Human umbilical cord blood cells do not improve sensorimotor or cognitive outcome following transient middle cerebral artery occlusion in rats

Mäkinen, Susanna; Kekarainen, Tuija; Nystedt, Johanna; Liimatainen, Timo; Huhtala, Tuulia; Närvänen, Ale; Laine, Jarmo; Jolkkonen, Jukka

doi:10.1016/j.brainres.2006.09.056

Cited by 81 publications

(59 citation statements)

References 31 publications

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“…2 The lung entrapment can be circumvented by intraarterial cell infusion, which can target cells to the ischemic brain as shown by intraarterial infusion of human bone marrow-derived stem cells (BMMSCs). 3 The most effective therapeutic time window for intraarterial cell transplantation is not known.…”

Section: Journal Of Cerebral Bloodmentioning

confidence: 99%

Unexpected Complication in a Rat Stroke Model: Exacerbation of Secondary Pathology in the Thalamus by Subacute Intraarterial Administration of Human Bone Marrow-Derived Mesenchymal Stem Cells

Mitkari

Kerkelä

Nystedt

et al. 2015

J Cereb Blood Flow Metab

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This study examined whether human bone marrow mesenchymal stromal/stem cells (BMMSCs) could alleviate the secondary pathology in the thalamus after middle cerebral artery occlusion (MCAO) in rats. Atypical accumulation of both amyloid-β (Aβ) and calcium in the thalamus was significantly higher in rats receiving the BMMSCs infusion 48 hours after MCAO as compared with the vehicle MCAO group. The elevated Aβ/calcium accumulation correlated with the level of impaired sensorimotor function. Although secondary pathology in the thalamus seems to be rodent specific, it needs to be taken into account because it may impair long-term behavioral recovery and negate therapeutic treatment effects. Flow & Metabolism (2015) 35, 363-366; doi:10.1038/jcbfm.2014; published online 7 January 2015 Journal of Cerebral BloodKeywords: β-amyloid; calcium; cell therapy; cerebral ischemia; secondary pathology INTRODUCTION At present therapeutic options in stroke are extremely limited and thus much effort is being directed at developing innovative treatments, such as cell therapies. In particular, intravascular cell therapy is a promising approach for the treatment of stroke and is claimed to achieve an efficient and wide cell engraftment in case of large or multiple lesions. 1 Since it is relatively noninvasive, application of this approach would be feasible in stroke therapy.We have previously shown that intravenous infusion of human umbilical cord blood cells in rats after middle cerebral artery occlusion (MCAO) results in the accumulation of cells primarily in the lungs. 2 The lung entrapment can be circumvented by intraarterial cell infusion, which can target cells to the ischemic brain as shown by intraarterial infusion of human bone marrow-derived stem cells (BMMSCs). 3 The most effective therapeutic time window for intraarterial cell transplantation is not known. Acute cell infusion after stroke has been postulated to be neuroprotective, whereas cell delivery at later time points (424 hours) may enhance brain repair mechanisms. 4 Late cell delivery is also thought to target the delayed secondary degeneration occurring in remote areas of the brain such as the ventroposterolateral and ventroposteromedial thalamic nuclei. 5,6 In most animal models, the thalamus is spared from the acute ischemic damage but the region is affected because it has synaptic connections with the primary injury site. The widespread corticostriatal damage results in retrograde and anterograde degeneration, 7 which is also associated with atypical accumulation of amyloid precursor protein (APP) and amyloid-β (Aβ) in the thalamus. 6 The initially diffuse APP and Aβ staining becomes later transformed into dense plaque-like deposits in the thalamus. Interestingly, the APP/Aβ depositions show an overlapping distribution with calcium deposits. 8 The secondary pathology in the thalamus takes place in a delayed manner after the ischemic event and thus represents a novel target for stroke therapy. The aim of the present work was to study whether human BMMSCs (1 × 10 6 ...

