Harvard Confirms the Stem Cell Existence in the Human Lungs

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On May 12, 2011 the New England Journal of Medicine published a very exciting and interesting study of the Brigham and Women’s Hospital, Harvard Medical School, Boston; and the University of Parma, Italy; confirming strong and convincing evidence about the finding and isolation of Human Lung Stem Cells.

Researchers of those Universities found that human lungs contain undifferentiated human lung stem cells nested in niches in the distal airways.

This is a very important scientific finding because confirm the fact that stem cells exist in the human lung with the capacity to regenerate the pulmonary tissues and improve some diseases like chronic obstructive pulmonary disease (COPD), emphysema and fibrosis.

Many series of exciting reports over the last 5 to 10 years have demonstrated that adult bone marrow-derived stem cells may have more plasticity and are able to differentiate into bronchial and alveolar epithelium, vascular endothelium, and interstitial cell types, making them prime candidates for lung repair.

The above mentioned studies provide direct evidence that mesenquimal stem cells (MSCs) and other bone marrow-derived cells can be used for COPD, or other lung disease, but the precise mechanism underlying this process needs to be completely understood.

For example, Lobinger (London, UK) have shown that bone marrow-derived progenitors have the ability to differentiate and function as airway and parenchyma lung cells, but the medical community do not know what is the biology role between the resident lung stem cells and bone marrow-derived cells.

The hypothesis that bone marrow-derived cells may be used for regenerative purposes in lung diseases is confirmed by the fact that these cells engraft in the lung, acquire characteristics of certain respiratory cell populations and reduce the degree of respiratory fibrosis in the patient.

Due to the relevance of this fact, hereafter you will find a short overview of the main concepts of the Harvard and Parma Universities scientific paper related with the lung stem cells evidence. (Evidence for Human Lung Stem Cells, J. Kajstura, M. Rota, el al.; N Engl J Med 2011;364:1795-806.)

Various cell populations with some of the stem cells features have been described in distinct anatomical regions of the lung, but the demonstration of a noncommitted cell without specialized functions remains elusive.

In order to demonstrate the stem cell exist in the human lungs, researchers obtained samples of normal human lung tissue from unused donor organs, fetal lungs after cases of fetal death and samples of normal lung tissue from the Brigham and Women’s Hospital Thoracic Surgery Tissue Bank.

To establish whether the human lung possesses a stem-cell pool, they used the stem-cell antigen c-kit as a marker of identification and characterization. Their criteria for human lung stem cells were self-renewal, clonogenicity, and multipotentiality in vitro and in vivo. All samples were prepared for transplant.

After cells recovery, anesthetized female mice immunosuppressed with the use of cyclosporine underwent thoracotomy, and 2 to 3 mm2 of lung tissue was damaged with a steel probe that had been cooled in liquid nitrogen. The area adjacent to the damaged tissue then received six injections (with about 20,000 cells in each injection) of human lung stem cells mixed with labeled polystyrene microspheres. The mice chests were then closed and the animals were killed at 12 hours, 2 days, or 10 to 14 days after surgery. In some mice, lung tissue that had regenerated was excised, prepared and and injected into another mouse with the same cool damaged lung.

After 2 days, approximately 30% of the delivered cells were present within the damaged tissue and the bordering region, and after 10 to 14 days, clonal human lung stem cells had formed human bronchioles, alveoli, and pulmonary vessels, partly restoring the structural integrity of the mice lung tissue.  Thus, the clonal human lung stem cells showed self-renewal and multipotentiality in vivo.

Human lung stem cells generated bronchioles, approximately 30 to 250 μm in diameter, as well as small and intermediate-sized pulmonary arterioles approximately 20 to 70 μm in diameter and the newly formed human lung parenchyma replaced more than 30% of the original damaged tissue.

Ten to 14 days after cryoinjury and cell implantation, undifferentiated, human lung stem cells were identified within the regenerated human lung parenchyma and in the adjacent, intact recipient mouse lung. Approximately 20,000 human lung stem cells were present in each treated mouse.

After enzymatic digestion of the damaged lung, cells were recovered and delivered immediately to the cryoinjured portion of the lung of another new recipient mouse. Ten days after cell treatment, all treated mice were killed, and human bronchi, alveoli, and vessels were identified, documenting that the newly formed human lung structures derived from the serially transplanted human lung stem cells.

Those human lung stem cells that were detected in these mice, providing further evidence in support of the self-renewal and long-term proliferation of human lung stem cells in vivo. Furthermore, direct connections were found between preexisting pulmonary vessels and regenerated pulmonary vessels documenting the integration of temporally distinct preexisting (mouse) and new (human) segments of the pulmonary vasculature.

These results suggest that the human lung possesses a pool cells that have the fundamental properties of stem cells: they are selfrenewing, clonogenic, and multipotent in vitro and in vivo. The ability of human lung stem cells to create human bronchioles, alveoli, and pulmonary vessels in the mouse provides evidence in favor of the crucial role that human lung stem cells may have in lung homeostasis and tissue regeneration after injury. cells.

These findings do not rule out or challenge the notion that basal epithelial cells, bronchoalveolar stem cells, Clara cells, side population cells, and type II alveolar epithelial cells are involved in the epithelial-cell response to inflammation or injury.

Similarly, the presence of a human lung stem cell does not rule out the possibility that mature cells within the adult lung dedifferentiate or reprogram themselves to form a committed progeny, a phenomenon shown to be operative in other organ.

These findings, together with the results of our in vitro studies, provide evidence of a resident multipotent stem cell in the human lung.

In conclusion, this study provide several lines of evidence of the existence of human lung stem cells. Clonal human lung stem cells divided asymmetrically and generated bronchioles, alveoli, and pulmonary vessels of various dimensions, including capillaries, in vivo in a mouse model.

Furthermore, human lung stem cells obtained from regenerated lung tissue were able to selfrenew and create lung parenchyma in vivo in another mouse with lung damage. The immunohistochemical identification of newly regenerated pulmonary structures is strengthened by the recognition of human sex chromosomes and human transcripts of epithelial and vascular genes within the regenerated mouse lung.

Thus, human lung stem cells show self-renewal, clonogenicity, and multipotentiality and could be used in lung regeneration.

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