Cell-based strategies are of particular interest in neurological conditions because mature brains have limited capacity for self-repair. MSCs have great potential as therapeutic agents for stroke treatment, because they are easily obtained and can be expanded rapidly ex vivo for transplantation [2, 27]. MSCs transplanted into an ischemic region of the rat brain are capable of differentiation into neural cells and promote functional improvement [11, 24, 28]. Furthermore, MSCs can improve neurological dysfunctions in stroke patients . However, it is often argued that stem cells might be used to replace lost neurons and restore functions .
hUCB-MSCs have proven to be more advantageous than bone marrow-derived MSCs in terms of cell procurement, storage, and transplantation . Moreover, the number and differentiation ability of bone marrow-derived MSCs significantly decrease with age . These characteristics make hUCB-MSCs potent candidates for the clinical application of allogenic MSC-based therapies.
The route of cell administration is a key point in stem cell transplantation. The need for development of effective cell delivery methods to enhance the therapeutic efficacy of stem cells is pressing because the safety and efficacy of cell therapy depend on the mode of cell administration. Several studies reported functional recovery in animal stroke models and in humans using different modes of delivery [33–35]. However, the optimal delivery route for cell transplantation after stroke is not yet well defined.
The present results demonstrate that administration of allogenic hUCB-MSCs intrathecally by LP is a valuable transplantation method for efficient cell delivery and therapy in a rat stroke model. Intravenous administration of 1 × 106 hUCB-MSCs is equally effective for improving neurological recovery and decreasing cerebral damage in ischemic stroke (Figure 4). A most important finding of the present study is that 5 × 105 hUCB-MSCs administered intrathecally are significantly effective for decreasing ischemic infarction volume, but not in the intravenous administration group (Figure 5). A relationship between cell dose and therapeutic effect has been identified by Chen and colleagues . Rats intravenously infused with 3 × 106 MSCs after MCAO showed better neurological recovery than animals infused with 1 × 106 MSCs. Rats intravenously infused with 1 × 106 MSCs after MCAO showed improved neurological recovery, but rats administered 3 × 106 MSCs demonstrated better neurological recovery than animals infused with 1 × 106 MSCs. Although 1 or 3 × 106 cells in animal experiments are acceptable for therapeutic effect, extrapolation of these doses to humans may be difficult because of the large number of cells needed. This difficulty in converting the amount into a human dose will limit clinical trials. MSCs therapy for stroke patients has been performed using 1 × 108 cells [29, 36]. A potential therapeutic effect at an acceptable cell dose is important in human therapy.
Homing is the process by which cells migrate to, and engraft in, the tissue in which they will exert functional effects [37, 38]. Capacity for migration towards an injured region is an important characteristic of MSCs. When transplanted into the striatum or tail vein after MCAO, MSCs survived and migrated to the ischemic site, where they restored damaged neural cells in adult rodents [11, 12, 24]. The present study indicates that both administration routes were equally effective in neurological deficit recovery, but the intravenous administration did not produce MSC migration to the lesion zone (Figure 1). In addition, many more grafted cells survived in animals after intrathecal administration when compared with animals after intravenous administration (Figure 2). Our outcome suggests that it may not be necessary for the stem cells to successfully migrate and graft onto the lesion site to obtain good functional results.
Several factors are probably influential in achieving the benefits of MSCs in the ischemic brain, and a possible mechanism that could explain the improvement in functional recovery of models is believed to be associated with the differentiation of transplanted MSCs into a neural cell lineage. Numerous studies have reported that transplanted MSCs in animals with ischemic stroke expressed the neural cell lineage markers, such as the neuronal-specific protein NeuN, microtubule-associated protein 2 (MAP-2), and the astrocytic marker GFAP [11, 24, 28]. The neural differentiation capacity of MSCs in vitro and in vivo has been intensively explored; previous studies in our laboratory have also demonstrated that MSCs differentiate into neurons or glial cells in vitro under special experimental conditions [39, 40]. In the present study, hUCB-MSCs delivered by LP grafted efficiently and differentiated into neurons and glial cells (Figures 3 and 7), supporting the hypothesis that transdifferentiation of transplanted MSCs is influential in achieving the benefits of MSCs in the ischemic brain.
On the basis of these results, both intrathecal and intravenous routes of administration of 1 × 106 cells have demonstrated similar effectiveness for promoting neurological recovery in ischemic stroke regardless of migration and grafting differences within the ischemic brain. However, intrathecal administration was significantly more effective for the 5 × 105 cell dose in reducing the ischemic damage. Our study indicates that intrathecal delivery of hUCB-MSCs by LP is an attractive and potentially successful method by which to treat stroke damage and may be a clinically feasible means of providing less invasive and repeatable transplantation therapy.