Feasibility and safety of intranasally administered mesenchymal stromal cells after perinatal arterial ischaemic stroke in the Netherlands (PASSIoN): a first-in-human, open-label intervention study

Baak, Lisanne M; Wagenaar, Nienke; Aa, Niek E. van der; Groenendaal, Floris; Dudink, Jeroen; Tataranno, Maria Luisa; Mahamuud, Ubah; Verhage, Cornelia H.; Eijsermans, Rian; Smit, Liesbeth S.; Jellema, Reint K.; Haan, Timo R. de; Horst, Hendrik J. ter; Boode, Willem P. de; Steggerda, Sylke J.; Prins, Henk-Jan; Haar, Colin de; Vries, Linda S. de; Bel, Frank van; Heijnen, Cobi J.; Nijboer, Cora H.; Benders, Manon J. N. L.

doi:10.1016/s1474-4422(22)00117-x

Cited by 73 publications

(42 citation statements)

References 34 publications

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“…delivery of stem cell-based therapies in neonates suffering from brain injury. Accordingly, a first clinical feasibility and safety trial in intranasally MSC-treated infants with neonatal stroke was recently successfully conducted [ 35 ].…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, in the majority of studies, MSC-EVs were administered intravenously or intraperitoneally [ 8 , 12 – 15 , 25 – 27 , 32 – 34 ]. A less invasive intranasal route has been successfully established as an alternative administration mode for MSCs and MSC-EVs in various small and large animal models of perinatal brain injury and in a pilot clinical trial in neonatal stroke patients [ 10 , 16 , 35 – 41 ].…”

Section: Introductionmentioning

confidence: 99%

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Extracellular vesicles from immortalized mesenchymal stromal cells protect against neonatal hypoxic-ischemic brain injury

et al. 2023

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Background Human mesenchymal stromal cell (MSC)-derived extracellular vesicles (EV) revealed neuroprotective potentials in various brain injury models, including neonatal encephalopathy caused by hypoxia–ischemia (HI). However, for clinical translation of an MSC-EV therapy, scaled manufacturing strategies are required, which is challenging with primary MSCs due to inter- and intra-donor heterogeneities. Therefore, we established a clonally expanded and immortalized human MSC line (ciMSC) and compared the neuroprotective potential of their EVs with EVs from primary MSCs in a murine model of HI-induced brain injury. In vivo activities of ciMSC-EVs were comprehensively characterized according to their proposed multimodal mechanisms of action. Methods Nine-day-old C57BL/6 mice were exposed to HI followed by repetitive intranasal delivery of primary MSC-EVs or ciMSC-EVs 1, 3, and 5 days after HI. Sham-operated animals served as healthy controls. To compare neuroprotective effects of both EV preparations, total and regional brain atrophy was assessed by cresyl-violet-staining 7 days after HI. Immunohistochemistry, western blot, and real-time PCR were performed to investigate neuroinflammatory and regenerative processes. The amount of peripheral inflammatory mediators was evaluated by multiplex analyses in serum samples. Results Intranasal delivery of ciMSC-EVs and primary MSC-EVs comparably protected neonatal mice from HI-induced brain tissue atrophy. Mechanistically, ciMSC-EV application reduced microglia activation and astrogliosis, endothelial activation, and leukocyte infiltration. These effects were associated with a downregulation of the pro-inflammatory cytokine IL-1 beta and an elevated expression of the anti-inflammatory cytokines IL-4 and TGF-beta in the brain, while concentrations of cytokines in the peripheral blood were not affected. ciMSC-EV-mediated anti-inflammatory effects in the brain were accompanied by an increased neural progenitor and endothelial cell proliferation, oligodendrocyte maturation, and neurotrophic growth factor expression. Conclusion Our data demonstrate that ciMSC-EVs conserve neuroprotective effects of primary MSC-EVs via inhibition of neuroinflammation and promotion of neuroregeneration. Since ciMSCs can overcome challenges associated with MSC heterogeneity, they appear as an ideal cell source for the scaled manufacturing of EV-based therapeutics to treat neonatal and possibly also adult brain injury.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Extracellular vesicles from immortalized mesenchymal stromal cells protect against neonatal hypoxic-ischemic brain injury

et al. 2023

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“…However, intracerebroventricular administration would be difficult to translate to the clinic, unlike intravenous and potentially intranasal routes of administration. Interestingly, a small first in human study in 10 neonates, presenting with perinatal arterial ischemic stroke, demonstrated that intranasal bone marrow derived mesenchymal stromal cell administration is feasible in neonates, with no evidence of serious adverse effects [ 29 ].…”

