Fig. 6.1
Schematic drawing of the transplantation route with its advantage and disadvantage
6.2.1 Intravenous Route
One of the major advantages of using intravenous route for cell transplantation is its simplicity of administration with minimal invasiveness. Most of the cell transplantation in experimental research is conducted within 24 h from ischemic insult with favorable results; however, there are several reports showing that transplantation was also effective even 4 weeks after ischemia [9]. It is quite interesting that intravenously transplanted cells work not only by penetrating through blood-brain barrier (BBB) and settled in the brain but also work as exogenous supporter of the damaged cells. In fact, quite a few cells (approximately 0.4–4 %) or even no cells were found in the ischemic brain regardless of their neuroprotective results [10–15], and most of the transplanted cells are shown to be trapped in the peripheral organ such as the lungs and spleen [16, 17]. There are several possible mechanisms for the functional recovery without direct cell entry into the brain for intravenous transplantation, such as the secretion of trophic factor and cytokines which leads to facilitate damaged brain cell survival, and activation of neurogeneration [18–20]. There are interesting report saying transplanted cells trapped in the peripheral organ inhibited the secretion of tumor necrosis factor (TNF)-a and interleukin (IL)-6 from the spleen and prevented the systemic inflammatory response from progression [17]. Despite the advantage, intravenous routes have safety issues which cells may stick together and cause microemboli, including lethal pulmonary emboli.
6.2.2 Intra-arterial Route
Intra-arterial route has also been considered as less invasive method and contains several advantages over intravenous route. This method can deliver stem cells directly to the damaged area without trapped by the peripheral filtering organ, resulting in higher amount of cells delivered in the brain, and can distribute stem cells widely to the ischemic lesion [11, 21, 22]. However, recent reports have revealed that cells once injected and settled in the brain will move in the course of time and are trapped in the peripheral organ at the later time point [23–25]. There are also safety issues against intra-arterial route than microemboli causing higher mortality rate compared to other transplantation routes [26]. The use of microneedle injection methods might preserve anterograde blood flow throughout the transplantation process and may avoid the development of microstrokes [27].
6.2.3 Intracerebral Route
Intracerebral route results in most implanted cells delivered in the infarcted area compared with other delivery routes [28]. After injection, transplanted cells will migrate to the ischemic boundary zone navigated by chemotactic cytokines such as SDF-1a [29–31]. The cells are shown to proliferate and differentiate to neuronal cells in order to cover the damaged neuronal cells [32] and also shown to ameliorate neurological damage by secreting trophic factors. Interestingly, Jin et al. have shown that the ratio of transplanted cells to neuronal cell transformation in the brain does not differ between different transplantation routes. In that case, intracerebral route can deliver most neuronal cells in to the brain compare to other routes [33]. Intracerebral route has also shown to have longer therapeutic time window that this method was effective 4 weeks after the ischemic insult [32]. On the other hand, it is worth noting that intracerebral injection at acute stage of ischemic stroke did not show good cell engraftment probably because the circumstances of the injured brain at acute stage contain abundant excitatory amino acid and reactive oxygen species (ROS), which is not suitable for transplanted cells to settle and proliferate. From these results, intracerebral transplantation might be more effective when it is transplanted between subacute and chronic stage of ischemia. However, the procedural risk for stereotaxic injection raises safety concern. Early clinical trials using intraparenchymal cell transplantation have reported severe adverse events involving motor worsening, seizures, syncope, and chronic subdural hematoma [34, 35].
6.2.4 Intraventricular/Intrathecal Route
Intraventricular/intrathecal route seems less invasive than intracerebral route in which transplanted cells adhere to the ventricular wall and penetrate through the ventricular surface to the lesion [36]. However, there are conflicting results regarding the efficacy of intraventricular/intrathecal route in that, in one hand, intrathecal transplantation improved motor function and reduced ischemic damage with quite a small number of cells (0.5 × 106) [37], but on the other hand, no benefit of intraventricular transplantation was reported compared to the beneficial effect through intracerebral route [38].
6.2.5 Intranasal Route
Intranasal route has recently been recognized as an alternative route for cell delivery. Intranasally delivered cells can travel across the cribriform plate and migrates throughout the forebrain and olfactory bulbs by bypassing BBB [39]. Although the exact mechanism of intranasal delivery has not been elucidated, accumulating evidence suggests that several pathways such as olfactory nerve, trigeminal nerve, and vascular are involved. There has been accumulating evidence that intranasal transplantation is beneficial for stroke, especially in experimental neonatal hypoxia model [40, 41]. However, it is still unknown that intranasal delivery can be clinically applicable for the aged stroke patients.
6.2.6 Comparing Transplantation Routes
It is quite difficult to determine the optimal transplantation route because even the studies focused on direct comparison of the cell transplantation route adapts different stroke model, stem cell types, cell dose, and transplantation timing [42].
6.2.6.1 Comparing Routes at Acute Stage
Several reports have focused on the comparison of transplantation routes in acute stage (Table 6.1), and intravenous transplantation seems to be the most promising route compared to others [42, 43]. As aforementioned, the reason for effectiveness of intravenous transplantation might be from not only by direct cell migration and neural differentiation, but by bystander effect of stem cells, such as BBB stabilization, upregulating neurotrophic factors (VEGF, BDNF), and modulation of immune responses, also called as indirect paracrine mechanisms. Doeppner et al. have reported that intravenous, intra-arterial, and intra-striatum transplantation 6 h after ischemic stroke showed better neurological recovery compared to contralateral intra-striatum, intraventricular transplantation; however, intra-arterial transplantation had higher mortality rate and intra-striatum had shorter period of neurological recovery. They also reported that transplantation route did not affect endogenous angioneurogenesis but played important role in preserving BBB integrity and modulation of inflammatory responses [42]. Willing et al. have also compared intravenous vs. intracerebral transplantation 24 h after ischemia and found that intravenous was superior to intracerebral injection [44]. On the other hand, there are several reports showing that intra-arterial and intraventricular transplantation were as effective as intravenous transplantation and that intra-arterial and intraventricular showed even faster neurological recovery [43, 45–47]. Li et al. further have reported that intra-arterial transplantation showed significantly increased cell distribution compared to intravenous and intracerebral transplantation; however intra-arterial transplantation showed higher mortality [26].
