Human amnion cells reverse acute and chronic pulmonary damage in experimental neonatal lung injury

Dandan Zhu, Jean Tan, Amina S. Maleken, Ruth Muljadi, Siow T. Chan, Sin N. Lau, Kirstin Elgass, Bryan Leaw, Joanne Mockler, Daniel Chambers, Kristen T. Leeman, Carla F. Kim, Euan M. Wallace, Rebecca Lim

Research output: Contribution to journalArticleResearchpeer-review

7 Citations (Scopus)

Abstract

Background: Despite advances in neonatal care, bronchopulmonary dysplasia (BPD) remains a significant contributor to infant mortality and morbidity. While human amnion epithelial cells (hAECs) have shown promise in small and large animal models of BPD, there is scarce information on long-term benefit and clinically relevant questions surrounding administration strategy remain unanswered. In assessing the therapeutic potential of hAECs, we investigated the impact of cell dosage, administration routes and timing of treatment in a pre-clinical model of BPD. Methods: Lipopolysaccharide was introduced intra-amniotically at day 16 of pregnancy prior to exposure to 65% oxygen (hyperoxia) at birth. hAECs were administered either 12 hours (early) or 4 days (late) after hyperoxia commenced. Collective lung tissues were subjected to histological analysis, multikine ELISA for inflammatory cytokines, FACS for immune cell populations and 3D lung stem cell culture at neonatal stage (postnatal day 7 and 14). Invasive lung function test and echocardiography were applied at 6 and 10 weeks of age. Results: hAECs improved the tissue-to-airspace ratio and septal crest density in a dose-dependent manner, regardless of administration route. Early administration of hAECs, coinciding with the commencement of postnatal hyperoxia, was associated with reduced macrophages, dendritic cells and natural killer cells. This was not the case if hAECs were administered when lung injury was established. Fittingly, early hAEC treatment was more efficacious in reducing interleukin-1β, tumour necrosis factor alpha and monocyte chemoattractant protein-1 levels. Early hAEC treatment was also associated with reduced airway hyper-responsiveness and normalisation of pressure-volume loops. Pulmonary hypertension and right ventricle hypertrophy were also prevented in the early hAEC treatment group, and this persisted until 10 weeks of age. Conclusions: Early hAEC treatment appears to be advantageous over late treatment. There was no difference in efficacy between intravenous and intratracheal administration. The benefits of hAEC administration resulted in long-term improvements in cardiorespiratory function.

Original languageEnglish
Article number257
Number of pages24
JournalStem Cell Research and Therapy
Volume8
Issue number1
DOIs
Publication statusPublished - 10 Nov 2017

Keywords

  • Cell therapy
  • Chronic neonatal lung disease
  • Hyperoxia
  • Intra-amniotic inflammation
  • Secondary pulmonary hypertension

Cite this

Zhu, Dandan ; Tan, Jean ; Maleken, Amina S. ; Muljadi, Ruth ; Chan, Siow T. ; Lau, Sin N. ; Elgass, Kirstin ; Leaw, Bryan ; Mockler, Joanne ; Chambers, Daniel ; Leeman, Kristen T. ; Kim, Carla F. ; Wallace, Euan M. ; Lim, Rebecca. / Human amnion cells reverse acute and chronic pulmonary damage in experimental neonatal lung injury. In: Stem Cell Research and Therapy. 2017 ; Vol. 8, No. 1.
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abstract = "Background: Despite advances in neonatal care, bronchopulmonary dysplasia (BPD) remains a significant contributor to infant mortality and morbidity. While human amnion epithelial cells (hAECs) have shown promise in small and large animal models of BPD, there is scarce information on long-term benefit and clinically relevant questions surrounding administration strategy remain unanswered. In assessing the therapeutic potential of hAECs, we investigated the impact of cell dosage, administration routes and timing of treatment in a pre-clinical model of BPD. Methods: Lipopolysaccharide was introduced intra-amniotically at day 16 of pregnancy prior to exposure to 65{\%} oxygen (hyperoxia) at birth. hAECs were administered either 12 hours (early) or 4 days (late) after hyperoxia commenced. Collective lung tissues were subjected to histological analysis, multikine ELISA for inflammatory cytokines, FACS for immune cell populations and 3D lung stem cell culture at neonatal stage (postnatal day 7 and 14). Invasive lung function test and echocardiography were applied at 6 and 10 weeks of age. Results: hAECs improved the tissue-to-airspace ratio and septal crest density in a dose-dependent manner, regardless of administration route. Early administration of hAECs, coinciding with the commencement of postnatal hyperoxia, was associated with reduced macrophages, dendritic cells and natural killer cells. This was not the case if hAECs were administered when lung injury was established. Fittingly, early hAEC treatment was more efficacious in reducing interleukin-1β, tumour necrosis factor alpha and monocyte chemoattractant protein-1 levels. Early hAEC treatment was also associated with reduced airway hyper-responsiveness and normalisation of pressure-volume loops. Pulmonary hypertension and right ventricle hypertrophy were also prevented in the early hAEC treatment group, and this persisted until 10 weeks of age. Conclusions: Early hAEC treatment appears to be advantageous over late treatment. There was no difference in efficacy between intravenous and intratracheal administration. The benefits of hAEC administration resulted in long-term improvements in cardiorespiratory function.",
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author = "Dandan Zhu and Jean Tan and Maleken, {Amina S.} and Ruth Muljadi and Chan, {Siow T.} and Lau, {Sin N.} and Kirstin Elgass and Bryan Leaw and Joanne Mockler and Daniel Chambers and Leeman, {Kristen T.} and Kim, {Carla F.} and Wallace, {Euan M.} and Rebecca Lim",
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Human amnion cells reverse acute and chronic pulmonary damage in experimental neonatal lung injury. / Zhu, Dandan; Tan, Jean; Maleken, Amina S.; Muljadi, Ruth; Chan, Siow T.; Lau, Sin N.; Elgass, Kirstin; Leaw, Bryan; Mockler, Joanne; Chambers, Daniel; Leeman, Kristen T.; Kim, Carla F.; Wallace, Euan M.; Lim, Rebecca.

