Mesenchymal Stem Cells Induce T-Cell Tolerance and Protect the Preterm Brain after Global Hypoxia-Ischemia

Hypoxic-ischemic encephalopathy (HIE) in preterm infants is a severe disease for which no curative treatment is available. Cerebral inflammation and invasion of activated peripheral immune cells have been shown to play a pivotal role in the etiology of white matter injury, which is the clinical hallmark of HIE in preterm infants. The objective of this study was to assess the neuroprotective and anti-inflammatory effects of intravenously delivered mesenchymal stem cells (MSC) in an ovine model of HIE. In this translational animal model, global hypoxia-ischemia (HI) was induced in instrumented preterm sheep by transient umbilical cord occlusion, which closely mimics the clinical insult. Intravenous administration of 2 x 106MSC/kg reduced microglial proliferation, diminished loss of oligodendrocytes and reduced demyelination, as determined by histology and Diffusion Tensor Imaging (DTI), in the preterm brain after global HI. These anti-inflammatory and neuroprotective effects of MSC were paralleled by reduced electrographic seizure activity in the ischemic preterm brain. Furthermore, we showed that MSC induced persistent peripheral T-cell tolerance in vivo and reduced invasion of T-cells into the preterm brain following global HI. These findings show in a preclinical animal model that intravenously administered MSC reduced cerebral inflammation, protected against white matter injury and established functional improvement in the preterm brain following global HI. Moreover, we provide evidence that induction of T-cell tolerance by MSC might play an important role in the neuroprotective effects of MSC in HIE. This is the first study to describe a marked neuroprotective effect of MSC in a translational animal model of HIE

Mesenchymal stem cells induce T-cell tolerance and protect the preterm brain after global hypoxia-ischemia

\u3cp\u3eHypoxic-ischemic encephalopathy (HIE) in preterm infants is a severe disease for which no curative treatment is available. Cerebral inflammation and invasion of activated peripheral immune cells have been shown to play a pivotal role in the etiology of white matter injury, which is the clinical hallmark of HIE in preterm infants. The objective of this study was to assess the neuroprotective and anti-inflammatory effects of intravenously delivered mesenchymal stem cells (MSC) in an ovine model of HIE. In this translational animal model, global hypoxia-ischemia (HI) was induced in instrumented preterm sheep by transient umbilical cord occlusion, which closely mimics the clinical insult. Intravenous administration of 2 x 10(6) MSC/kg reduced microglial proliferation, diminished loss of oligodendrocytes and reduced demyelination, as determined by histology and Diffusion Tensor Imaging (DTI), in the preterm brain after global HI. These anti-inflammatory and neuroprotective effects of MSC were paralleled by reduced electrographic seizure activity in the ischemic preterm brain. Furthermore, we showed that MSC induced persistent peripheral T-cell tolerance in vivo and reduced invasion of T-cells into the preterm brain following global HI. These findings show in a preclinical animal model that intravenously administered MSC reduced cerebral inflammation, protected against white matter injury and established functional improvement in the preterm brain following global HI. Moreover, we provide evidence that induction of T-cell tolerance by MSC might play an important role in the neuroprotective effects of MSC in HIE. This is the first study to describe a marked neuroprotective effect of MSC in a translational animal model of HIE. \u3c/p\u3

Reproducibility of 25 min umbilical cord occlusion (UCO).

<p>(<b>A</b>) Fetal mean arterial blood pressure (MABP) and (<b>B</b>) fetal heart rate (FHR) measurements indicated that all animals exposed to global HI experienced the same degree of hypotension and bradycardia, respectively, at the end of UCO; means (thick line) ± SD (shaded areas) of n=8 animals per experimental group are shown. MABP and FHR normalized within one hour after the end of UCO and were stable throughout the rest of the study period. All sham operated animals had similar MABP and FHR parameters during the entire duration of the study. For clarity reasons the sham-SAL and sham-MSC groups are depicted as one sham group. (<b>C</b>–<b>E</b>) Blood gas analysis indicated that twenty five minutes of umbilical cord occlusion induced comparable acidosis, hypoxemia and hypercarboxemia in all animals exposed to global HI, as demonstrated by (<b>C</b>) arterial pH, (<b>D</b>) arterial partial oxygen pressure (pO₂) and (<b>E</b>) arterial partial carbon dioxide pressure (pCO₂), respectively; means (lines) ± SD (error bars) of n=8 animals are depicted. Blood gas indices in animals exposed to global HI normalized within one hour after the end of UCO and stayed within the normal range throughout the rest of the study period.</p

MSC were detected in the fetal ovine brain.

