Intermittent, low dose carbon monoxide exposure enhances survival and dopaminergic differentiation of human neural stem cells

Abstract

Exploratory studies using human fetal tissue have suggested that intrastriatal transplantation of dopaminergic neurons may become a future treatment for patients with Parkinson’s disease. However, the use of human fetal tissue is compromised by ethical, regulatory and practical concerns. Human stem cells constitute an alternative source of cells for transplantation in Parkinson’s disease, but efficient protocols for controlled dopaminergic differentiation need to be developed. Short-term, low-level carbon monoxide (CO) exposure has been shown to affect signaling in several tissues, resulting in both protection and generation of reactive oxygen species. The present study investigated the effect of CO produced by a novel CO-releasing molecule on dopaminergic differentiation of human neural stem cells. Short-term exposure to 25 ppm CO at days 0 and 4 significantly increased the relative content of β-tubulin III-immunoreactive immature neurons and tyrosine hydroxylase expressing catecholaminergic neurons, as assessed 6 days after differentiation. Also the number of microtubule associated protein 2-positive mature neurons had increased significantly. Moreover, the content of apoptotic cells (Caspase3) was reduced, whereas the expression of a cell proliferation marker (Ki67) was left unchanged. Increased expression of hypoxia inducible factor-1α and production of reactive oxygen species (ROS) in cultures exposed to CO may suggest a mechanism involving mitochondrial alterations and generation of ROS. In conclusion, the present procedure using controlled, short-term CO exposure allows efficient dopaminergic differentiation of human neural stem cells at low cost and may as such be useful for derivation of cells for experimental studies and future development of donor cells for transplantation in Parkinson’s disease.

Hypoxia‐inducible factor 1 alpha and nuclear‐related receptor 1 as targets for neuroprotection by albendazole in a rat rotenone model of Parkinson's disease

“…Interestingly, HIF‐1α is vital for the development of brain and midbrain neural precursor cells . Moreover, it plays a role in the development and survival of dopaminergic neurons via its target gene, vascular endothelial growth factor (VEGF) . VEGF is a hypoxia‐inducible secreted protein that induces angiogenesis and has favourable effects in the brain, including neurogenesis and neuroprotection .…”

“…Nurr1 is involved in regulating gene expression of tyrosine hydroxylase (TH), aromatic amino acid decarboxylase and vesicular monoamine transporter (VMAT), which are essential for regulation of DA synthesis and storage, in dopaminergic neurons . Similarly, c‐Ret, a glial cell line‐derived neurotrophic factor (GDNF) receptor, is another downstream target of Nurr1 and has a role in the development and maintenance of dopaminergic neurons . In addition, Nurr1 effectively protects dopaminergic neurons from inflammation‐induced death by suppressing the expression of inflammatory response genes .…”

Regenerative Potential of Carbon Monoxide in Adult Neural Circuits of the Central Nervous System

“…CORM-1 and CORM-2 are lipid-soluble CORMs [8] (Figure 1). CORM-A1, CORM-3, CORM-401, methyldiphenylsilacarboxylic acid and CORM ALF-186 are water-soluble CORMs [22,33] (Figure 1). Application of the same concentrations of structurally different CORMs does not elicit the same fluorescent signal of CO [28].…”

“…Treatment of neuroblastoma cells with CORM-A1 possesses neuroprotective and neurogenic effects [104]. New CORM (MePh 2 SiCO 2 H) or short-term exposure to low doses (25 ppm) of CO gas stimulates differentiation of human NSCs into dopaminergic neurons [33]. CORM-3 inhibits pericyte apoptosis and establishes brain pericytes-NSC crosstalk 3 d after TBI, which may enhance NSC proliferation, migration and neuronal differentiation in SVZ and SGZ at 14 d after TBI [9].…”

Roles of Gasotransmitters in Synaptic Plasticity and Neuropsychiatric Conditions

“…Their research led to broad investigations into CO, heme oxygenase, and the exogenous administration of CO as a method of imparting neuroprotection and regulating tissue homeostasis in response to pathophysiological conditions, such as cerebral ischemia, cerebrovasodilation, and neurodegenerative diseases [ 61 ]. In neurons, CO-induced cGMP generation helps protect from cell death, and NO signaling is associated with the anti-inflammatory effects of CO in microglia [ 62 ].…”