In: Stem Cell Research and Therapy, Vol. 8, No. 1, 257, 10.11.2017.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Human amnion cells reverse acute and chronic pulmonary damage in experimental neonatal lung injury

AU - Zhu, Dandan

AU - Tan, Jean

AU - Maleken, Amina S.

AU - Muljadi, Ruth

AU - Chan, Siow T.

AU - Lau, Sin N.

AU - Elgass, Kirstin

AU - Leaw, Bryan

AU - Mockler, Joanne

AU - Chambers, Daniel

AU - Leeman, Kristen T.

AU - Kim, Carla F.

AU - Wallace, Euan M.

AU - Lim, Rebecca

PY - 2017/11/10

Y1 - 2017/11/10

N2 - Background: Despite advances in neonatal care, bronchopulmonary dysplasia (BPD) remains a significant contributor to infant mortality and morbidity. While human amnion epithelial cells (hAECs) have shown promise in small and large animal models of BPD, there is scarce information on long-term benefit and clinically relevant questions surrounding administration strategy remain unanswered. In assessing the therapeutic potential of hAECs, we investigated the impact of cell dosage, administration routes and timing of treatment in a pre-clinical model of BPD. Methods: Lipopolysaccharide was introduced intra-amniotically at day 16 of pregnancy prior to exposure to 65% oxygen (hyperoxia) at birth. hAECs were administered either 12 hours (early) or 4 days (late) after hyperoxia commenced. Collective lung tissues were subjected to histological analysis, multikine ELISA for inflammatory cytokines, FACS for immune cell populations and 3D lung stem cell culture at neonatal stage (postnatal day 7 and 14). Invasive lung function test and echocardiography were applied at 6 and 10 weeks of age. Results: hAECs improved the tissue-to-airspace ratio and septal crest density in a dose-dependent manner, regardless of administration route. Early administration of hAECs, coinciding with the commencement of postnatal hyperoxia, was associated with reduced macrophages, dendritic cells and natural killer cells. This was not the case if hAECs were administered when lung injury was established. Fittingly, early hAEC treatment was more efficacious in reducing interleukin-1β, tumour necrosis factor alpha and monocyte chemoattractant protein-1 levels. Early hAEC treatment was also associated with reduced airway hyper-responsiveness and normalisation of pressure-volume loops. Pulmonary hypertension and right ventricle hypertrophy were also prevented in the early hAEC treatment group, and this persisted until 10 weeks of age. Conclusions: Early hAEC treatment appears to be advantageous over late treatment. There was no difference in efficacy between intravenous and intratracheal administration. The benefits of hAEC administration resulted in long-term improvements in cardiorespiratory function.

AB - Background: Despite advances in neonatal care, bronchopulmonary dysplasia (BPD) remains a significant contributor to infant mortality and morbidity. While human amnion epithelial cells (hAECs) have shown promise in small and large animal models of BPD, there is scarce information on long-term benefit and clinically relevant questions surrounding administration strategy remain unanswered. In assessing the therapeutic potential of hAECs, we investigated the impact of cell dosage, administration routes and timing of treatment in a pre-clinical model of BPD. Methods: Lipopolysaccharide was introduced intra-amniotically at day 16 of pregnancy prior to exposure to 65% oxygen (hyperoxia) at birth. hAECs were administered either 12 hours (early) or 4 days (late) after hyperoxia commenced. Collective lung tissues were subjected to histological analysis, multikine ELISA for inflammatory cytokines, FACS for immune cell populations and 3D lung stem cell culture at neonatal stage (postnatal day 7 and 14). Invasive lung function test and echocardiography were applied at 6 and 10 weeks of age. Results: hAECs improved the tissue-to-airspace ratio and septal crest density in a dose-dependent manner, regardless of administration route. Early administration of hAECs, coinciding with the commencement of postnatal hyperoxia, was associated with reduced macrophages, dendritic cells and natural killer cells. This was not the case if hAECs were administered when lung injury was established. Fittingly, early hAEC treatment was more efficacious in reducing interleukin-1β, tumour necrosis factor alpha and monocyte chemoattractant protein-1 levels. Early hAEC treatment was also associated with reduced airway hyper-responsiveness and normalisation of pressure-volume loops. Pulmonary hypertension and right ventricle hypertrophy were also prevented in the early hAEC treatment group, and this persisted until 10 weeks of age. Conclusions: Early hAEC treatment appears to be advantageous over late treatment. There was no difference in efficacy between intravenous and intratracheal administration. The benefits of hAEC administration resulted in long-term improvements in cardiorespiratory function.

KW - Cell therapy

KW - Chronic neonatal lung disease

KW - Hyperoxia

KW - Intra-amniotic inflammation

KW - Secondary pulmonary hypertension

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U2 - 10.1186/s13287-017-0689-9

DO - 10.1186/s13287-017-0689-9

M3 - Article

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JO - Stem Cell Research and Therapy

JF - Stem Cell Research and Therapy

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