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

Reddy, Raghava; Buckley, Sue; Doerken, Melissa; Barsky, Lora; Weinberg, Kenneth I.; Anderson, Kathryn D.; Warburton, David; Driscoll, Barbara

doi:10.1152/ajplung.00159.2003

Cited by 144 publications

(111 citation statements)

References 24 publications

Supporting

Mentioning

107

Contrasting

Order By: Relevance

“…In contrast, E-cad À AEC II were undamaged and proliferative with a high telomerase activity under the pathological condition. 39 We have confirmed that LMDEC Maj are E-cad À by flow cytometric analysis (data not shown). This fact tempts us to consider that LMDEC Maj may be a sub-subpopulation of AEC II.…”

Section: Discussionsupporting

confidence: 63%

Therapeutic effect of lung mixed culture-derived epithelial cells on lung fibrosis

Tanaka

Fujita

Umezawa

et al. 2014

Laboratory Investigation

View full text Add to dashboard Cite

Cell-based therapy is recognized as one of potential therapeutic options for lung fibrosis. However, preparing stem/ progenitor cells is complicated and not always efficient. Here, we show easily prepared cell populations having therapeutic capacity for lung inflammatory disease that are named as 'lung mixed culture-derived epithelial cells' (LMDECs). LMDECs expressed surfactant protein (SP)-C and gave rise to type I alveolar epithelial cells (AECs) in vitro and in vivo that partly satisfied type II AEC-like characteristics. An intratracheal delivery of not HEK 293 cells but LMDECs to the lung ameliorated bleomycin (BLM)-induced lung injury. A comprehensive analysis of bronchoalveolar fluid by western blot array revealed that LMDEC engraftment could improve the microenvironment in the BLM-instilled lung in association with stromal cell-derived factor-1 (SDF-1)/CXC chemokine receptor 4 signaling axis. SDF-1 enhanced both migration activity and differentiating efficiency of LMDECs. Further classification of LMDECs by flow cytometric study showed that a major population of LMDECs (LMDEC Maj , 84% of total LMDECs) was simultaneously SP-C þ , CD44 þ , CD45 þ , and hematopoietic cell lineage þ and that LMDECs included bronchioalveolar stem cells (BASCs) showing SP-C þ Clara cell secretory protein þ stem cell antigen (Sca)1 þ as a small population (1.8% of total LMDECs). CD44 þ -sorted LMDEC Maj and Sca1 þ -sorted LMDECs equally ameliorated fibrosis induced by BLM like LMDECs did. However, infiltrated neutrophils were observed in Sca1 þ -sorted LMDEC-treated alveoli that was not typical in LMDEC Maj -or LMDEC-treated alveoli. These findings suggest that the protective effect of LMDECs against BLM-induced lung injury depends greatly on that of LMDEC Maj . Furthermore, the cells expressing both alveolar epithelial and hematopoietic cell lineage markers (SP-C þ CD45 þ ) that have characteristics corresponding to LMDEC Maj were observed in the alveoli of lung and increased approximately threefold in response to BLM instillation. Taken together, LMDECs newly classified in the present study are easily culture expanded and have a potential role in future regenerative cell therapy for pulmonary fibrosis.

show abstract

Section: Discussionsupporting

confidence: 63%

Therapeutic effect of lung mixed culture-derived epithelial cells on lung fibrosis

Tanaka

Fujita

Umezawa

et al. 2014

Laboratory Investigation

View full text Add to dashboard Cite

show abstract

“…The late phase (E16-E18) is characterized by the emergence of differentiated cell types for alveoli and bronchioli (Wuenschell et al, 1996). The alveolar epithelium includes alveolar epithelial type 1 (AT1) and AT2 cells, which are derived from common alveolar stem cells (AT2 cells) (Bishop, 2004;Reddy et al, 2004). The bronchiolar epithelium includes basal cells, ciliated cells, Clara cells, goblet cells, and a few pulmonary neuroendocrine cells (Bishop, 2004).…”

Section: Introductionmentioning

confidence: 99%

Runx3 is required for the differentiation of lung epithelial cells and suppression of lung cancer

Lee

et al. 2010

Oncogene

View full text Add to dashboard Cite

Human lung adenocarcinoma, the most prevalent form of lung cancer, is characterized by many molecular abnormalities. K-ras mutations are associated with the initiation of lung adenocarcinomas, but K-ras-independent mechanisms may also initiate lung tumors. Here, we find that the runt-related transcription factor Runx3 is essential for normal murine lung development and is a tumor suppressor that prevents lung adenocarcinoma. Runx3À/À mice, which die soon after birth, exhibit alveolar hyperplasia. Importantly, Runx3À/À bronchioli exhibit impaired differentiation, as evidenced by the accumulation of epithelial cells containing specific markers for both alveolar (that is SP-B) and bronchiolar (that is CC10) lineages. Runx3À/À epithelial cells also express Bmi1, which supports self-renewal of stem cells. Lung adenomas spontaneously develop in aging Runx3 þ /À mice (B18 months after birth) and invariably exhibit reduced levels of Runx3. As K-ras mutations are very rare in these adenomas, Runx3 þ /À mice provide an animal model for lung tumorigenesis that recapitulates the preneoplastic stage of human lung adenocarcinoma development, which is independent of K-Ras mutation. We conclude that Runx3 is essential for lung epithelial cell differentiation, and that downregulation of Runx3 is causally linked to the preneoplastic stage of lung adenocarcinoma.

