Production development (Davies et al., 2012), detecting


       Production of kidney organoids has a lot
of attention nowadays because of their importance in studying the mechanisms of
basic development (Davies et
al., 2012), detecting nephrotoxicants (Takasato,. et al 2015) and to produce
functional organs suitable  for  transplantation (Davies,
2014). The basic type of organoid is produced by simple
dissagregation-reagregation technique. Using either mixed nephron progenitors,
UB proginators and stromal progenitors from mouse embryos (Unbekandt, M. & Davies, 2010), or  pluripotent
stem cells differentiated into renogenic cells (Little
& Takasato, 2015).


        Even with the great advances in the
field of stem cell biology, using the pluripotent stem cells in production of
these complex structures remains challenging. (Taguchi &Nishinakamura, 2017)

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           Multiple, disconnected, immature collecting
ducts, multiple immature nephrons, and stromal cells can be seen in the
resulting organoids. The micro-anatomy is realistic but there is no macroscopic
organization . More advanced, multi-stage techniques developed for mouse cells
produce better macroscopic anatomy, producing nephrons in a distinct cortex
connected to a single collecting duct tree radiating from the medulla, and
loops of Henle dipping from the cortex into that medulla (Ganeva et al., 2011). A physiological activities of the
nephrons in these cultured oganoids could be detected (Lawrence et
al., 2015) but a significant unrealistic feature remains: the collecting duct
tree has no exit because due to lacking of the ureter so .


Mills et al, 2017 has
developed a technique using mouse ex-fetu cells derived organoids, in which
asymmetric BMP signalling environments can direct the development of one branch
of a collecting duct tree into a uroplakin-positive ureter while other branches
serve to organize a kidney.



mammalian embryonic metanephric kidney developed from three types of progenitor
cells; nephron progenitors NPs, stromal progenitors SPs) which forms the
metanephric mesenchyme and the ureteric bud (UB) (Costantini and Kopan, 2010). The urine collecting duct system is
formed by the UB  which undergoes
branching morphogenesis, and the tips of the UB signal to maintain
undifferentiated NPs and induce differentiation of a subset of NPs. A process
called mesenchymal-to-epithelial transition (MET)of NPs  is induced by a transient Wnt signaling from
the developing UB, and each epithelialized nephron then attaches to the UB tips
for connection to the collecting duct. Sequentially, a Gdnf is secreted by the
undifferentiated NPs to maintain the proliferation of the UB tips, at the same
time, the surrounding cortical SPs support ureteric branching by maintaining
Ret receptor tyrosine kinase expression in the UB tips. This triad interaction
enables concomitant NP maintenance and differentiation, thus millions of
nephrons with systemic connections are produced. Hence, the roles of the UB,
including dichotomous branch formation, NP maintenance, and NP differentiation,
are essential for organ-scale kidney morphogenesis. Recently, several groups
have reported induction of the renal lineage from PSCs. (Taguchi et al., 2014; Morizane et al., 2015)


2010, Unbekandt and Davies showed that mouse
embryonic kidneys, after being dissociated into single cell suspension and
cultured in presence of Rho- associated coiled-coil kinase inhibitor (ROCK
inhibitor) to inhibit dissociation-induced apoptosis, were able to
self-organise to form renal structures. This technique was modified to include
a second step, in which one of the collecting ducts formed in this system was
isolated and surrounded with fresh metanephric mesenchyme (MM):  the result was kidney tissue arranged much
more realistically, around single collecting duct tree (Ganeva et al., 2011)

Stem cells are
particularly promising for the production of pluripotent stem cell (PSC)-derived
organoids (Bartfeld and Clevers, 2017).


Recent progress in biology has enabled the induction of various types of
functional organ subunits from pluripotent stem cells (PSCs). In particular,
strategies employing the cellular “self-organization” phenomenon have enabled
successful generation of three-dimensional (3D) “organoids” in a dish (Lancaster and Knoblich, 2014; Sasai, 2013).


         Other groups have shown the derivation
of a UB-like population by selective (Xia
et al., 2013) or simultaneous (Takasato
et al., 2015) induction with NP and SP populations. Most protocols that
aimed to include the NP lineage resulted in epithelial nephron-like structure
formation to a certain extent (Taguchi
et al., 2014; Morizane et al., 2015; Takasato et al., 2015). However, the
induced UB-like cells did not show branching morphogenesis and the NP
induction/maintenance capacity was not proved, and therefore the inter-nephron
connection by the collecting ducts was lacking (Xia et al., 2013; Takasato et al., 2015). These findings suggest
that the currently available UB induction protocols are not sufficient to
induce a functional UB, which could be partly due to the lack of precise
knowledge about the differentiation signals for the early-stage UB lineage (Costantini and Kopan, 2010).

and Nishinakamura define signals that specifically induce ureteric bud and
nephron progenitor lineages from PSCs. Co-culturing these progenitors can
generate organoids that mimic organotypic architecture of the embryonic kidney
with nephrons interconnected by branched epithelium, showing that higher-order
organogenesis can be recapitulated in PSC-derived organoid, but there is no ureter so the collecting duct tree has no