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Section: Journal Of Cerebral Bloodmentioning

confidence: 99%

Unexpected Complication in a Rat Stroke Model: Exacerbation of Secondary Pathology in the Thalamus by Subacute Intraarterial Administration of Human Bone Marrow-Derived Mesenchymal Stem Cells

Mitkari

Kerkelä

Nystedt

et al. 2015

J Cereb Blood Flow Metab

Self Cite

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“…Although the cells have been shown to migrate to the brain and improve functional recovery after ischemic 77 and hemorrhagic 50 brain injury, contrasting evidence has shown that few cells were detected in the ischemic brain and that no functional improvements resulted. 43 The UCB cells may not require direct interaction with the neural tissue to initiate neuroprotection.…”

Section: Umbilical Cord Bloodmentioning

confidence: 99%

Cell therapies for traumatic brain injury

Harting

Baumgartner

Worth

et al. 2008

FOC

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Preliminary discoveries of the efficacy of cell therapy are currently being translated to clinical trials. Whereas a significant amount of work has been focused on cell therapy applications for a wide array of diseases, including cardiac disease, bone disease, hepatic disease, and cancer, there continues to be extraordinary anticipation that stem cells will advance the current therapeutic regimen for acute neurological disease. Traumatic brain injury is a devastating event for which current therapies are limited. In this report the authors discuss the current status of using adult stem cells to treat traumatic brain injury, including the basic cell types and potential mechanisms of action, preclinical data, and the initiation of clinical trials.

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“…However, next to a considerable body of indications corroborating the therapeutic efficacy of HUCB MNC after stroke, some investigators were unable to reproduce therapeutic findings, especially when applying more demanding functional tests as in the present study. 13 Furthermore, differences in cell storage and processing may potentially impair the efficacy of the treatment. In fact, while we recently failed to detect neuroprotective effects of cryopreserved HUCB MNC early after MCAO, 17 previous studies reporting beneficial results were generally conducted with freshly isolated HUCB MNC.…”

Section: Discussionmentioning

confidence: 99%

“…12 Some well-designed studies were not able to fully reproduce the aforementioned beneficial effects of HUCB MNC after experimental stroke. 13,14 It is conceivable that differences in cell storage and processing may contribute to these controversial results. In fact, there is an ongoing debate whether either the composition or the functionality of cord blood cells or both is altered by the process of cryopreservation.…”

Section: Introductionmentioning

confidence: 99%

Transplantation of Cryopreserved Human Umbilical Cord Blood Mononuclear Cells Does Not Induce Sustained Recovery after Experimental Stroke in Spontaneously Hypertensive Rats

Weise

Lorenz

Pösel

et al. 2013

J Cereb Blood Flow Metab

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Previous studies have highlighted the enormous potential of cell-based therapies for stroke not only to prevent ischemic brain damage, but also to amplify endogenous repair processes. Considering its widespread availability and low immunogenicity human umbilical cord blood (HUCB) is a particularly attractive stem cell source. Our goal was to investigate the neurorestorative potential of cryopreserved HUCB mononuclear cells (MNC) after permanent middle cerebral artery occlusion (MCAO) in spontaneously hypertensive rats (SHR). Human umbilical cord blood MNC or vehicle solution was administered intravenously 24 hours after MCAO. Experimental groups were as follows: (1) quantitative polymerase chain reaction (PCR) of host-derived growth factors up to 48 hours after stroke; (2) immunohistochemical analysis of astroglial scarring; (3) magnetic resonance imaging (MRI) and weekly behavioral tests for 2 months after stroke. Long-term functional outcome and lesion development on MRI were not beneficially influenced by HUCB MNC therapy. Furthermore, HUCB MNC treatment did not change local growth factor levels and glial scarring extent. In summary, we could not demonstrate neurorestorative properties of HUCB MNC after stroke in SHR. Our results advise caution regarding a prompt translation of cord blood therapy into clinical stroke trials as long as deepened knowledge about its precise modes of action is missing.

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Human umbilical cord blood cells do not improve sensorimotor or cognitive outcome following transient middle cerebral artery occlusion in rats

Cited by 81 publications

References 31 publications

Unexpected Complication in a Rat Stroke Model: Exacerbation of Secondary Pathology in the Thalamus by Subacute Intraarterial Administration of Human Bone Marrow-Derived Mesenchymal Stem Cells

Unexpected Complication in a Rat Stroke Model: Exacerbation of Secondary Pathology in the Thalamus by Subacute Intraarterial Administration of Human Bone Marrow-Derived Mesenchymal Stem Cells

Cell therapies for traumatic brain injury

Transplantation of Cryopreserved Human Umbilical Cord Blood Mononuclear Cells Does Not Induce Sustained Recovery after Experimental Stroke in Spontaneously Hypertensive Rats

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