Stem cells and cell therapies in lung biology and lung diseases.
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abstract
The University of Vermont College of Medicine and the Vermont Lung Center, with support from the National Heart, Lung, and Blood Institute (NHLBI), the American Thoracic Society, the Alpha-1 Foundation, and the Pulmonary Fibrosis Foundation, convened a workshop, "Stem Cells and Cell Therapies in Lung Biology and Lung Diseases," to review our current understanding of the role of stem and progenitor cells in lung repair after injury and to review the current status of cell therapy approaches for lung diseases. These are rapidly expanding areas of study that both provide further insight into and challenge traditional views of mechanisms of lung repair after injury and pathogenesis of several lung diseases. The goals of the conference were to summarize the current state of the field, discuss and debate current controversies, and to identify future research directions and opportunities for both basic and translational research in cell-based therapies for lung diseases. This workshop was a follow-up to an inaugural workshop held at the University of Vermont in 2005, "Adult Stem Cells, Lung Biology, and Lung Disease," sponsored by the NHLBI and the Cystic Fibrosis Foundation, together with the Vermont Lung Center and the University of Vermont College of Medicine (1). That workshop was instrumental in helping guide research and funding priorities. Since the 2005 workshop, investigations of stem cells and cell therapies in lung biology and diseases have continued to rapidly expand. However, there have been several distinct changes in focus and direction, particularly with respect to cell-based therapy approaches. For example, engraftment of airway or alveolar epithelium by stem or progenitor cells originating from outside of the lung is now viewed to be a rarer occurrence than previously described and of unclear physiologic or therapeutic significance. In contrast, circulating endothelial progenitor cells (EPCs) can contribute to regeneration of diseased pulmonary vasculature and are being investigated in patients with pulmonary hypertension in a clinical trial being conducted at the University of Toronto and in one recently completed at Zhejiang University, China. Circulating EPCs may also play roles in both acute lung injury and in fibrotic lung diseases. Furthermore, increasing evidence suggests that circulating fibrocytes can contribute to the pathophysiology of fibrotic lung diseases and thus may be a potential therapeutic target. In addition, novel areas of investigation have developed that include increasing exploration of three-dimensional culture systems and bioengineering approaches to generate functional lung tissue ex vivo and in vivo. Mesenchymal stem cells (MSCs) have been found to exert profound suppressive effects on immune cells and pathways and have demonstrated both safety and efficacy in phase 1 and 2 trials in immune-mediated diseases such as graft-versus-host disease (GVHD) and Crohn's disease. Recent publications and several abstracts presented at the workshop demonstrate that MSCs suppress lung injury and inflammation in several mouse models of inflammatory and immune-mediated lung diseases. These areas are predicted to be of intense investigation over the next several years. Progress continues to be made in investigations of local (endogenous) stem and progenitor cells resident in the lungs. Further understanding of the identity and lineage expansion properties of previously identified endogenous progenitor populations, including variant Clara cells, bronchoalveolar stem cells (BASCs), and side population cells, suggests an increasingly complex network of cellular repair after injury. Most recently, embryonic origin Oct-4+ Clara cell secretory protein (CCSP+) cells have been identified in neonatal mouse lungs and have been postulated to play a progenitor role in adult lung. However, study of endogenous lung stem and progenitor cells is complicated by the role of specific microenvironmental niches in which these cells reside. Alteration of the niches with experimental protocols or removal of cells from the niches can change their identifying characteristics and biologic activities. One of the challenges facing the field is to devise lineage tracing and other study mechanisms to define, characterize, and explore potential therapeutic and/or pathologic properties of endogenous lung progenitor cells. Notably, the existence of lung cancer stem cells is an area of increasing focus and high interest but remains poorly understood. Another challenge is that most studies of endogenous progenitor cells have used mouse models. Correlative information in human lungs remains poorly defined. Comparably, most studies of exogenous cells in lung repair have used mouse models, with relatively limited data in patient models. A continuing issue of confusion is that of terminology. Precise definitions and characterizations of specific cell populations, notably MSCs and EPCs, are not agreed upon. The terms "stem cell" and "progenitor cell" are still used with varying degrees of clarity and precision by different investigators and in recent publications. This continues to complicate comparison of different investigative approaches. A glossary of relevant working definitions applicable to lung is depicted in Table 1. This glossary does not necessarily reflect an overall consensus for the definition of each term and will undergo continuing revision as overall understanding of the cell types and mechanisms involved in lung repair continues to be elucidated. Nonetheless, it is a useful framework. In the first session, after an overview of the field by Diane Krause (Yale University), respective presentations by Wellington Cardoso (Boston University), Barry Stripp (Duke University), Ivan Bertoncello (Australian Stem Cell Center), and Douglas Ball (Johns Hopkins University School of Medicine) reviewed the current state of knowledge of endogenous stem cell populations and their potential to initiate or
published proceedings
Proc Am Thorac Soc
altmetric score
8
author list (cited authors)
Weiss, D. J., Kolls, J. K., Ortiz, L. A., Panoskaltsis-Mortari, A., & Prockop, D. J.
citation count
156
complete list of authors
Weiss, Daniel J||Kolls, Jay K||Ortiz, Luis A||Panoskaltsis-Mortari, Angela||Prockop, Darwin J