<p>A FISH probe specific for the human Y-chromosome detected the presence of systemically delivered MSC in the ovine brain. (<b>A</b>–<b>D</b>) Representative fluorescent images of the SCWM in the different experimental groups; (<b>A</b>) sham-SAL, (<b>B</b>) sham-MSC, (<b>C</b>) HI-SAL and (<b>D</b>) HI-MSC. (<b>A</b>–<b>B</b>) In saline treated animals the FISH probe did not react with any nucleus. (<b>C</b>–<b>D</b>) The FISH probe was detected in MSC treated animals indicating that MSC were present in the preterm brain 7 d after intravenous administration. Scale bars: (<b>A</b>–<b>D</b>) 50 µm, scale bars inserts: (<b>A</b>–<b>D</b>) 5 µm.</p

Intravenous MSC reduced proliferation of microglia after global HI.

<p>(<b>A</b>) Immunohistochemical IBA-1 staining in the SCWM of the four experimental groups with squares in the first panel indicating the regions where immunoreactivity was assessed. Global HI induced a profound increase of IBA-1 immunoreactivity, which was significantly reduced by intravenous MSC treatment. (<b>B</b>) Immunohistochemical IBA-1 staining in the hippocampus of the four experimental groups. Profound proliferation of microglia was observed in the hippocampus following global HI. MSC partially reduced the inflammatory response of microglia in the hippocampus after global HI. (<b>C</b>–<b>D</b>) Graphical presentation of area fraction of IBA-1 immunoreactivity in SCWM and hippocampus; (<b>C</b>) geometric means ± 95% CI and (<b>D</b>) means ± 95% CI and levels of significance are depicted, which were calculated by the random intercept model with all repeated measures (i.e. brain sections) per animal (sham-SAL n=6, sham-MSC n=3, HI-SAL n=6, HI-MSC n=6). Dots show the averaged results of the repeated measures (i.e. brain sections) per animal. * <i>P</i>≤0.05, ‡ <i>P</i>≤0.01, # <i>P</i>≤0.001. IBA-1 = ionized calcium binding adaptor molecule 1, HI = hypoxia-ischemia, SAL = saline, MSC = mesenchymal stem cells, IR = immunoreactivity. (<b>A</b>–<b>B</b>) Scale bars represent 1 mm.</p

Medication reviews and deprescribing as a single intervention in falls prevention : a systematic review and meta-analysis

Background: our aim was to assess the effectiveness of medication review and deprescribing interventions as a single intervention in falls prevention. Methods: Design: systematic review and meta-analysis. Data sources: Medline, Embase, Cochrane CENTRAL, PsycINFO until 28 March 2022. Eligibility criteria: randomised controlled trials of older participants comparing any medication review or deprescribing intervention with usual care and reporting falls as an outcome. Study records: title/abstract and full-text screening by two reviewers. Risk of bias: Cochrane Collaboration revised tool. Data synthesis: results reported separately for different settings and sufficiently comparable studies meta-analysed. Results forty-nine heterogeneous studies were included. Community: meta-analyses of medication reviews resulted in a risk ratio (RR) of 1.05 (95% confidence interval, 0.85–1.29, I2 = 0%, 3 studies(s)) for number of fallers, in an RR = 0.95 (0.70–1.27, I2 = 37%, 3 s) for number of injurious fallers and in a rate ratio (RaR) of 0.89 (0.69–1.14, I2 = 0%, 2 s) for injurious falls. Hospital: meta-analyses assessing medication reviews resulted in an RR = 0.97 (0.74–1.28, I2 = 15%, 2 s) and in an RR = 0.50 (0.07–3.50, I2 = 72% %, 2 s) for number of fallers after and during admission, respectively. Long-term care: meta-analyses investigating medication reviews or deprescribing plans resulted in an RR = 0.86 (0.72–1.02, I2 = 0%, 5 s) for number of fallers and in an RaR = 0.93 (0.64–1.35, I2 = 92%, 7 s) for number of falls. Conclusions: the heterogeneity of the interventions precluded us to estimate the exact effect of medication review and deprescribing as a single intervention. For future studies, more comparability is warranted. These interventions should not be implemented as a stand-alone strategy in falls prevention but included in multimodal strategies due to the multifactorial nature of falls. PROSPERO registration number: CRD4202021823