23112.5 Toward Clinical Application
Clinical translation of iPSC-LB technology to disease interventions remains com-
plicated by several issues (Daley 2012 ; Kuroda et al. 2012 , 2014 ). Among these,
precise validation of iPSC-LB and their source cells is crucial for safety and func-
tional quality. To this end, substantial improvements of iPSC safety may be achieved
using non-genome integrative methods with episomal vectors and confirmation of
genomic integration. These manipulations are required to exclude undifferentiated
iPSC from differentiated (target) cell sources for LB and to exclude hyper-
proliferative cells and cells in intermediate stages of differentiation. Undifferentiated
iPSCs have been shown to form teratomas from about 1 × 10^6 cells in immunodefi-
cient animal models. Thus, if transplantation of 1 × 10^8 cells is required to treat
diseases, at least 1% contamination with inappropriate cells could lead to the devel-
opment of hazardous teratomas. Similarly, if disease interventions require trans-
plantation of 1 × 10^10 cells, contamination with inappropriate cells will need to be
reduced to less than 0.01%.
Recent advances in next-generation sequencing technology allow interrogation
of whole genomes and could be used to exclude mutant cells from transplants. In
particular, cell products that have mutation(s) in well-known oncogenic genes must
be excluded. However, endogenous cells frequently carry mutations, and these are
highly heterogeneous. Thus, mutations in transplant cells may not necessarily result
in malignancy. Conversely, if mutant cells are excluded too stringently, patients may
not receive desirable therapy, and the cost of iPSC-LB technology will rise signifi-
cantly. Thus, risk-benefit assessments will be critical during initial human clinical
trials of these technologies.
Mass-scale production of LB is also required for therapeutic use, requiring estab-
lishment of uniform iPSC-LB and robustness of the manufacturing process. To this
end, several previous studies report automated culture systems and mass-scale float-
ing cultures. Clinical application of iPSC-LB technology will also require consider-
ation and optimization of methods for delivery to selected transplantation sites.
Currently, cells can be delivered in immunoprotective capsules, although the ensu-
ing methods for engraftment remain poorly validated, and most of these will require
further optimization for iPSC-LB transplantations. Finally, preservation of interme-
diate cell and tissue products will be desirable for precise validation of safety and
function.
12.6 Perspectives
The use of hPSC-based cell therapies in regenerative medicine still faces numerous
obstacles, including complications of delivery to diverse patients and cost-
effectiveness. However, iPSCs remain a promising and unlimited cell source for
regenerative medicine and will be further tested in imminent clinical trials.
12 Liver Regeneration Using Cultured Liver Bud