Stem Cell Therapy for Acute Cerebral Injury: What Do We Know?
Stem Cell Therapy for Acute Cerebral Injury: What Do We Know?
Translation of preclinical data to human clinical trials is confronted with many difficulties. Experimental studies that have used a wide variety of cells lack direct large-scale comparisons to help determine which cells are optimal to use in humans. The use of autologous bone marrow and potentially umbilical cord cells eliminates the risk for immune rejection. When autologous bone marrow cells are harvested by simple sorting on a Ficoll column, they can be used in the subacute or chronic phase (>= 24 h) after stroke and TBI. Allogeneic bone marrow and umbilical cord stem cells can be ready for infusion or transplantation earlier after the cerebral event as well as in the subacute and chronic phase, but risk of rejection is a concern. Immunosuppression regimens may, therefore, be necessary, at least for some period of time. The use of NSCs might be promising, considering their potential for neural replacement, but the risk of teratoma formation must be addressed and closely monitored, and rejection of embryonic-derived or fetal-derived NSCs even with immunosuppression remains a possibility. Future strategies using allogeneic iPSCs will face similar hurdles, and the risk of rejection can only be dealt with by using autologous iPSCs. This latter technology, however, is not available in the acute setting because the time necessary for induction and differentiation of these cells exceeds the time frame of acute stroke and TBI (hours to day).
After establishing which cell type to use, the dose, timing and route of administration must be determined. Larger cell numbers are associated with smaller infarct sizes, but the association with specific processes of neural repair is less clear, and there is no established optimal cell dosage. Using higher cell concentrations and numbers will not necessarily result in increased efficacy. Optimal transplant timing depends on several factors, including preclinical results, cell type, hypothesized mechanism of action and route of administration. Most experimental data have been generated from transplantation within 24 h after stroke onset, but cell therapy initiated up to 4 weeks after stroke has been shown to significantly enhance functional recovery. A strong association between functional efficacy and transplant timing after stroke could not be determined, but there was an association between structural outcome and time of intervention. Interestingly, stroke and TBI might have different optimal timing patterns. Studies in experimental stroke suggest that there is greater functional recovery from mesenschymal stem cell and NSC transplantation at 24 h compared with 7 days after stroke, with opposite results in experimental TBI.
The proposed mechanism of action of cells used might influence the timing of transplantation. If a neuroprotective effect of the therapeutic intervention is suspected, acute delivery (within 24 h) may be essential. In contrast, endogenous repair mechanisms exert their greatest potential in the subacute phase after stroke (within the first month in rodents and within 3 months in humans), thus this timing might be most optimal to promote endogenous functional recovery. Hyperacute administration, however, might be less beneficial because of the hostile environment during this phase.
The mode of delivery is also influenced by various factors such as type of cell used, timing, as well as safety and efficacy profiles. Intracerebral and intracerebroventricular (ICV) techniques precisely administer cells to a chosen location, but may have higher risks because of their invasive procedures. Homing of cells in the brain has been shown to be highest with intracerebral administration compared with intra-arterial and intravenous delivery, but whether this correlates with functional improvement has not been established. Systemic delivery might be safer and more feasible, particularly in the acute and subacute phase after stroke onset. One study found that intra-arterial infusion compared with systemic intravenous delivery increased homing around the ischemic lesion, but with no difference in therapeutic benefit. An analogous difference in engrafting after intra-arterial versus intravenous delivery has been described in TBI. Invasive intraparenchymal delivery of cells may not be required for efficiency when neural replacement is not expected – although there may still be a therapeutic advantage with the local release of cell-secreted paracrine molecules and proteins in the peri-infarct region – and systemic infusion may be the preferred mode of delivery for these transplantation strategies from a safety perspective.
From Preclinical Research to Translation
Translation of preclinical data to human clinical trials is confronted with many difficulties. Experimental studies that have used a wide variety of cells lack direct large-scale comparisons to help determine which cells are optimal to use in humans. The use of autologous bone marrow and potentially umbilical cord cells eliminates the risk for immune rejection. When autologous bone marrow cells are harvested by simple sorting on a Ficoll column, they can be used in the subacute or chronic phase (>= 24 h) after stroke and TBI. Allogeneic bone marrow and umbilical cord stem cells can be ready for infusion or transplantation earlier after the cerebral event as well as in the subacute and chronic phase, but risk of rejection is a concern. Immunosuppression regimens may, therefore, be necessary, at least for some period of time. The use of NSCs might be promising, considering their potential for neural replacement, but the risk of teratoma formation must be addressed and closely monitored, and rejection of embryonic-derived or fetal-derived NSCs even with immunosuppression remains a possibility. Future strategies using allogeneic iPSCs will face similar hurdles, and the risk of rejection can only be dealt with by using autologous iPSCs. This latter technology, however, is not available in the acute setting because the time necessary for induction and differentiation of these cells exceeds the time frame of acute stroke and TBI (hours to day).
After establishing which cell type to use, the dose, timing and route of administration must be determined. Larger cell numbers are associated with smaller infarct sizes, but the association with specific processes of neural repair is less clear, and there is no established optimal cell dosage. Using higher cell concentrations and numbers will not necessarily result in increased efficacy. Optimal transplant timing depends on several factors, including preclinical results, cell type, hypothesized mechanism of action and route of administration. Most experimental data have been generated from transplantation within 24 h after stroke onset, but cell therapy initiated up to 4 weeks after stroke has been shown to significantly enhance functional recovery. A strong association between functional efficacy and transplant timing after stroke could not be determined, but there was an association between structural outcome and time of intervention. Interestingly, stroke and TBI might have different optimal timing patterns. Studies in experimental stroke suggest that there is greater functional recovery from mesenschymal stem cell and NSC transplantation at 24 h compared with 7 days after stroke, with opposite results in experimental TBI.
The proposed mechanism of action of cells used might influence the timing of transplantation. If a neuroprotective effect of the therapeutic intervention is suspected, acute delivery (within 24 h) may be essential. In contrast, endogenous repair mechanisms exert their greatest potential in the subacute phase after stroke (within the first month in rodents and within 3 months in humans), thus this timing might be most optimal to promote endogenous functional recovery. Hyperacute administration, however, might be less beneficial because of the hostile environment during this phase.
The mode of delivery is also influenced by various factors such as type of cell used, timing, as well as safety and efficacy profiles. Intracerebral and intracerebroventricular (ICV) techniques precisely administer cells to a chosen location, but may have higher risks because of their invasive procedures. Homing of cells in the brain has been shown to be highest with intracerebral administration compared with intra-arterial and intravenous delivery, but whether this correlates with functional improvement has not been established. Systemic delivery might be safer and more feasible, particularly in the acute and subacute phase after stroke onset. One study found that intra-arterial infusion compared with systemic intravenous delivery increased homing around the ischemic lesion, but with no difference in therapeutic benefit. An analogous difference in engrafting after intra-arterial versus intravenous delivery has been described in TBI. Invasive intraparenchymal delivery of cells may not be required for efficiency when neural replacement is not expected – although there may still be a therapeutic advantage with the local release of cell-secreted paracrine molecules and proteins in the peri-infarct region – and systemic infusion may be the preferred mode of delivery for these transplantation strategies from a safety perspective.
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