Cell therapy for ischemic stroke: Are differences in preclinical and clinical study design responsible for the translational loss of efficacy?

Cui, Lili; Gołubczyk, Dominika; Tolppanen, Anna‐Maija; Boltze, Johannes; Jolkkonen, Jukka

doi:10.1002/ana.25493

Cited by 57 publications

(44 citation statements)

References 61 publications

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“…On the other hand, previous has demonstrated that cryopreservation of cells would reduce the efficacy [29]. Additionally, ageing and senescence effects due to cryopreservation [30] that could also contribute to negative or neutral results [31]. Accordingly, when hemopoietic-derived stem cell therapy is taken into consideration for acute IS patients, minimal manipulation (i.e., cells without cultivation) method to collect the circulatory-derived/bone marrowderived autologous CD34+ cells would be more practical and suitable for the IS patients in our daily clinical practice.…”

Section: Discussionmentioning

confidence: 99%

Intra-carotid arterial transfusion of circulatory-derived autologous endothelial progenitor cells in rodent after ischemic stroke — evaluating the impact of therapeutic time points on prognostic outcomes

Lin

Chai

Chen

et al. 2020

Preprint

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Background: This study tested the optimal time point for left intra-carotid arterial (LICA) administration of circulatory-derived autologous endothelial progenitor cells (EPCs) for improving the outcome in rat after acute ischemic stroke (IS). Methods and Results: Adult-male SD rats (n=70) were equally categorized into group 1 (sham-operated control), group 2 (IS), group 3 (IS+EPCs/1.2x106 cells/by LICA administration 3h after IS), group 4 (IS+EPCs/LICA administration post-day-3 IS), group 5 (IS+EPCs/LICA administration post-day-7 IS), group 6 (IS+EPCs/LICA administration post-day-14 IS) and group 7 (IS+EPCs/LICA administration post-day-28 IS). The brain-infarct volume (BIV) (at day 60/MRI) was lowest in group 1, highest in group 2 and significantly progressively increased from groups 3 to 7, whereas among the IS animals, the neurological function was significantly preserved in groups 3 to 6 than in groups 2 and 7 post-day-60 IS (all p<0.0001). By day 60, the endothelial cell markers at protein and cellular levels, and number of small vessels exhibited an opposite pattern of BIV among the groups (all p<0.0001). The protein and cellular levels of inflammation, and protein levels of oxidative stress, autophagy and apoptosis, were highest in group 2, lowest in group 1 and progressively increased from groups 3 to 7 (all p<0.0001). The angiogenesis biomarkers at protein and cellular levels were significantly progressively increased from groups 1 to 3, then significantly progressively decreased from groups 4 to 7 (all p<0.0001). Conclusion: Early EPC administration provided better benefits on improving functional/image/molecular-cellular outcomes after acute IS in rat.

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Section: Discussionmentioning

confidence: 99%

Intra-carotid arterial transfusion of circulatory-derived autologous endothelial progenitor cells in rodent after ischemic stroke — evaluating the impact of therapeutic time points on prognostic outcomes

Lin

Chai

Chen

et al. 2020

Preprint

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“…Most types of cells are impaired by the process of freezing and thawing. Indeed, clinical islet transplantation is performed with freshly isolated islets and recent meta-analysis reported the inferiority of cryopreserved cells in the therapeutic efficacy of cell therapy for ischemic stroke [22]. Hepatocytes also easily lose their viability after freezing and thawing [23].…”

Section: Discussionmentioning

confidence: 99%

Natural Flavonol, Myricetin, Enhances the Function and Survival of Cryopreserved Hepatocytes In Vitro and In Vivo