Section: Discussionmentioning

confidence: 99%

Lack of Neuroprotection with a Single Intravenous Infusion of Human Amnion Epithelial Cells after Severe Hypoxia–Ischemia in Near-Term Fetal Sheep

Davidson

Heuij

Dhillon

et al. 2022

IJMS

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Background: Hypoxic–ischemic encephalopathy (HIE) around the time of birth results from loss of oxygen (hypoxia) and blood supply (ischemia). Exogenous infusion of multi-potential cells, including human amnion epithelial cells (hAECs), can reduce hypoxic–ischemic (HI) brain injury. However, there are few data on treatment of severe HI in large animal paradigms at term. The aim of the current study was to determine whether infusion of hAECs early after injury may reduce brain damage after ischemia in near-term fetal sheep. Methods: Chronically instrumented fetal sheep (0.85 gestation) received 30 min of global cerebral ischemia followed by intravenous infusion of hAECs from 2 h after the end of ischemia (ischemia-hAEC, n = 6) or saline (ischemia-vehicle, n = 7). Sham control animals received sham ischemia with vehicle infusion (sham control, n = 8). Results: Ischemia was associated with significant suppression of EEG power and spectral edge frequency until the end of the experiment and a secondary rise in cortical impedance from 24 to 72 h, which were not attenuated by hAEC administration. Ischemia was associated with loss of neurons in the cortex, thalamus, striatum and hippocampus, loss of white matter oligodendrocytes and increased microglial numbers in the white matter, which were not affected by hAEC infusion. Conclusions: A single intravenous administration of hAECs did not reduce electrographic or histological brain damage after 30 min of global cerebral ischemia in near-term fetal sheep.

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“…Another study by Elena de Celis-Ruiz also demonstrated the safety of intravenous adipose tissue-derived mesenchymal stem cell therapy from the first 2 weeks after ischemic stroke to 24 months of follow-up ( 89 , 91 ). A first-in-human, open-label intervention study by Lisanne M. Baak and team used intranasally delivered bone marrow-derived allogeneic MSCs for neonates with perinatal arterial ischaemic stroke ( 98 ). All ten enrolled neonates were welltolerated with the therapy, and no serious adverse events were observed until 3 months of age follow-up.…”

Section: The Role and Research Progress Of Msc Transplantation In The...mentioning

confidence: 99%

The role of mesenchymal stem cell transplantation for ischemic stroke and recent research developments

et al. 2022

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Ischemic stroke is a common cerebrovascular disease that seriously affects human health. However, most patients do not practice self-care and cannot rely on the current clinical treatment for guaranteed functional recovery. Stem cell transplantation is an emerging treatment studied in various central nervous system diseases. More importantly, animal studies show that transplantation of mesenchymal stem cells (MSCs) can alleviate neurological deficits and bring hope to patients suffering from ischemic stroke. This paper reviews the biological characteristics of MSCs and discusses the mechanism and progression of MSC transplantation to provide new therapeutic directions for ischemic stroke.

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Feasibility and safety of intranasally administered mesenchymal stromal cells after perinatal arterial ischaemic stroke in the Netherlands (PASSIoN): a first-in-human, open-label intervention study

Cited by 73 publications

References 34 publications

Extracellular vesicles from immortalized mesenchymal stromal cells protect against neonatal hypoxic-ischemic brain injury

Extracellular vesicles from immortalized mesenchymal stromal cells protect against neonatal hypoxic-ischemic brain injury

Lack of Neuroprotection with a Single Intravenous Infusion of Human Amnion Epithelial Cells after Severe Hypoxia–Ischemia in Near-Term Fetal Sheep

The role of mesenchymal stem cell transplantation for ischemic stroke and recent research developments

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