Impact of age on the efficacy of bone marrow mononuclear cell transplantation in experimental stroke

Wagner, Daniel-Christoph; Bojko, Mitja; Peters, Myriam; Lorenz, Marlene; Voigt, Cornelia; Kaminski, Alexander; Hasenclever, Dirk; Scholz, Markus; Kranz, Alexander; Weise, Gesa; Boltze, Johannes

doi:10.1186/2040-7378-4-17

Cited by 25 publications

(24 citation statements)

References 41 publications

(45 reference statements)

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“…Degree of heterogeneity in the pooled estimates is represented at I 2 statistic. The studies included in meta-analysis of absolute 5,6,41,54 and relative 39,40,44,46,49,50 decrease in infarct size are cited.…”

Section: Figurementioning

confidence: 99%

Systematic Review and Meta-Analysis of Bone Marrow–Derived Mononuclear Cells in Animal Models of Ischemic Stroke

Vahidy¹,

Rahbar²,

Zhu³

et al. 2016

Stroke

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Background and Purpose Bone marrow derived mononuclear cells (BMMNCs) offer the promise of augmenting post-stroke recovery. There is mounting evidence of safety and efficacy of BMMNCs from pre-clinical studies of ischemic stroke (IS), however their pooled effects have not been described. Methods Using PRIMSA guidelines, we conducted a systematic review of pre-clinical literature for intravenous use of BMMNCs followed by meta-analyses of histological and behavioral outcomes. Studies were selected based on pre-defined criteria. Data were abstracted by two independent investigators. Following quality assessment, the pooled effects were generated using mixed effect models. Impact of possible biases on estimated effect size was evaluated. Results Standardized mean difference (SMD), 95% confidence interval (CI) for reduction in lesion volume was significantly beneficial for BMMNC treatment (SMD −3.3, 95% CI: −4.3, −2.3), n = 113 each for BMMNC and controls. BMMNC treated animals (n = 161) also had improved function measured by cylinder test (SMD −2.4, 95% CI: −3.1, −1.6), as compared to controls (n = 205). A trend for benefit was observed for adhesive removal test and neurological deficit score. Study quality score (median: 6, Q1-Q3: 5-7) was correlated with year of publication. There was funnel plot asymmetry, however the pooled effects were robust to the correction of this bias and remained significant in favor of BMMNC treatment. Conclusions BMMNCs demonstrate beneficial effects across histological and behavioral outcomes in animal IS models. Though study quality has improved over time, considerable degree of heterogeneity calls for standardization in the conduct and reporting of experimentation.

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Section: Figurementioning

confidence: 99%

Systematic Review and Meta-Analysis of Bone Marrow–Derived Mononuclear Cells in Animal Models of Ischemic Stroke

Vahidy¹,

Rahbar²,

Zhu³

et al. 2016

Stroke

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“…Although BM cells play an important role in hypertensiveinduced diseases (Wagner et al, 2012) and that 2K1C hypertension leads to increased production of ROS , the impact of this renovascular hypertension on apoptosis in BM cells has not yet been investigated in this murine model. Therefore, the present study was designed to test the hypothesis that the augmented production of superoxide anions ( O 2 -) and hydrogen peroxide (H 2 O 2 ) leads to DNA fragmentation and apoptosis in the 2K1C hypertension model.…”

mentioning

confidence: 99%

Renovascular Hypertension Leads to DNA Damage and Apoptosis in Bone Marrow Cells

Campagnaro

Tonini

Doche

et al. 2013

DNA and Cell Biology

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Angiotensin II (Ang II), which plays a pivotal role in the pathophysiology of the two-kidney, one-clip (2K1C) Goldblatt hypertension, has been associated with augmented generation of reactive oxygen species (ROS) in some cells and tissues. In the present study, we evaluated the influence of 2K1C hypertension on oxidative stress, DNA fragmentation, and apoptosis of bone marrow (BM) cells. Two weeks after the renal artery clipping or Sham operation, flow cytometry analysis showed a higher production of superoxide anions (approximately sixfold) and hydrogen peroxide (approximately twofold) in 2K1C hypertensive than in Sham normotensive mice. 2K1C mice also showed an augmented DNA fragmentation (54%) and apoptotic cells (21%). Our data show that the 2K1C renovascular hypertension is characterized by an increased production of ROS, DNA damage, and apoptosis of BM, which is a fundamental source of the cells involved in tissue repair.

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“…Furthermore, to minimize the risk for false-negative interpretation of the results a priori, sample size calculations were performed based on the data derived from previous studies of our group. 16 In fact, hardly any previous study applying cord blood therapy for ischemic injury reported on sample size calculations and if so, these studies were powered to detect improvements in primary outcome parameters of X40%. 44 Nevertheless, it has to be mentioned that s.d.…”

Section: Discussionmentioning

confidence: 99%

“…were derived from former experiments and set to 20% of the area under the curve for the ladder rung test and 15% for the modified neurologic severity score (mNSS). 16 Thus, the required sample size (two-tailed) was 12 animals per group for the ladder rung test and seven animals per group for the mNSS. Secondary endpoints comprised infarct volume and secondary hemispheric atrophy on MRI.…”

Section: Methodsmentioning

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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Impact of age on the efficacy of bone marrow mononuclear cell transplantation in experimental stroke

Cited by 25 publications

References 41 publications

Systematic Review and Meta-Analysis of Bone Marrow–Derived Mononuclear Cells in Animal Models of Ischemic Stroke

Systematic Review and Meta-Analysis of Bone Marrow–Derived Mononuclear Cells in Animal Models of Ischemic Stroke

Renovascular Hypertension Leads to DNA Damage and Apoptosis in Bone Marrow Cells

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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