Acute or Delayed Systemic Administration of Human Amnion Epithelial Cells Improves Outcomes in Experimental Stroke

Evans, Megan C.; Lim, Rebecca; Kim, Hyun Ah; Chu, Hannah X; Gardiner-Mann, Chantelle V.; Taylor, Kimberly; Chan, Christopher T.; Brait, Vanessa H; Lee, Seyoung; Dinh, Quynh Nhu; Vinh, Antony; Phan, Thanh G.; Srikanth, Velandai; Ma, Henry; Arumugam, Thiruma V.; Fann, David Y.; Poh, Luting; Hunt, Cameron P.J.; Pouton, Colin W.; Haynes, John M.; Selemidis, Stavros; Kwan, William C.; Teo, Leon; Bourne, James A.; Neumann, Silke; Young, Sarah L.; Gowing, Emma K.; Drummond, Grant R; Clarkson, Andrew N.; Wallace, Euan M.; Sobey, Christopher G.; Broughton, Brad R.S.

doi:10.1161/strokeaha.117.019136

Cited by 61 publications

(92 citation statements)

References 30 publications

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“…Median (range) Apgar score at 5 minutes of life was 6 (0-9). The first three infants were dependent on invasive mechanical ventilation with a median mean airway pressure of 18 (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23) Table 1.…”

Section: Resultsmentioning

confidence: 99%

First-In-Human Administration of Allogeneic Amnion Cells in Premature Infants With Bronchopulmonary Dysplasia: A Safety Study

Lim

Malhotra

Tan

et al. 2018

Stem Cells Translational Medicine

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Bronchopulmonary dysplasia (BPD) is a chronic lung disease that mainly affects premature babies who require ventilator support. The pathogenesis of BPD is complex but includes vascular maldevelopment, alveolarization arrest, and lung inflammation. There is no cure for BPD. Clinical care is limited to supportive respiratory measures. A population of stem‐like cells derived from placental membranes, human amnion epithelial cells (hAECs), has shown therapeutic promise in preclinical models of BPD. With a view to future efficacy trials, we undertook a first‐in‐human clinical trial of hAECs in babies with BPD to assess the safety of these cells. In a single‐center, open‐label phase I trial, we administered allogeneic hAECs (1 × 106 per kilogram bodyweight) by intravenous infusion to six premature babies with BPD. The primary outcomes of the study were focused on safety, including local site reaction, anaphylaxis, infection, features of rejection, or tumor formation. Outcomes to discharge from neonatal unit were studied. The hAECs were well tolerated. In the first baby, there was transient cardiorespiratory compromise during cell administration consistent with a pulmonary embolic event. Following changes to cell administration methods, including introduction of an inline filter, and reducing the cell concentration and the rate of cell infusion, no such events were observed in the subsequent five babies. We did not see evidence of any other adverse events related to cell administration. Allogeneic hAECs can be safely infused into babies with established BPD. Future randomized clinical trials to assess efficacy in this patient population are justified. Stem Cells Translational Medicine 2018;7:628–635

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Section: Resultsmentioning

confidence: 99%

First-In-Human Administration of Allogeneic Amnion Cells in Premature Infants With Bronchopulmonary Dysplasia: A Safety Study

Lim

Malhotra

Tan

et al. 2018

Stem Cells Translational Medicine

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110

119

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“…Intravenous (IV) administration of hAECs has recently shown great potential for improving outcomes following ischemic brain injury [17]; an injury with considerable pathophysiological overlap with TBI [8,18,19]. Evans and colleagues found that when administered at acute or delayed stages following experimental ischemic stroke, hAECs migrated to the injured brain as well as the spleen, resulting in reduced infarct size and improved functional recovery in mice [17]. Notably, hAEC treatment had a profound effect on immune cell infiltration into the injured brain, with reductions in the number of neutrophils, T cells and macrophages detected in the first 24-72 h post-injury [17].…”

Section: Introductionmentioning

confidence: 99%

Systemic treatment with human amnion epithelial cells after experimental traumatic brain injury

