Continued Progress in Tissue Engineered Lungs

Tissue engineered lungs are a desirable cure for end-stage PPH because allografts inevitably give rise to chronic rejection.  In addition, allografts are in short supply, with the result that many people with PPH die waiting for one, or are intubated by the time of transplant.  Intubation has been shown to correlate negatively with post-transplant survival.

However, it is very, very difficult to tissue engineer a lung.  The lung has over 40 different cell types.  All of these must be grown from progenitor cells, interweaved together for normal functionality, and then grafted into the transplant recipient.  Despite the challenge, recent progress has been reported.

Julia Polak and colleagues at the Imperial College of Medicine have successfully coaxed murine embryonic stem cells to differentiate into both epithelial and mesenchymal cells using a unique solution.  The differentiated cells are viable and replication competent.  They are now prepared to duplicate the experiment with human embryonic stem cells as well as with human bone marrow cells.  Other researchers have reported during the past year that human bone marrow cells can differentiate into hepatocytes.

There are two basic options with regard to further differentiation and implantation.  One option is to coax all 40+ lung cell types to differentiate ex vivo, embed them on a bio-active matrix and provide the matrix with circulation.  This option should result in a lung lobe or lung functional unit of some sort existing ex vivo in a form that can be transplanted into a patient.  A second option is to coal a progenitor cell into differentiating into only a few key lung cell types, and then transplanting these “seeds” into a diseased lung in vivo.  The goal here would be for the lung to regenerate itself using the disease-free “seeds” and the body’s own chemical signaling system to tell the seeds how to further differentiate and integrate into the lung.

The advantage of growing an entire lung function unit ex vivo is that one knows, for sure, that they are transplanting something that works.   However, this is a mighty challenge, since no one has ever kept even a lung bud (a minute collection of cells from an embryo that would eventually form the core of a growing lung) viable ex vivo for more than a day.  The problems are how to differentiate into an entire lung, how to integrate the differentiated cells into a functioning lung, and how to keep the growing proto-organ viable ex vivo prior to transplantation.

The advantage of “seeding” a diseased lung with tissue engineered lung cells (differentiated from a progenitor cell ex vivo) is that the body itself is used as the machine to produce a new lung.  The body in this case is simply given a big “jump start” with the “lung seeds.”  The problems of full lung cell differentiation and integration are solved by mysterious endogenous processes which human do not yet understand, much less replicate ex vivo.  On the other hand, such a lung regeneration effort is in its neo-infancy.  There is, however, some pioneering work being done with generating new alveoli in vivo from pharmaceutical stimulants.

Whichever path is pursued, it must be remembered for PPH that the disease is characterized by diffuse occlusion of distal arterioles.  Hence, new alveoli, new interstitial lung growth or new venous structures will do little good for the PPH patient.  Their problem lies in the distal arterioles, not the proximal branches of the pulmonary vein, or the air sacs, or the elastin lining of the lung.  It may well be that the only way to get new distal arterioles is to replace the entire lung.  This does not solve the choice between growing the lung ex vivo or in vivo, but it does provide an important technology development constraint.  This constraint should be kept constantly in mind in weighing the evolving technology risks and hypothesized therapeutic benefits of each approach.