211opportunities for clinical trials in the treatment of Parkinson’s disease (Barker et al.
2012 ), and the generation of retinal pigmented epithelium from iPSC is being tri-
alled for the treatment of macular degeneration (Ouyang et al. 2016 ). However, the
delivery and integration of iPSC-derived tissues brings with it considerable chal-
lenges. It is not clear what residual risk of teratoma formation exists with the deliv-
ery of cells differentiated in vitro. The prospect of accumulated genomic instability
in pluripotent stem cell lines may also bring with it a risk of cancer in the resulting
progeny. From a more practical standpoint, getting the cell type you wish to deliver
into the right location and functionally integrating into the desired organ, particu-
larly in the face of existing tissue injury, as is likely in any patient with underlying
disease, is a major challenge. Hence, while directed differentiation to cardiomyo-
cyte was first described over a decade ago, the successful integration and electrical
coupling of such cells have not been successful (Mummery et al. 2010 ).
Directed differentiation of human pluripotent stem cells to organoids, while gen-
erating a highly complex multicellular structure similar to the developing organ
itself, does not at this point in time provide a tissue available for the treatment of
renal disease. What it does do is create the progenitor populations for all of the final
structures within the kidney. There are, therefore, several pathways from organoid
that may ultimately deliver regenerative approaches to the treatment of kidney dis-
ease (Fig. 11.4). These include cellular therapy and bioengineering.
11.5.1 Provision of Cell Sources for Cellular Therapy
We would define the cellular therapy of kidney disease as the restoration of kidney
function via the delivery and site-appropriate functional integration of specific kid-
ney cell types into a patient. A number of studies have reported that it is feasible to
deliver specific cell types into animal models of renal injury and see evidence that
these cells reached the kidney and reside in appropriate locations. This has been
reported for adult renal progenitor cells (Lazzeri et al. 2007 ) and was initially pro-
posed for bone marrow-derived stem cells specifically in response to acute renal
injury (Poulsom et al. 2001 ). In the case of the latter studies, it was subsequently
shown that such events were extremely rare and involved fusion with existing renal
epithelial cells rather than functional integration (Lin et al. 2005 ). A number of
clinical trials have examined the delivery of human mesenchymal stem cells (bone
marrow derived) in the treatment of acute kidney injury and the modulation of graft
rejection in transplant recipients (Reinders et al. 2013 ; Fleig and Humphreys 2014 ).
In this instance, in both mouse and man, the MSCs delivered into the patient survive
only transiently with the apparent clinical improvement a product of an alteration in
the growth factor milieu within the patient rather than any evidence of cellular inte-
gration. As such, this is likely to represent a transient modulation rather than a cel-
lular therapy with prolonged functional integration. Now it is possible to direct
differentiation of pluripotent stem cells to kidney cell types, it is perhaps now time
to systematically reassess whether any given kidney cell type can be successfully
11 Recapitulating Development to Generate Kidney Organoid Cultures