24513.6 3D Functional Organization of In Vitro Derived Lung
Lineages
As discussed in the previous section, there has been considerable progress in the
in vitro derivation of putative lung primordial epithelial progenitors in both mouse
and human PSC systems (Ikonomou and Kotton 2015 ). Novel culture systems, such
as decellularized lung scaffolds (Song and Ott 2011 ) and in vitro organoids (Clevers
2016 ), offer unprecedented opportunities for multilineage differentiation, tissue-
like structure formation, and functional evaluation of PSC-derived lung progenitors.
Despite their structural differences, both systems are powerful 3D inductive culture
environments for the study of morphogenetic/differentiation processes that either
are inaccessible – in the case of human lung development – or require complex
mouse genetic models. The preponderant role of “dynamic reciprocity” (Bissell
et al. 1982 ) between ECM and cells in these systems reflects the importance of
ECM-cell interactions in in vivo lung development, homeostasis, and disease. In
this section, we will review recent advances in 3D culture of PSC-derived lung pro-
genitors and discuss how the acquired knowledge will inform future design of bio-
artificial lungs, including organ-scale 3D bioprinting.
13.7 Decellularized Lung Scaffolds for In Vitro PSC Lung
Differentiation
While grafts based on decellularized 2D tissues, such as the skin, have been in clini-
cal use for many years (van der Veen et al. 2010 ), it was only recently that solid
organ decellularization was introduced as a novel platform for human tissue/organ
engineering. The publication of the first proof-of-principle paper on heart
decellularization- recellularization (decell-recell) (Ott et al. 2008 ) was followed by
the demonstration of lung scaffold decell-recell (Fig. 13.3a) (Ott et al. 2010 ;
Petersen et al. 2010 ) and soon after several publications established that this
approach can be standardized and generalized for the creation of natural scaffolds
from a plethora of organs (Song et al. 2013 ; Totonelli et al. 2012 , 2013 ; Uygun et al.
2010 ).
In the following years, various studies have exhaustingly characterized the com-
position, morphology, and mechanical properties of adult decellularized lung scaf-
folds from various species. Morphometric and micro-CT analysis has demonstrated
that decellularized scaffolds retain intact airway, vascular tree, and alveolar septum
architecture without appreciable alveolar surface area loss (Ott et al. 2010 ; Petersen
et al. 2010 ; Price et al. 2010 ). The decellularization process does, however, result in
the loss of varying degrees of ECM protein. Proteomic analysis by mass spectrom-
etry has provided valuable insights in the matrisome – ECM and ECM-associated
proteins – composition (Naba et al. 2012 ) of decellularized human and porcine
lungs (Booth et al. 2012 ; Gilpin et al. 2014a; Li et al. 2016 ). White and coworkers
13 Development and Bioengineering of Lung Regeneration