Therapeutic effects of human umbilical cord blood-derived mesenchymal stem cells after intrathecal administration by lumbar puncture in a rat model of cerebral ischemia

Abstract

IntroductionStem cell transplantation is a promising therapeutic strategy for the treatment of stroke. Mesenchymal stem cells (MSCs) are a potential cell source for clinical application because they can be easily obtained and cultivated with a high proliferative capacity. The safety and efficacy of cell therapy depends on the mode of cell administration. To determine the therapeutic potential of intrathecal administration of MSCs by lumbar puncture (LP), we administrated human umbilical cord blood-derived MSCs (hUCB-MSCs) intrathecally into the lumbar spinal cord or intravenously into the tail vein in a rat model of stroke, and then investigated whether hUCB-MSCs could enter the brain, survive, and improve post-stroke neurological functional recovery.MethodshUCB-MSCs (1.0 × 106) were administrated three days after stroke induced by occlusion of the middle cerebral artery. The presence of hUCB-MSCs and their survival and differentiation in the brain tissue of the rats was examined by immunohistochemistry. Recovery of coordination of movement after administration of hUCB-MSCs was examined using a Rotarod test and adhesive-removal test on the 7th, 14th, 21st, and 28th days after ischemia. The volume of ischemic lesions seven days after the experimental procedure was evaluated using 2-3-5-triphenyltetrazolium (TTC) staining.ResultsRats receiving hUCB-MSCs intrathecally by LP had a significantly higher number of migrated cells within the ischemic area when compared with animals receiving cells intravenously. In addition, many of the cells administered intrathecally survived and a subset of them expressed mature neural-lineage markers, including the mature neuron marker NeuN and glial fibrillary acidic protein, typical of astrocytes. Animals that received hUCB-MSCs had significantly improved motor function and reduced ischemic damage when compared with untreated control animals. Regardless of the administration route, the group treated with 1 × 106 hUCB-MSCs showed better neurological recovery, without significant differences between the two treatment groups. Importantly, intrathecal administration of 5 × 105 hUCB-MSCs significantly reduced ischemic damage, but not in the intravenously treated group. Furthermore, the cells administered intrathecally survived and migrated into the ischemic area more extensively, and differentiated significantly into neurons and astrocytes.ConclusionsTogether, these results indicate that intrathecal administration of MSCs by LP may be useful and feasible for MSCs treatment of brain injuries, such as stroke, or neurodegenerative disorders.

Human umbilical cord blood mesenchymal stem cell transplantation suppresses inflammatory responses and neuronal apoptosis during early stage of focal cerebral ischemia in rabbits

“…Therefore, the elucidation of potential mechanisms is vital for the further development of stem cell therapy techniques and, ultimately, their translation to the bedside. A number of proposed mechanisms have been investigated in preclinical cerebral ischemia models, including the formation of new neuronal circuitry, reduced apoptosis, promotion of angiogenesis, neurogenesis, and other endogenous www.nature.com/aps Zhu Y et al Acta Pharmacologica Sinica npg repair processes [3][4][5][6] .…”

Mesenchymal stem cell-based therapy for ischemic stroke

“…Many of these studies report a lowering of deficits as assessed by the composite modified neurological severity score (mNSS), while others demonstrated reduced inflammation and apoptosis, as well as increased neurite outgrowth and plasticity [38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57]. Interestingly, recent studies have also determined that exosomes secreted by MSCs are capable of inducing functional recovery in models of ischemic stroke [24,41,47,55,58].…”

“…Many, but not all, of these studies reported MSCs reduced infarct size and induced functional recovery as reported by lessening of motor deficits or special learning as measured by the radial maze test [38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57]. Many of these studies report a lowering of deficits as assessed by the composite modified neurological severity score (mNSS), while others demonstrated reduced inflammation and apoptosis, as well as increased neurite outgrowth and plasticity [38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57]. Interestingly, recent studies have also determined that exosomes secreted by MSCs are capable of inducing functional recovery in models of ischemic stroke [24,41,47,55,58].…”

Functional recovery after acute intravenous administration of human umbilical cord mesenchymal stem cells in rats with cerebral ischemia-reperfusion injury

“…In many studies, different routes have been tested, including intrastriatal (11), intracerebral (12), intraventricular (13), and intrathecal by lumbar puncture (14). However, these techniques raise the possibility of additional trauma from transplantation surgery and are often impractical for patients with clinically serious conditions.…”