Mesenchymal stem cells attenuate MRI‐identifiable injury, protect white matter, and improve long‐term functional outcomes after neonatal focal stroke in rats

Abstract

Cell therapy has emerged as a potential treatment for many neurodegenerative diseases including stroke and neonatal ischemic brain injury. Delayed intranasal administration of mesenchymal stem cells (MSC) after experimental hypoxia-ischemia and after a transient middle cerebral artery occlusion (tMCAO) in neonatal rats has shown improvement in long-term functional outcomes, but the effects of MSC on white matter injury (WMI) are insufficiently understood. In this study we utilized longitudinal T2W and diffusion tensor MRI to characterize chronic injury after tMCAO induced in postnatal day 10 (P10) rats and examined the effects of delayed MSC administration on WMI, axonal coverage and long-term somatosensory function. We show unilateral injury- and region- dependent changes in diffusion fraction anisotropy 1 and 2 weeks after tMCAO that correspond to accumulation of degraded myelin basic protein, astrocytosis, and decreased axonal coverage. With the use of stringent T2W–based injury criteria at 72 hours after tMCAO to randomize neonatal rats to receive intranasal MSC or vehicle, we show that a single MSC administration attenuates WMI and enhances somatosensory function 28 days after stroke. A positive correlation was found between MSC-enhanced white matter integrity and functional performance in injured neonatal rats. Collectively these data indicate that the damage induced by tMCAO progresses over time and is halted by administration of MSC.

The Potentials and Caveats of Mesenchymal Stromal Cell-Based Therapies in the Preterm Infant

“…So far, most preclinical studies in the rodent model were performed for brain pathologies of the term newborn infant including hypoxic brain injury following perinatal asphyxia and neonatal stroke. Actual studies also evaluated the therapeutic potential of MSC therapy in periventricular leukomalacia and intraventricular hemorrhage [ 115 – 128 ]. For intraventricular hemorrhage, the contributions of inflammatory reaction to disease pathologies are well established and include brain damage by cell death induction of neurons and distortion of further myelination and gliosis [ 34 , 129 ].…”

Promoting neuroregeneration after perinatal arterial ischemic stroke: neurotrophic factors and mesenchymal stem cells

“…MSC treatment also stimulated neurogenesis, leading to better sensorimotor and social functions (70). In addition, van Velthoven et al (71,72) showed that intranasal MSC treatment at 3 days after neonatal stroke also significantly reduced infarct size and white and gray matter loss in newborn rats, leading to improved motor performance at 28 days after the infarct.…”

Transplantation of neural stem cells in the mouse model of ischemic brain stroke and expression of genes involved in programmed cell death

“…Our study suggests that the part of the answer can be found in the tissue treated by transplanted stem cells. The presence of transplanted stem cells supports regenerative events ( 13 , 14 , 17 ). For example, stroke increases the levels of Ripk1 , a necroptosis promotor, while transplanted medium and NSC oppose this process ( Figure 2A ).…”

“…There is growing evidence that stem cells transplantation measurably reduces the stroke area and accelerates recovery, both in preclinical ( 13 - 15 ) and clinical ( 16 , 17 ) trials. However, since the transplanted stem cells’ mechanisms of action in the injured tissue are not yet fully understood, we analyzed the influence of stem cell transplantation on the expression of genes involved in AIF-mediated cell death ( Aifm1 , Iduna , CypA ), necroptosis ( Ripk1 , Ripk3 , Mlkl ), and apoptosis ( Casp3 , Casp8 ).…”