bone Marrow Stem Cell Medium Significantly Improves Outcome After Retinal Ischemia in Rats

“… 30 In vivo, the cells reside under hypoxic conditions between 4% and 7%. 31 Yet culture of MSCs under normoxia (21% oxygen) causes premature senescence and reduction in MSC differentiation capacity with each subsequent population doubling or passage. 32 As a result, recent attention has focused on MSC isolation and expansion under hypoxic or relatively hypoxic conditions in order to “precondition” the cells to the subsequent in vivo hypoxia.…”

Effects of normobaric versus hyperbaric oxygen on cell injury induced by oxygen and glucose deprivation in acute brain slices

“…That said, both NBO and HBO have been shown to reduce infarct size (Veltkamp et al, 2000(Veltkamp et al, , 2005Singhal et al, 2002;Henninger et al, 2007;Eschenfelder et al, 2008;Yang et al, 2010;David et al, 2012;Xu et al, 2016), to promote endogenous tPA-induced thrombolysis (David et al, 2012;Chazalviel et al, 2016b), to improve ischemiainduced decrease in tissue oxygenation (Liu et al, 2004(Liu et al, , 2006Shin et al, 2007;Sun et al, 2008;Baskerville et al, 2011), and to induce neurogenesis (Lee et al, 2013;Wagenfuhr et al, 2016), thereby questioning the interest of HBO compared to NBO in stroke. In the present study, to investigate this question, we compare the oxygen diffusion effects of NBO and HBO in acute brain slices exposed to OGD, an ex vivo model of brain ischemia that allows investigating the acute effects of NBO and HBO on tissue (parenchyma) oxygenation independently of their facilitating action on cerebral blood flow and thrombolysis at the vascular level and of their long term effects on neurogenesis.…”

“…emia (Sun et al, 2008), to promote thrombolysis through activation of endogenous tPA (Chazalviel et al, 2016b), and to reduce the decrease in regional glucose metabolism (Lou et al, 2007). Likewise, interestingly, normobaric oxygen (NBO) has also been shown to reduce infarct size (Singhal et al, 2002;Henninger et al, 2007;David et al, 2012), to induce neurogenesis (Wagenfuhr et al, 2016), to promote endogenous tPA-induced thrombolysis (David et al, 2012) , to increase cerebral blow flow and to improve the decrease in tissue oxygenation induced by ischemia (Liu et al, 2004(Liu et al, , 2006Shin et al, 2007;Baskerville et al, 2011), thereby questioning the interest of HBO compared to NBO in the treatment of acute brain ischemia.…”

Lung bioengineering: physical stimuli and stem/progenitor cell biology interplay towards biofabricating a functional organ

“…Indeed, whereas most of the research has been carried out under room-air oxygenation conditions (~21% O 2 ), it is well documented that, in vivo, both embryonic and adult tissues, and specifically the different lung compartments, are subjected to oxygen partial pressures far below the ones corresponding to room air [67]. Given that embryogenesis is heavily influenced by oxygen gradients, small shifts in oxygen tension have shown to stimulate differentiation into many cell types: dopaminergic neurons [68], cardiomyocytes [69], chondrocytes [70], and, most particularly, endothelial cells [71]. More specifically, adult adipose [72] and murine bone-marrow-derived [73] MSC have shown different differentiation fates depending on oxygen concentration.…”