Table 2.

Overall conference summary recommendations

Basic
• For studies evaluating putative engraftment, advanced histologic imaging techniques (e.g., confocal microscopy, deconvolution microscopy, electron microscopy, laser capture dissection, etc.) must be used to avoid being misled by inadequate photomicroscopy and immunohistochemical approaches. Imaging techniques must be used in combination with appropriate statistical and other analyses to maximize detection of rare events.
• Continue to elucidate mechanisms of recruitment, mobilization, and homing of circulating or therapeutically administered cells to lung epithelial, interstitial, and pulmonary vascular compartments for purposes of either engraftment or of immunomodulation.
• Encourage new research to elucidate molecular programs for development of lung cell phenotypes
• Continue to refine the nomenclature used in study of endogenous and exogenous lung stem cells
• Comparatively identify and study endogenous stem/progenitor cell populations between different lung compartments and between species.
• Increase focus on study of endogenous pulmonary vascular and interstitial progenitor populations
• Develop robust and consistent methodologies for the study of endogenous lung stem and progenitor cell populations.
• Develop more sophisticated tools to identify, mimic, and study ex vivo the relevant microenvironments (niches) for study of endogenous lung progenitor/stem cells.
• Continue to develop functional outcome assessments for endogenous progenitor/stem cells.
• Elucidate how endogenous lung stem and progenitor cells are regulated in normal development and in diseases.
• Identify and characterize putative lung cancer stem cells and regulatory mechanisms guiding their behavior.
• Continue to elucidate mechanisms by which embryonic and induced pluripotent stem cells develop into lung cells/tissue.
• Develop disease-specific populations of ESCs and iPS, for example for CF and α1-antitrypsin deficiency with the recognition that no strategy has yet been devised to overcome the propensity of ESCs and iPS cells to produce tumors.
• Continue to explore lung tissue bioengineering approaches such as artificial matrices and three-dimensional culture systems for generating lung ex vivo and in vivo from stem cells, including systems that facilitate vascular development.
• Evaluate effect of environmental influences including oxygen tension and mechanical forces including stretch and compression pressure on development of lung from stem and progenitor cells.
• Identify additional cell surface markers which characterize lung cell populations for use in visualization and sorting techniques.
• Strong focus must be placed on understanding immunomodulatory and other mechanisms of cell therapy approaches in different specific preclinical lung disease models.
• Improved preclinical models of lung diseases are necessary.
• Disseminate information about and encourage use of existing core services, facilities, and weblinks.
• Actively foster inter-institutional, multidisciplinary research collaborations and consortiums as well as clinical/basic partnerships. Include a program of education on lung diseases and stem cell biology. A partial list includes NHLBI Production Assistance for Cellular Therapies (PACT), NCRR stem cell facilities, GMP Vector Cores, small animal mechanics and CT scanner facilities at several pulmonary centers.
Translational
• Support high-quality translational studies focused on cell-based therapy for human lung diseases. Preclinical models will provide proof of concept; however, these must be relevant to the corresponding human lung disease. Disease-specific models, including large animal models where feasible, should be used and/or developed for lung diseases.
• Basic/translational/preclinical studies should include rigorous comparisons of different cell preparations with respect to both outcome and toxicological/safety endpoints. For example, it is not clear which MSC or EPC preparation (species and tissue source, laboratory source, processing, route of administration, dosing, vehicle, etc.) is optimal for clinical trials in different lung diseases.
• Incorporate rigorous techniques to unambiguously identify outcome measures in cell therapy studies. Preclinical models require clinically relevant functional outcome measures (e.g. pulmonary physiology/mechanics, electrophysiology, and other techniques).
Clinical
• Proceed with design and implementation of initial exploratory safety investigations in patients with lung diseases where appropriate such as ARDS/ALI, asthma, and others. This includes full consideration of ethical issues involved, particularly which patients should be initially studied.
• Provide increased clinical support for cell therapy trials in lung diseases. This includes infrastructure, use of NIH resources such as the PACT program and the NCRR/NIH Center for Preparation and Distribution of Adult Stem Cells (MSCs; http://medicine.tamhsc.edu/irm/msc-distribution.html), coordination among multiple centers, and registry approaches to coordinate smaller clinical investigations.
• Clinical trials must include evaluations of potential mechanisms and this should include mechanistic studies as well as assessments of functional and safety outcomes. Trials should include whenever feasible, collection of biologic materials should as lung tissue, BAL fluid, blood, etc. for investigation of mechanisms as well as for toxicology and other safety endpoints.
• Partner with existing networks, such as ARDSNet or ACRC, nonprofit respiratory disease foundations, and/or industry as appropriate to maximize the scientific and clinical aspects of clinical investigations.
• Integrate with other ongoing or planned clinical trials in other disciplines in which relevant pulmonary information may be obtained. For example, inclusion of pulmonary function testing in trials of MSCs in graft–vs.-host disease will provide novel and invaluable information about potential MSC effects on development and the clinical course of bronchiolitis obliterans.
• Work with industry to have access to information from relevant clinical trials.

Definition of abbreviations: ARDS/ALI = acute respiraory distress syndrome/acute lung injury; ESC = embryonic stem cell; MSC = mesenchymal stromal (stem) cells.