Hypoxic preconditioning enhances neural stem cell transplantation therapy after intracerebral hemorrhage in mice

Abstract

Previous studies have shown that intraparenchymal transplantation of neural stem cells ameliorates neurological deficits in animals with intracerebral hemorrhage. However, hemoglobin in the host brain environment causes massive grafted cell death and reduces the effectiveness of this approach. Several studies have shown that preconditioning induced by sublethal hypoxia can markedly improve the tolerance of treated subjects to more severe insults. Therefore, we investigated whether hypoxic preconditioning enhances neural stem cell resilience to the hemorrhagic stroke environment and improves therapeutic effects in mice. To assess whether hypoxic preconditioning enhances neural stem cell survival when exposed to hemoglobin, neural stem cells were exposed to 5% hypoxia for 24 hours before exposure to hemoglobin. To study the effectiveness of hypoxic preconditioning on grafted-neural stem cell recovery, neural stem cells subjected to hypoxic preconditioning were grafted into the parenchyma 3 days after intracerebral hemorrhage. Hypoxic preconditioning significantly enhanced viability of the neural stem cells exposed to hemoglobin and increased grafted-cell survival in the intracerebral hemorrhage brain. Hypoxic preconditioning also increased neural stem cell secretion of vascular endothelial growth factor. Finally, transplanted neural stem cells with hypoxic preconditioning exhibited enhanced tissue-protective capability that accelerated behavioral recovery. Our results suggest that hypoxic preconditioning in neural stem cells improves efficacy of stem cell therapy for intracerebral hemorrhage.

Hypoxia-Inducible Factor 1α (HIF-1α) Counteracts the Acute Death of Cells Transplanted into the Injured Spinal Cord

“…Compared to control SCs, HIF-1 levels were increased by 5.9 ± 0.2 fold in VP16-HIF SCs. This is within the physiological increase in HIF-1 achieved with hypoxia treatment in other cell types [e.g., stem cells: (Theus et al, 2008;Wakai et al, 2016); bone marrow stromal cells (BMSCs; Theus et al, 2008)], where HIF-1 increases by 2-to 6.5-fold. It is, however, less than the 8-14-fold increase achievable following pharmacological treatment of SCs with the HIF stabilizer, deferoxamine Thus, retroviral expression of a non-degradable form of HIF-1 fused to the VP16transactivation domain elevated HIF-1 levels in SCs to the physiological levels, and was sufficient to elevate the expression of HIF's transcriptional targets.…”

White matter repair and treatment strategy after intracerebral hemorrhage

“…In addition, after ICH, hemoglobin can cause the death of a large number of transplanted NSCs. Hypoxic preconditioning can increase the expression of VEGF secreted by the NSCs and allow adaptation to the toxic effects of hemoglobin around the hematoma . In the experimental model of a subcortical stroke with WMI, ADMSCs could facilitate the reconstruction of WM fiber tracts and alleviate functional defects …”

“…Hypoxic preconditioning can increase the expression of VEGF secreted by the NSCs and allow adaptation to the toxic effects of hemoglobin around the hematoma. 107 In the experimental model of a subcortical stroke with WMI, ADMSCs could facilitate the reconstruction of WM fiber tracts and alleviate functional defects. 97,108 The use of induced pluripotent stem cells (iPS) is the current focus of attention, because these cells can be tailored to patients for self-use in order to avoid immune rejection, ethical constraints, and tissue donation.…”

Preconditioning and Cellular Engineering to Increase the Survival of Transplanted Neural Stem Cells for Motor Neuron Disease Therapy

“…NSCs can also differentiate into non-neuronal progeny (oligodendrocytes, astrocytes) known to promote homeostasis and support regenerating host axons [31]. Indeed, NSCs can also elicit protection or regeneration of perilesional tissues and circuitries [31,33]. In the past ten years, several preclinical studies focusing on the use of stem cells in ALS transgenic animal models have shown promising results [26,27,31,[34][35][36][37].…”

“…In another study, Wakai and colleagues further demonstrated that mild hypoxia (5% O2 for 24 h) also promotes NSC proliferation and resilience to transplantation by upregulating phospho-Akt (pAkt) expression via HIF-1α and subsequent expression of VEGF [33]. Akt is well known to contribute to self-renewal and differentiation in NSCs.…”