Table 6.1
Comparison of the different stem cell transplantation route in experimental stroke
Year | Author | Journal | Cell type | Ischemic model | Transplantation timing | Arterial | Venous | Striatal | Striatal (contralateral) | Cortical | Intraventricular |
|---|---|---|---|---|---|---|---|---|---|---|---|
2015 | Doeppner | Experimental Neurology | NPC | 6 h | + | ++ | + | − | − | − | |
2014 | Du | Acta Histochemica | ADSC | tMCAO | 24 h | ++ | + | ++ | |||
2013 | Yang | Stroke | BMMC | tMCAO | 24 h | + | + | ||||
2012 | Vasconcelo-dos-Santos | Stem Cell Research | BMMC | pMCAO | 24 h | + | + | ||||
2012 | Zhang | Brain Research | hUCSC | tMCAO | 24 h | +++ | ++ | +++ | + | ||
2010 | Li | J Cereb Blood Flow Metab | NPC | tMCAO | 24 h | + | +++ | ++ | |||
2003 | Willing | J Neurosci Res | hUCSC | 24 h | ++ | + | |||||
2011 | Lim | Stem Cell | hUCSC | tMCAO | Day 3 | + | ++ | ||||
2012 | Kawabori | Neuropathology | BMSC | pMCAO | Day 7 | − | + |
6.2.6.2 Comparing Routes at Chronic Stage
There are quite a few reports focusing on the different transplantation route at chronic stage between a few days and 1 month after ischemic insult. Intravenous transplantation does not seem to be the optimal treatment strategy in this stage as is seen in the acute stage. Lim et al. have found that intrathecally injected stem cells showed similar neurological recovery compare to intravenous injection when transplanted 3 days from ischemia [37]. However, intravenous required larger cell dose to achieve recovery. Kawabori et al. have focused on the route problem and conducted a study comparing intravenous and intracerebral transplantation 7 days after permanent ischemia in rat. They adopted permanent ischemic model which mimics the actual situation for ischemic stroke. They found that significant neurological recovery and intracerebral cell graft were seen in intracerebral transplantation, but not in intravenous group [32, 48]. They also found that this intracerebral transplantation was also effective 28 days after stroke with 1 × 106 cells but not with 1 × 105 cells. These differences are thought to be from the fact that neurological restore and replacement rather than neuroprotection seem to play important role at the chronic stage.
6.3 Transplantation Cell Dose
As Hess and Borlongan have mentioned in their report [49], it is quite difficult to determine the optimal stem cell transplantation dose for treating ischemic stroke patients from the experimental data available, since most of the reports are done by rodents. They mentioned that the current best approach to determine the optimal dose is to extrapolate the dose from rodents to humans based on their weight or brain size. However, there are a few studies which focused on this issue [14, 32, 50–55]. According to the limited data, it seems that the transplanted cell dosage is “the more, the better” (Table 6.2) [40, 56–59]. Most of the reports here found that cells more than 1 × 106 constantly showed better neurological recovery compare to lower doses. However, higher dose may cause unwanted complication such as plumbing of vessel, which Yavagal et al. reported that higher dose (1 × 106) showed decreased MCA flow up to 45 %, while low dose (1 × 105 cells) via intra-arterial transplantation did not compromise MCA blood flow in rat model [60].
Table 6.2
Comparison of the different stem cell transplantation cell dose in experimental stroke
Year | Author | Journal | Cell type | Ischemic model | Transplantation timing | Transplantation route | 1 × 105 cells/animal | 1 × 106 cells/animal | 1 × 107 cells/animal |
|---|---|---|---|---|---|---|---|---|---|
2015 | Cameron | Mol Cell Neurosci | BMSC | Hypoxia | Day 7 | Parenchymal | + | ++ | |
2014 | Greggio | Life Sci | UCSC | Hypoxia | Day 1 | Arterial | − | + | |
2014 | Doeppner | Cell Death Dis | NPC | tMCAO | 0 h | Venous | + | ++ | |
2014 | Donega | Plos One | BMSC | Hypoxia | Day 10 | − | + | ||
2013 | Kawabori | Neuropathology | BMSC | pMCAO | Day 7 | Cerebral | + | + | |
2013 | Kawabori | Neuropathology | BMSC | pMCAO | Day 28 | Cerebral | − | + | |
2013 | Yang | Stroke | BMMC | tMCAO | Day 1 | Venous | − | + | |
2013 | Yang | Stroke | BMMC | tMCAO | Day 1 | Arterial | − | + | |
2012 | Shehadah | Plos One | UCSC | tMCAO | Day 1 | Venous | +
Related posts: iPS Cells and iN Cells
Role of Biomaterials as Scaffolding in Cell Therapy for Stroke
Review of Previous Clinical Trials and Guidelines of Cell Therapy
 Neural Stem Cells/Neuronal Progenitor Cells
 In Vivo Cell Tracking Techniques for Applications in Central Nervous System Disorders
 Mesenchymal Stem Cells
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