show abstract

“…To replace damaged cells throughout the life span of any animal, a particular subpopulation within the total population must retain the ability to divide. In the alveolar epithelium, this progenitor cell-like function has been ascribed to AEC2 (13,31,36). AEC2 proliferate during embryonic and fetal life but, in the adult lung, in the absence of injury, are highly differentiated and do not normally divide (9,37).…”

mentioning

confidence: 99%

“…This is followed by extensive remodeling, requiring participation of the surviving AEC2 that are still capable of proliferation (8). We have recently characterized a specific subpopulation of rat AEC2 that is proliferative, expresses telomerase, and is capable of surviving hyperoxic damage, features that may allow it to orchestrate repair (12,31).…”

mentioning

confidence: 99%

Contribution of proliferation and DNA damage repair to alveolar epithelial type 2 cell recovery from hyperoxia

Lee

Reddy²,

Barsky³

et al. 2006

American Journal of Physiology-Lung Cellular and Molecular Phys

Self Cite

View full text Add to dashboard Cite

. Contribution of proliferation and DNA damage repair to alveolar epithelial type 2 cell recovery from hyperoxia. Am J Physiol Lung Cell Mol Physiol 290: L685-L694, 2006. First published November 18, 2005 doi:10.1152/ajplung.00020.2005In this study, C57BL/6J mice were exposed to hyperoxia and allowed to recover in room air. The sublethal dose of hyperoxia for C57BL/6J was 48 h. Distal lung cellular isolates from treated animals were characterized as 98% epithelial, with minor fibroblast and endothelial cell contaminants. Cells were then verified as 95% pure alveolar epithelial type II cells (AEC2) by surfactant protein C (SP-C) expression. After hyperoxia exposure in vivo, fresh, uncultured AEC2 were analyzed for proliferation by cell yield, cell cycle, PCNA expression, and telomerase activity. DNA damage was assessed by TdT-dUTP nick-end labeling, whereas induction of DNA repair was evaluated by GADD-153 expression. A baseline level for proliferation and damage was observed in cells from control animals that did not alter significantly during acute hyperoxia exposure. However, a rise in these markers was observed 24 h into recovery. Over 72 h of recovery, markers for proliferation remained elevated, whereas those for DNA damage and repair peaked at 48 h and then returned back to baseline. The expression of GADD-153 followed a distinct course, rising significantly during acute exposure and peaking at 48 h recovery. These data demonstrate that in healthy, adult male C57BL/6J mice, AEC2 proliferation, damage, and repair follow separate courses during hyperoxia recovery and that both proliferation and efficient repair may be required to ensure AEC2 survival. C57BL/6J; GADD-153; telomerase IN LATE GESTATION OF MICE and rats, the alveolar epithelial cell (AEC) lineage develops from a multipotent population of stem cells that line the primitive respiratory tract (15). Alveolar epithelial type 2 cells (AEC2) manufacture surfactant and can differentiate, as required, into alveolar epithelial type 1 cells (AEC1), which regulate the gas exchange function of the organ (2, 14). To replace damaged cells throughout the life span of any animal, a particular subpopulation within the total population must retain the ability to divide. In the alveolar epithelium, this progenitor cell-like function has been ascribed to AEC2 (13,31,36). AEC2 proliferate during embryonic and fetal life but, in the adult lung, in the absence of injury, are highly differentiated and do not normally divide (9, 37). However, in response to environmental insult, some AEC2 become both hypertrophic and hyperplastic, such that cells undergo phenotypic and functional changes (17, 24). Regenerating rat AEC2 exhibit elevated cyclin and cyclin-dependent kinase (cdk) expression and activity during recovery following injury, indicating the regain of proliferative function (10, 39). During this period, the number of proliferating AEC2 has been reported to increase severalfold in rats (10, 36), mice (2), and humans (4). In human patients, this phase of recovery fr...

show abstract

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

Cited by 144 publications

References 24 publications

Therapeutic effect of lung mixed culture-derived epithelial cells on lung fibrosis

Therapeutic effect of lung mixed culture-derived epithelial cells on lung fibrosis

Runx3 is required for the differentiation of lung epithelial cells and suppression of lung cancer

Contribution of proliferation and DNA damage repair to alveolar epithelial type 2 cell recovery from hyperoxia

Contact Info

Product

Resources

About