Protective Effect of Mesenchymal Stem Cells Against the Development of Intracranial Aneurysm Rupture in Mice

Abstract

Intravenous administration of MSCs after aneurysm formation prevented aneurysmal rupture in mice. The protective effect of MSCs against the development of aneurysm rupture appears to be mediated in part by the stabilization of mast cells by MSCs.

The Role of Mast Cells in Stroke

“…For their anti-inflammatory effects, MSCs have been investigated for the treatment of inflammatory pathologies [174]. Intravenous injection of MSCs reduced aneurysm rupture rate and MCs infiltration in a intracranial aneurysm mouse model [175]. The modulatory effect of MSCs on MCs appeared to be mediated by the cyclooxygenase-2 (COX-2)-dependent production of prostaglandin E2 (PGE2) [175].…”

Mesenchymal stem cells for hemorrhagic stroke: status of preclinical and clinical research

“…2 × 10 6 cells by the tail vein injection - timing not recordedImprovement in mNSS; reduced injury volume; increased vascular density in intracerebral administration group 46 Human, amniotic membraneMale Wistar rats (240–260 g)Collagenase type VII into the striatum5 × 10 5 cells, by intracerebral injection, 24 h post-ICHImprovement in mNSS; increased blood vessel density; reduced apoptosis; increased proliferation and differentiation of neurons; increased growth factor levels; reduced neutrophil infiltration and microglial activation 39 Rat, bone marrow *compared to conditioned media Male Sprague-Dawley rats (250–280 g)100 µl autologous arterial blood into right basal gangliaDose not reported, by tail vein injection, immediately post-ICH.Improvements in forelimb-placing, corner turn tests, and mNSS; no effect on Morris water maze performance; reduced brain water content; increased phosphorylation of downstream signaling molecules; decreased inflammatory cytokines 56 Rat, bone marrow *with 2nd messenger signaling inhibitors Male rats (250–280 g)100 µl autologous arterial blood into right basal gangliaDose not reported, by IV injection, 1 and 24 h post-ICH.Improvement in mNSS which are blocked by inhibitor treatment; attenuation of second messenger signaling by inhibitors 57 Rat, bone marrowMale Spontaneously Hypertensive Rats (250–300 g)20 µl of hemoglobin into right caudate nucleus1 × 10 6 cells, by intracerebral injection, 6 h post-ICHImprovements in mNSS and modified limb placing test; reduced brain water content; reduced apoptosis; increased ZO-1 staining; reduced microglial activation; decreased inflammatory cytokines 40 Human, bone marrow *MSCs to prevent aneurysmal rupture Male C57BL/6 J mice, weight unknownDeoxycorticosterone acetate-salt to induce systemic hypertension. Elastase into the right basal cistern1 × 10 6 cells, by IV injection, 6 and 9 days after aneurysm inductionReduced both the incidence of ruptured aneurysms and rupture rate 50 Human, placenta derivedMale Sprague-Dawley rats (250–350 g)Collagenase type IV into striatum1 × 10 6 cells, by tail vein injection, one hour post-ICHDecreased mortality rate; reduced hematoma volume and ventricular enlargement; reduced brain edema; increased ZO-1 and occludin 41 Rat, bone marrowMale Wistar rats (300–350 g)Perforation of the Circle of Willis1.5 × 10 6 cells, by intranasal delivery, 6 days post-SAHImprovement in sensorimotor and mechanosensory function; reduced gray and white matter loss; increased activation of astrocytes and microglia 61 mNSS modified neurological severity score, BDNF brain-derived neurotrophic factor, BM bone marrow, MSC mesench...…”

“…Most hemorrhagic stroke models used rats; two studies used C57BL/6J mice; 45,50 and one used Macaca fascicularis monkeys (first in primate study). 51 Sprague-Dawley rats were the most commonly used, followed by Wistar rats, and two separate studies used the spontaneously hypertensive rat (SHR) model, which would seem well-suited for a cerebral hemorrhage model as hypertension is the primary risk factor of human intracerebral hemorrhage.…”

Pharmacological inhibition of STAT3 by BP‐1‐102 inhibits intracranial aneurysm formation and rupture in mice through modulating inflammatory response

“…Nine‐week‐old male C57BL/6 mice were kept in SPF animal house. IA was induced according to the previously described methods involving induced hypertension and stereotactic elastase injection 23,24 . First, we perform unilateral nephrectomy on the animal, where the left stiff artery and the left renal artery were ligated under general anesthesia using pentobarbital sodium injection (50 mg/kg).…”

“…Neurological symptoms were scored as follows: 0: normal function; 1: reduced eating or drinking activity demonstrated by a weight loss >2 grams of body weight (≈10% weight loss) for 24 h; 2: flexion of the torso and forelimbs on lifting the whole animal by the tail; 3: circling to one side with a normal posture at rest; 4: leaning to one side at rest; and 5: no spontaneous activity. When mice were found to show neurological symptoms associated with aneurysmal rupture (neurological score, 1–5), they were euthanized immediately (within 4 h) 24 . A total of 150 mice were employed in this study.…”