european urology 51 (2007) 1173–1174
available at www.sciencedirect.com
journal homepage: www.europeanurology.com
Editorial – referring to the article published on pp. 1217–1228 of this issue
The Stem Cell Revolution: A Biologic Nanotechnology
Hiten R.H. Patel *
Institute of Urology, University College London Hospitals, Rosenheim Wing, London WC1E 6DB, United Kingdom
We have witnessed revolutionary advances in the
prevention, diagnosis, and treatment of human
diseases; however, debilitating illnesses such as
heart disease, diabetes, cancer, and diseases of the
nervous system (eg, Parkinson’s and Alzheimer’s
diseases) continue to deprive people of health,
independence, and well-being. The discovery by
developmental biologists of human stem cells,
such as embryonic stem cells, embryonic germ
cells, and adult stem cells, has been a major
breakthrough in understanding disease modelling,
therapeutic targeting, and tissue engineering. As
a result, scientists can now perform experiments
aimed at determining the mechanisms underlying
the conversion of a single, undifferentiated cell into
the different cells comprising the organs and tissues
of the human body. Taking this further, the concept
of producing replacement parts of the body for
damaged or lost organs lies at the core of the varied
biotechnologic practices referred to generally as
tissue engineering. Use of postnatal adult stem cells
has the potential to significantly alter the perspec-
tive of tissue engineering, avoiding fetal tissues.
Successful long-term restoration of continuously
self-renewing tissues such as skin or mucosal lining,
for example, depends on the use of extensively
self-renewing stem cells.
In the current edition of European Urology, Becker
and Jakse [1] elegantly summarise the stem cell
revolution in urology, concluding that ‘‘several
populations of adult stem cells and progenitor cells
have been studied as useful cellular sources in the
treatment and reconstruction of urological organs
DOI of original article: 10.1016/j.eururo.2007.01.029
* Tel. +44 20 73809194; Fax: +44 20 73809063.
E-mail address: hiten.patel@uclh.org.
0302-2838/$ – see back matter # 2007 European Association of Urology. Published by Elsevier B.V. All rights reserved.
such as urothelium, sphincter muscle, kidney and
gonads.’’ However, they also sensibly concluded
that ‘‘considerable basic research still needs to be
performed to ensure the controlled differentiation
and long-term fate of stem cells following trans-
plantation.’’
The most important breakthrough in clinical
translational urology has been the seminal work
of Anthony Atala’s group. This team recently
published an article in the Lancet regarding seven
patients with high-pressure bladders, suitable for
cystoplasty. Using autologous bladder biopsies,
urothelial and muscle cells were grown in culture
and seeded on a biodegradable bladder-shaped
collagen scaffold for 7 weeks. The autologous
engineered bladder constructs were used for bladder
reconstruction and implanted either with or without
an omental wrap. Two to 5 years after surgery, the
functional outcomes were remarkable, with no
adverse events reported [2].
This work highlights a significant issue with stem
cell tissue engineering: Should we attempt ex vivo
reconstruction or correct the disease process in situ?
Thus, should we replace an entire organ as Atala’s
group has nearly achieved, by ex vivo regeneration
using tissue engineering scaffolds, or should we use
the natural in situ scaffolding of a dysfunctional/
nonfunctional organ and stimulate the local stem
cells? Either way, the potential adverse outcomes
that must be noted and considered ethically are
uncontrolled growth such as neobladder cancer or
dysfunctional aspects (high-pressure neobladder or
umbrella cell abnormalities).
doi:10.1016/j.eururo.2007.01.068
1174 european urology 51 (2007) 1173–1174
In situ stimulation has been problematic for
several reasons, including delivery of stimulating
factors at appropriate doses and ability to sustain
these factors in situ. As with ex vivo scaffolds/
matrices, gene-activated matrices are being inves-
tigated that comprise plasmids coding for factors
that would transduce cells in vivo allowing regen-
eration. A clinical trial in fractured bone has been
planned using this technology [3]. Ultimately,
reconstruction is merely a beginning, with the end
goal being genetic correction. Targeting stem cells
would appear the key to this strategy. Currently,
viral and nonviral transducing agents allow us to
safely genetically manipulate cells ex vivo without
the potential hazards of direct gene transfer in
humans [4].
Where to aim?
Within this immense field, solid organ (kidney,
prostate, gonads) replacement is the most complex.
A bovine tissue engineering model reproducing
renal tissue has been reported [5]. However, a
sensible strategy would be in situ targeting of the
diseased renal, prostate, or gonadal stem cell with in
situ factors. The hollow organs lined by urothelium
have a similar structure to both bowel enterocytes
and skin, with basal undifferentiated cells with the
stem cell present to terminally differentiated apical
compartment cells. Currently, as for bowel [6] and
skin the urothelium can be grown for in vivo use as
previously discussed [2]. This has practically been
shown to be easier than dealing with solid organs.
Also, follow-up is simple with direct visualisation
and biopsies; however, functional testing at the
cellular level is important (eg, transporter protein
expression in enterocytes, umbrella cell differentia-
tion in bladder).
We have shown via an enterocyte regeneration
model that early regeneration can leave the epithe-
lium devoid of carcinogenic defence mechanisms,
increasing the susceptibility to mutations [6,7]. This
would probably be true for regenerating urothelium,
particularly because urinary carcinogens are well
known and lead to mutagenesis [8].
In this exciting field where new organs and
tissues may be formed, the next ultimate area is
stem cell-mediated gene therapy, which changes
tissue engineering into tissue functionality engi-
neering. Perhaps, as we travel along this pathway to
ever smaller and more directed therapies (stem cell
gene therapy, nanotechnology, minimally invasive
therapies), we as surgeons need to embrace these
exciting changes. Although the ‘‘spare parts’’ to aid
our patients are important, the stem cell holds a
greater fascination because it may unlock nature’s
key to the debilitating diseases that affect so many.
References
[1] Becker C, Jakse G. Stem cells for regeneration of urological
structures. Eur Urol 2007;51:1217–28.
[2] Atala A, Bauer SB, Soker S, Yoo JJ, Retik AB. Tissue-
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[3] Bonadio J. Tissue engineering via local gene delivery: update
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