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The promise of stem cells in bronchopulmonary dysplasia

https://doi.org/10.1053/j.semperi.2013.01.003Get rights and content

Abstract

Bronchopulmonary dysplasia (BPD) is a chronic lung disease of prematurity, which affects very preterm infants. Advances in perinatal care have enabled the survival of infants born as early as 23–24 weeks of gestation, but make the task more challenging of protecting injury to an ever more immature lung. Currently, there is no specific treatment for BPD. Recent advances in our understanding of stem/progenitor cells and their potential to repair damaged organs offer the possibility of cell-based treatments for neonatal lung injury. This review summarizes the recent advances in our understanding of lung stem cells during normal and impaired lung growth and the exciting pre-clinical data using mesenchymal stromal cells to prevent/repair impaired alveolar growth in experimental models of BPD.

Introduction

With advances in perinatal care, prematurely born infants are now capable of being delivered as early as 23–24 weeks of gestation. However, this has made the task increasingly challenging in protecting the extremely immature lung from injury. According to a publication by the World Health Organization, preterm birth affects approximately 10.6% of all births in North America.1 Although there has been a shift in the improvement of survival of these prematurely born infants, there has been no decrease in morbidity. In particular, rates of bronchopulmonary dysplasia (BPD) have not dramatically changed over recent years.2 Recent evidence shows that BPD has long-term respiratory complications, which reach beyond childhood and into adult life, with follow-up studies demonstrating increased risk of respiratory symptoms (i.e. cough and wheeze), poor lung function, and low exercise capacity.3., 4., 5., 6., 7. However, currently there is a lack of efficient treatment for BPD. Such a treatment should not only target the repair of lung injury, but also promote normal lung growth. In doing so, long-term lung function and respiratory health in prematurely born infants could improve. Exciting discoveries in stem/progenitor cell biology over recent years may offer new insight into the pathogenesis of BPD and, more importantly, open new therapeutic avenues.

Section snippets

Current understanding of lung stem cell biology

Stem cells are primitive cells capable of extensive self-renewal with the potential to give rise to multiple differentiated cellular phenotypes.8 Not only are they critical for organogenesis and growth during the early stages of development, but they also contribute to organ repair and regeneration throughout life. In the lung, several local epithelial cell types function as both differentiated functional cells and transit-amplifying progenitors that proliferate in response to airway or

How far have we come? Progress made over past years

Although there are currently no published clinical trials on the use of stem cells in treating or preventing BPD, significant progress in our understanding of stem cell therapy for BPD has been achieved. Advances in our knowledge in this field of research have arisen from an array of studies that have focused not only on the therapeutic benefit of stem cells in experimental models of BPD, but have also focused on resident lung stem cells in health and disease.

Conclusions

In recent years we have uncovered imperative insights and gained extensive knowledge on the stem cells and the lungs in health and disease, and now their therapeutic potential in regenerative medicine is being harnessed for the treatment of neonatal lung injury. Various types of stem cells have shown benefit in experimental models of neonatal lung injury. Before safe clinical translation of cell-based therapies is warranted, we must broaden our knowledge and understanding in this novel and

References (56)

  • A.H. Jobe

    The new bronchopulmonary dysplasia

    Curr Opin Pediatr

    (2011)
  • L.W. Doyle et al.

    Bronchopulmonary dysplasia in very low birth weight subjects and lung function in late adolescence

    Pediatrics

    (2006)
  • M. Filippone et al.

    Evidence of unexpected oxidative stress in airways of adolescents born very preterm

    Eur Respir J

    (2012)
  • I. Narang et al.

    Longitudinal evaluation of airway function 21 years after preterm birth

    Am J Respir Crit Care Med

    (2008)
  • L.J. Smith et al.

    Reduced exercise capacity in children born very preterm

    Pediatrics

    (2008)
  • E.L. Rawlins et al.

    Epithelial stem cells of the lung: privileged few or opportunities for many?

    Development

    (2006)
  • J.L. McQualter et al.

    Endogenous fibroblastic progenitor cells in the adult mouse lung are highly enriched in the sca-1 positive cell fraction

    Stem Cells

    (2009)
  • J.L. McQualter et al.

    Evidence of an epithelial stem/progenitor cell hierarchy in the adult mouse lung

    Proc Natl Acad Sci USA

    (2010)
  • E.L. Rawlins et al.

    The Id2+ distal tip lung epithelium contains individual multipotent embryonic progenitor cells

    Development

    (2009)
  • A.E. Hegab et al.

    Novel stem/progenitor cell population from murine tracheal submucosal gland ducts with multipotent regenerative potential

    Stem Cells

    (2011)
  • A. Giangreco et al.

    Molecular phenotype of airway side population cells

    Am J Physiol Lung Cell Mol Physiol

    (2004)
  • K.U. Hong et al.

    Clara cell secretory protein-expressing cells of the airway neuroepithelial body microenvironment include a label-retaining subset and are critical for epithelial renewal after progenitor cell depletion

    Am J Respir Cell Mol Biol

    (2001)
  • T. Volckaert et al.

    Parabronchial smooth muscle constitutes an airway epithelial stem cell niche in the mouse lung after injury

    J Clin Invest

    (2011)
  • R. Reddy et al.

    Isolation of a putative progenitor subpopulation of alveolar epithelial type 2 cells

    Am J Physiol Lung Cell Mol Physiol

    (2004)
  • D.F. Alvarez et al.

    Lung microvascular endothelium is enriched with progenitor cells that exhibit vasculogenic capacity

    Am J Physiol Lung Cell Mol Physiol

    (2008)
  • I. Bertoncello et al.

    Endogenous lung stem cells: what is their potential for use in regenerative medicine?

    Expert Rev Respir Med

    (2010)
  • J.C. Snyder et al.

    Endogenous lung stem cells and contribution to disease

    J Pathol

    (2009)
  • I.Y. Adamson et al.

    The type 2 cell as progenitor of alveolar epithelial regeneration. A cytodynamic study in mice after exposure to oxygen

    Lab Invest

    (1974)
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