238
13.1 Introduction
Degenerative lung diseases, such as COPD and pulmonary fibrosis, are both com-
mon and a major cause of morbidity and mortality for afflicted patients. In contrast
to some other organs or tissues, the various cell types that comprise the lung are
largely quiescent at baseline, with a variety of localized stem/progenitor pools
maintaining a low turnover index to collectively support tissue homeostasis. In the
setting of either acute or chronic degenerative lung disease, these progenitor popula-
tions are either unable to regenerate dying cell types, as occurs in emphysema, or
respond to injury with an aberrant repair program, as occurs in pulmonary fibrosis
or acute interstitial pneumonia (AIP). In each example, the architecture of the lung
is damaged in a manner that prevents it from performing its function of gas exchange
and in many cases results in an increased risk of infection. To date, treatment modal-
ities with the capacity to restore lung tissue or functional capacity, short of lung
transplant, are not available. The apparent limited ability of the lung to respond to
these common and devastating degenerative disease entities provides the impetus to
develop new, cell-based, restorative therapies. Approaches to meet this need could
include either the production of stem/progenitor cells that could then be delivered to
the damaged, native lung to regenerate damaged tissue or the engineering of a de
novo transplantable organ. Previous works to accomplish the former approach
through the transplantation of bone marrow-derived cells or via tracheal delivery or
both have proven to be technically difficult and met with limited success, consistent
with cellular transplant results in organ systems outside of the bone marrow and the
eye in this regard. While technical advances might ultimately solve the challenge of
engrafting exogenously delivered progenitor cells in their local lung niche, the
capacity of this approach to restore the architecture of damaged lung tissue could
remain a significant challenge. In this chapter, we will focus instead on the goal of
building an entire transplantable organ, starting with the derivation in vitro of the
cell types that comprise the proximal and distal lung compartments from pluripotent
stem cells (PSCs), moving next to the various three-dimensional (3D) systems cur-
rently employed for spatial organization and functional characterization of lung lin-
eages, and finally discussing future possibilities for creating a human-scale
bioartificial lung based on developmental principles and in vitro organogenesis.
13.2 In Vitro Derivation of Lung Lineages from Pluripotent
Stem Cells
The construction of a bioengineered organ requires the ability to produce large
quantities of the various differentiated cell types that make up an adult lung. This
variety of specialized cells, in turn, needs to come from the same genetic back-
ground, ideally that of the eventual organ transplant recipient. PSCs and specifically
induced pluripotent stem cells (iPSCs) are the cell type best suited to this task at the
A. Wilson and L. Ikonomou