Cui

Enosawa

Matsunari

et al. 2019

IJMS

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To improve the therapeutic potential of hepatocyte transplantation, the effects of the mitogen-activated protein kinase kinase 4 (MKK4) inhibitor, myricetin (3,3′,4′,5,5′,7-hexahydroxylflavone) were examined using porcine and human hepatocytes in vitro and in vivo. Hepatocytes were cultured, showing the typical morphology of hepatic parenchymal cell under 1–10 µmol/L of myricetin, keeping hepatocyte specific gene expression, and ammonia removal activity. After injecting the hepatocytes into neonatal Severe combined immunodeficiency (SCID) mouse livers, cell colony formation was found at 10–15 weeks after transplantation. The human albumin levels in the sera of engrafted mice were significantly higher in the recipients of myricetin-treated cells than non-treated cells, corresponding to the size of the colonies. In terms of therapeutic efficacy, the injection of myricetin-treated hepatocytes significantly prolonged the survival of ornithine transcarbamylase-deficient SCID mice from 32 days (non-transplant control) to 54 days. Biochemically, the phosphorylation of MKK4 was inhibited in the myricetin-treated hepatocytes. These findings suggest that myricetin has a potentially therapeutic benefit that regulates hepatocyte function and survival, thereby treating liver failure.

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“…There are several routes currently available for cell transplantation, including intraparenchymal, intravenous, intra-arterial, and intrathecal injections. Although the optimal cell transplantation route has not been determined, most clinical studies have applied intraparenchymal or intravenous routes of transplantation [15]. The intraparenchymal route delivers a sufficient number of cells into the desired brain lesion, having a strong advantage over the intravenous route, by which only a small number of cells can be delivered [2], most of which are trapped in the lung and spleen.…”

Section: Discussionmentioning

confidence: 99%

“…The intravenous delivery method is still efficient because neurotrophic factors are released from the cells and are critical in immunomodulation and anti-inflammation, especially at the acute stage of disease. However, when considering the subacute and chronic stages, delivering cells to the damaged area needs to be important to reorganize the damaged neurons, and recent systemic analyses have reported that intraparenchymal cell transplantation is superior to the intravenous one from an efficacy point of view, as demonstrated in both the preclinical and clinical trials [15]. Nevertheless, the intraparenchymal transplantation has a serious burden, which is that the transplantation cannula can induce intraparenchymal hemorrhage, and occlusion of the cannula may occur.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of Novel Stereotactic Cannula for Stem Cell Transplantation against Central Nervous System Disease

Kawabori

Tanimori

Kitta

et al. 2020

Stem Cells International

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Cell therapy for central nervous system (CNS) disorders is beginning to prove its safety and efficiency. Intraparenchymal transplantation can be an option for cell delivery; however, one concern regarding this method is that the transplantation cannula may cause additional brain injuries. These include vessel damage, which results in brain hemorrhage, and clogging of the cannula by brain debris and/or cell clusters, which requires replacement of the cannula or forced injection causing jet flow of the cell suspension. We compared cannulas for cell delivery used in clinical trials, the Pittsburg and Mizuho cannulas, to a newly designed one, MK01, to assess their usability. MK01 has a spherical-shaped tip with a fan-like open orifice on the side of the cannula, which prevents vessel damage, clogging of brain debris, and jet flow phenomenon. We compared the extent of rat cervical and abdominal arterial damage with the cannula, the amount of debris in the cannula, the force needed to cause jet flow, and cell viability. While the viability of cells passed through the cannulas was almost the same among cannulas (approximately 95%), the Pittsburg cannula caused cervical arterial injury and subsequent hemorrhage, as it required a significantly smaller force to penetrate the arterial wall. Moreover, the Pittsburg cannula, but not the Mizuho and MK01 cannulas, showed high frequency of brain debris in the needle tip (approximately 80%) after brain puncture. While jet flow of the injection liquid was observed even when using smaller forces in the Pittsburg and Mizuho cannulas, MK01 constantly showed low jet flow occurrence. Thus, MK01 seems to be safer than the previously reported cannulas, although further investigation is necessary to validate its safety for clinical use.

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Cell therapy for ischemic stroke: Are differences in preclinical and clinical study design responsible for the translational loss of efficacy?

Cited by 57 publications

References 61 publications

Intra-carotid arterial transfusion of circulatory-derived autologous endothelial progenitor cells in rodent after ischemic stroke — evaluating the impact of therapeutic time points on prognostic outcomes

Intra-carotid arterial transfusion of circulatory-derived autologous endothelial progenitor cells in rodent after ischemic stroke — evaluating the impact of therapeutic time points on prognostic outcomes

Natural Flavonol, Myricetin, Enhances the Function and Survival of Cryopreserved Hepatocytes In Vitro and In Vivo

Evaluation of Novel Stereotactic Cannula for Stem Cell Transplantation against Central Nervous System Disease

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