Mesenchymal Stem Cells for Severe Intraventricular Hemorrhage in Preterm Infants: Phase I Dose-Escalation Clinical Trial

Abstract

We previously demonstrated that transplanting mesenchymal stem cells (MSCs) improved recovery from brain injury induced by severe intraventricular hemorrhage (IVH) in newborn rats. To assess the safety and feasibility of MSCs in preterm infants with severe IVH, we performed a phase I dose‐escalation clinical trial. The first three patients received a low dose of MSCs (5 × 106 cells/kg), and the next six received a high dose (1 × 107 cells/kg). We assessed adverse outcomes, including mortality and the progress of posthemorrhagic hydrocephalus. Intraventricular transplantation of MSCs was performed in nine premature infants with mean gestational age of 26.1 ± 0.7 weeks and birth weight of 808 ± 85 g at 11.6 ± 0.9 postnatal days. Treatment with MSCs was well tolerated, and no patients showed serious adverse effects or dose‐limiting toxicities attributable to MSC transplantation. There was no mortality in IVH patients receiving MSCs. Infants who underwent shunt surgery showed a higher level of interleukin (IL)‐6 in cerebrospinal fluid (CSF) obtained before MSC transplantation in comparison with infants who did not receive a shunt. Levels of IL‐6 and tumor necrosis factor‐α in initially obtained CSF correlated significantly with baseline ventricular index. Intraventricular transplantation of allogeneic human UCB‐derived MSCs into preterm infants with severe IVH is safe and feasible, and warrants a larger, and controlled, phase II study. Stem Cells Translational Medicine 2018;7:847–856

Mechanisms underlying the protective effects of mesenchymal stem cell-based therapy

“…Although 74% of the publications reported some promising results, only 18% of the publications showed that this treatment was safe [115]. Although the safety of MSC transplantation was confirmed, less than 40% of the studies and clinical trials with available and published results showed [128] positive improvements in the use of MSCs for patients with amyotrophic lateral sclerosis [116]. Administration of MSCs in clinical trials exhibited beneficial effects on diabetes.…”

Umbilical cord blood stem cell therapy in premature brain injury: Opportunities and challenges

“…The study was performed by intraventricular injection of allogeneic UCB‐MSCs in nine preterm infants with severe IVH, with a follow‐up to 40 weeks of corrected age (Table ). The outcomes indicated that UCB‐MSC therapy was well tolerated with attenuated periventricular hemorrhagic infarct, and no infants suffered from dose‐limiting toxicities or serious adverse reactions such as anaphylaxis or death within 6 hr after injection (Ahn et al, ). Although the results were encouraging, randomized controlled clinical trials with long‐term follow‐up are necessary.…”

“…For example, autologous cord blood was imported back into preterm infants to test for any therapeutic effects on various complications (Sun et al, ), and autologous UCBC therapy has been applied in preterm infants with WMI (Cotten et al, ; Li et al, ) . Also, allogeneic UCB‐derived mesenchymal stem cells (UCB‐MSCs) have been administered in preterm infants with severe IVH (Ahn, Chang, Sung, & Park, ). These studies suggest that the application of autologous and allogeneic UCB‐SCs in preterm infants is feasible and safe.…”

“…Also, allogeneic UCB-derived mesenchymal stem cells (UCB-MSCs) have been administered in preterm infants with severe IVH (Ahn, Chang, Sung, & Park, 2018). These studies suggest that the application of autologous and allogeneic UCB-SCs in preterm infants is feasible and safe.…”

Peptidome Analysis of Umbilical Cord Mesenchymal Stem Cell (hUC-MSC) Conditioned Medium from Preterm and Term Infants

“…Mechanically, MSCs function in vivo via direct differentiation or paracrine action. The therapeutic potential of MSC engraftment has been proved in premature infant diseases, and early clinical trials in preterm neonates with BPD (NCT01297205 [9], NCT01632475 [10]) and severe intraventricular hemorrhage (NCT02274428 [11]) have been conducted. A myriad of bioactive factors are readily available in the conditioned medium (CM) of MSCs and the medium can mediate multiple known functions of MSCs, such as angiogenesis, anti-brosis and anti-in ammatory effects [12].…”