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reintroduced to a patient and functionally contribute. Two such studies have been
reported. The first of these (Imberti et al. 2015 ) delivered a PAX2/8+OSR1+ progeni-
tor population derived using a previously undescribed differentiation protocol (RA/
PI3K inhibition, activin A, then BMP7/GDNF/FGF2) into a cisplatin-induced acute
injury model performed in NOD-SCID mice via tail vein injection (5 x 10^5 cells/
mouse). They report the presence of human cells within the immunocompromised
recipient animals, although cell contribution was not quantified, fusion was not
investigated and functional integration was not proven. However, evidence was pre-
sented to suggest that the delivery of these cells improved BUN, reduced necrosis
and showed less protein casts. The second of these studies (Toyohara et al. 2015 )
employed a distinct protocol for the generation of OSR1+SIX2+ renal progenitors
which were enriched based upon the insertion of GFP into the OSR1 locus. When
isolated, this cell population proved capable of forming nephrons in vitro in response
to Wnt signalling. These human iPSC-derived progenitors were delivered via renal
subcapsular transplantation into immunodeficient mice subjected to an ischemia/
reperfusion injury, BUN and serum creatinine levels were reduced, and histological
analyses also suggested less protein casts, reduced tubular dilatation and improved
brush borders and less necrosis (Toyohara et al. 2015 ). However, in this instance,
there was no evidence that the cells themselves integrated into the recipient kidney
with the effect presumed to arise due to the production of pro-reparative growth fac-
tors by the implanted cells (Toyohara et al. 2015 ). The dissociation and delivery of
multiple cell types from an organoid has not been performed. Perhaps the advantage
of starting preclinical trials using this as a source of cells would rest with the diver-
sity of cell types present. However, irrespective of the kidney cell type used, there is
likely to be much preclinical work to be done to improve the delivery of such cells
to optimise integration.
11.5.2 Implantation of Regenerated Tissue
It may also be possible to deliver the entire organoids for in vivo vascularisation.
The protocol of Takasato et al. ( 2015 ) generates a human kidney organoid com-
prised of different renal cell types and measuring approximately 5 mm in diameter
after 25 days of culture. While these organoids contain SOX17+ KDR+ CD31+ endo-
thelial cells, scaling up the volume of tissue regeneration under such conditions is
not likely to be optimal without a blood supply. Indeed, while the formation of
glomerular capillaries is present within some forming glomeruli in these cultures,
the majority of glomeruli are immature and avascular. Expression profiling also
suggests that this tissue represents a trimester 1 human kidney, a time at which
nephrogenesis has commenced but there are few maturing nephrons (Little 2015 ).
It has been demonstrated that the implantation of organoid-like structures under
the renal capsule can successfully draw in a vasculature from the recipient animal
M.H. Little et al.