Clara cell: Progenitor for the bronchiolar epithelium

doi:10.1016/j.biocel.2009.09.002

The International Journal of Biochemistry & Cell Biology

Volume 42, Issue 1, January 2010, Pages 1-4

https://doi.org/10.1016/j.biocel.2009.09.002 Get rights and content

Abstract

Clara cells were first described as a morphologically distinct cell type by Kolliker in 1881, but they take their name from the seminal study of human and rabbit bronchioles by Max Clara in 1937. Since their discovery, Clara cells have been identified as central players in protecting the airway from environmental exposures. The diverse functions of Clara cells in lung homeostasis include roles in xenobiotic metabolism, immune system regulation, and progenitor cell activity. Recent identification of a sub-population of Clara cells as a bronchiolar tissue-specific stem cell and a potential tumor initiating cell has focused the attention of cell and molecular biologists on the Clara cell and its behavior under normal and disease conditions.

Introduction

The Clara cell is a multifunctional cell that has been under intensive study for 70 years (Fig. 1). It is a cuboidal, non-ciliated cell in human and rabbit terminal bronchioles, containing a basally situated nucleus, an apical dome extending variable distances into the airway lumen, and discrete, oval densely staining granules (Fig. 2). Ultrastructural and morphometric analysis by Plopper and colleagues provided insights into Clara cell function, and led to ongoing studies demonstrating critical roles in barrier maintenance, secretion, and metabolism (Stripp and Reynolds, 2006). Multispecies comparisons established diversity as a defining hallmark of Clara cell biology (Fig. 3). In spite of extensive structural and functional variation, antibody reagents specific to the secretoglobin (SCGB1A1) family allowed Clara cells and their variants to be identified on the basis of secreted protein expression (Reynolds et al., 2002). Members of the SCGB protein class are referred to as uteroglobin (Ug) in humans and rabbits or Clara cell secretory protein (CCSP, CC10) in mice and rats. We will use CCSP as a catch-all phrase to indicate secretoglobin 1A1.

This review describes unique aspects of Clara cell biochemistry, cell biology, and molecular biology that define this cell as a facultative progenitor (i.e., a proliferatively senescent, metabolically active cell that retains the ability to reenter the cell cycle in response to injury of the bronchiolar epithelium) and a subset of Clara cells as tissue-specific stem cells. These functional characteristics support the potential for Clara cells to serve as cancer-initiating cells (Fig. 4).

Section snippets

Origin and plasticity: establishment of the Clara cell pool

Embryological studies established that all airway epithelial cells, with the possible exception of neuroepithelial cells, are derived sequentially from the foregut endoderm (Rawlins et al., 2008). Subdivision of the conducting airway epithelium begins during the second trimester in human lung, and the earliest CCSP-expressing cells are positioned within the luminal aspect of neuroepithelial bodies (NEBs) (Khoor et al., 1996). Continuous labeling studies in hamsters supported the conclusion that

Functions: Clara cells as reparative cells for the airway epithelium

Within the normal lung, Clare cell proliferation maintains the facultative progenitor cell pool (self-renewal) and restores terminally differentiated cells of the conducting airway epithelium (ciliated cells). This vast reparative reservoir distinguishes lung epithelia from tissues such as the intestine that are maintained through proliferation and differentiation of tissue-specific stem cells. The unique features of lung epithelial maintenance and repair suggest that chronic lung disease could

Associated pathologies: Clara cells and cancer

Inflammation encourages neoplasia, as shown by elevated cancer risk in patients with chronic obstructive pulmonary disease (COPD) and the inverse correlation between lung tumor macrophage content and patient survival (Malkinson, 2005). Clara cells may regulate inflammation through secretion of CCSP and consequent regulation of eicosanoid production and the clotting cascade, immune effector cell chemotaxis and phagocytosis. In human adenocarcinomas, most tumor cells are CCSP-negative even if

Acknowledgments

The scanning electron micrograph presented in Fig. 2A was provided by Dr. David Dinsdale, University of Leicester, UK. The transmission electron micrograph shown in Fig. 2B was generated in the Center for Biologic Imaging, University of Pittsburgh, Pittsburgh PA, USA and was generated in collaboration with Dr. Barry R. Stripp while at the University of Pittsburgh. The authors thank the National Institutes of Health CA33497 (AMM), CA132552 (AMM), HL075585 (SDR) and the Cystic Fibrosis Foundation

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Cells in focusClara cell: Progenitor for the bronchiolar epithelium

Abstract

Introduction

Section snippets

Origin and plasticity: establishment of the Clara cell pool

Functions: Clara cells as reparative cells for the airway epithelium

Associated pathologies: Clara cells and cancer

Acknowledgments

Cell

Cell Stem Cell

Am J Pathol

Mucin is produced by clara cells in the proximal airways of antigen-challenged mice

Am J Respir Cell Mol Biol

Stem cells are dispensable for lung homeostasis but restore airways after injury

Proc Natl Acad Sci USA

Neuroepithelial bodies stimulate proliferation of airway epithelium in fetal hamster lung

Am J Physiol

Basic helix–loop–helix transcription factors regulate the neuroendocrine differentiation of fetal mouse pulmonary epithelium

Development

Ontogeny of Clara cell-specific protein and its mRNA: their association with neuroepithelial bodies in human fetal lung and in bronchopulmonary dysplasia

J Histochem Cytochem

Direct effects of interleukin-13 on epithelial cells cause airway hyperreactivity and mucus overproduction in asthma

Nat Med

Proximal airway mucous cells of ovalbumin-sensitized and -challenged Brown Norway rats accumulate the neuropeptide calcitonin gene-related peptide

Am J Physiol Lung Cell Mol Physiol

Cells in focus
Clara cell: Progenitor for the bronchiolar epithelium