Kim

Semple

Dill

et al. 2020

Preprint

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Background: Systemic administration of human amnion epithelial cells (hAECs) was recently shown to reduce neuropathology and improve functional recovery following ischemic stroke in both mice and marmosets. Given the significant neuropathological overlap between ischemic stroke and traumatic brain injury (TBI), we hypothesized that a similar hAEC treatment regime would also improve TBI outcomes. Methods: Male mice (12 weeks old, n=40) were given a sham injury or moderate severity TBI by controlled cortical impact. At 60 minutes post-injury, mice were given a single tail vein injection of either saline (vehicle) or 1x10 6 hAECs suspended in saline. At 24 h post-injury, mice were assessed for locomotion and anxiety using an open field, and sensorimotor ability using a rotarod. At 48 h post-injury, brains were collected for analysis of immune cells via flow cytometry, or histological evaluation of lesion volume and hAEC penetration. To assess the impact of TBI and hAECs on lymphoid organs, spleen and thymus weights were determined. Results: Treatment with hAECs did not prevent TBI-induced sensorimotor deficits at 24 h post-injury. hAECs were detected in the injured brain parenchyma; however, lesion volume was not altered by hAEC treatment. Robust increases in several leukocyte populations in the ipsilateral hemisphere of TBI mice were found when compared to sham mice at 48 h post-injury; however, hAEC treatment did not alter brain immune cell numbers.Both TBI and hAEC treatment were found to increase spleen weight. Conclusions: Taken together, these findings indicate that -unlike in ischemic stroke -treatment with hAEC was unable to prevent immune cell infiltration and sensorimotor deficits in the acute stages following controlled cortical impact in mice. Although further investigations are required, our data suggests that the lack of hAECinduced neuroprotection in the current study may be explained by the differential splenic contributions to neuropathology between these brain injury models. Background Traumatic brain injury (TBI) is a leading causing of death and disability worldwide [1, 2]. Although numerous treatments have proved promising in rodent models of experimental TBI, all pharmacological agents investigated to date have failed to improve outcomes in clinical trials [3-6]. The diverse nature of clinical TBI is likely to be a major contributor to such failures, with individual Declarations Ethics approval and consent to participate: All procedures were approved by the Animal Ethics Committee at La Trobe University (AEC #18-032). Authors' contributions: HK, BDS, CGS and SJM conceptualized the study. HK, BDS, LP and SJM conducted animal surgeries. RL isolated and quantified hAECs. SJM and LP conducted behavioral testing. LKD, SD, SZ and BDS conducted histology. HK conducted flow cytometry. All authors contributed to data interpretation, manuscript preparation and finalization. Acknowledgments: traumatic brain injury and spinal cord injury, 1990-2016: a systematic analysis for the Global Burden of Disease St...

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“…This means that the risk of host rejection upon transplantation is low while the cells still retain potential disease‐modifying properties . The therapeutic utility of hAECs has been explored for a variety of disease conditions including lung disease, liver disease, and stroke in small and large animal models . In preclinical models of BPD, hAECs have been shown to prevent alveolar simplification and lung inflammation, two of the hallmarks of BPD, and to prevent pulmonary hypertension, a key sequelae of BPD …”

Section: Introductionmentioning

confidence: 99%

“…12 The therapeutic utility of hAECs has been explored for a variety of disease conditions including lung disease, liver disease, and stroke in small and large animal models. [13][14][15] In preclinical models of BPD, hAECs have been shown to prevent alveolar simplification and lung inflammation, two of the hallmarks of BPD, 7 and to prevent pulmonary hypertension, a key sequelae of BPD. 15 With a view to future clinical efficacy trials, we undertook a first-in-human phase I trial to assess the safety and tolerability of allogeneic hAECs in premature babies with established BPD.…”

Section: Introductionmentioning

confidence: 99%

Two-year outcomes of infants enrolled in the first-in-human study of amnion cells for bronchopulmonary dysplasia

Malhotra

Lim

Mockler

et al. 2019

Stem Cells Translational Medicine

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We previously reported on the immediate safety and neonatal outcomes of six premature infants with severe bronchopulmonary dysplasia (BPD) who were administered human amnion epithelial cells (hAECs). One infant died in the neonatal period due to unrelated causes. In this study, we aimed to assess the long‐term safety and follow‐up outcomes of the five surviving infants until 2 years corrected age (CA). hAECs were administered intravenously at a dose of 1 × 106 cells per kilogram after 36 weeks postconceptional age in infants with established BPD. Study follow‐up consisted of assessment of any adverse events, growth, and respiratory, cardiac, and neurodevelopmental outcomes over four time points (6, 12, 18, and 24 months CA). Investigations included chest x‐rays, cranial and abdominal ultrasounds, and echocardiograms at regular intervals as well as a magnetic resonance imaging (MRI) brain at 2 years CA. All five infants were alive at 2 years CA. Median time to wean off oxygen was 24 (10‐36) months. Two infants had pulmonary hypertension, which resolved by 2 years of age. Four infants were rehospitalized briefly for viral or bacterial infections during the 2 years. MRI brain findings included normal (n = 1), and mild to moderate white matter loss (n = 2). Neurodisabilities diagnosed included hemiplegic cerebral palsy (n = 1), global developmental delay (n = 3), and severe hearing loss (n = 3). No evidence of tumor formation was noted on physical examinations or on any imaging. There were no long‐term adverse events observed that could be attributed to hAEC administration. We observed long‐term effects of extreme prematurity and severe BPD in the cohort.

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Acute or Delayed Systemic Administration of Human Amnion Epithelial Cells Improves Outcomes in Experimental Stroke

Abstract: Systemic poststroke administration of hAECs elicits marked neuroprotection and facilitates mechanisms of repair and recovery.

Cited by 61 publications

References 30 publications

First-In-Human Administration of Allogeneic Amnion Cells in Premature Infants With Bronchopulmonary Dysplasia: A Safety Study

First-In-Human Administration of Allogeneic Amnion Cells in Premature Infants With Bronchopulmonary Dysplasia: A Safety Study

Systemic treatment with human amnion epithelial cells after experimental traumatic brain injury

Two-year outcomes of infants enrolled in the first-in-human study of amnion cells for bronchopulmonary dysplasia

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