Kidney Development, Disease, Repair and Regeneration

575 Pages·2015·61.414 MB·English

by  Little, Melissa Helen

KIDNEY
DEVELOPMENT,
DISEASE, REPAIR AND
REGENERATION
Edited by
M H. l
elissa ittle
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Contributors
Qais Al-Awqati Department of Medicine, Columbia Benjamin Dekel Pediatric Stem Cell Research Institute,
University College of Physicians & Surgeons, New York, Edmond & Lili Safra Children’s Hospital, Sheba Medical
NY, USA Center, Sackler School of Medicine, Tel Aviv University, Tel
H.H. Arts Department of Human Genetics, Radboud Aviv, Israel; Division of Pediatric Nephrology, Edmond &
Lili Safra Children’s Hospital, Sheba Medical Center,
Institute for Molecular Life Sciences, Radboudumc,
Sackler School of Medicine, Tel Aviv University, Tel Aviv,
Nijmegen, The Netherlands
Israel
Anthony Atala Wake Forest School of Medicine, Wake
Rachel C. Dodd Department of Molecular Medicine &
Forest Institute for Regenerative Medicine, Winston-Salem,
Pathology, School of Medical Sciences, Faculty of Medical
NC, USA
Health Sciences, The University of Auckland, Auckland,
Felicity J. Barnes Department of Anatomy and
New Zealand
Developmental Biology, Monash University, Clayton,
Gregory R. Dressler Department of Pathology, University
VIC, Australia
of Michigan, Ann Arbor, MI, USA
Ariela Benigni IRCCS — Istituto di Ricerche Farmacologiche
Jeremy S. Duffield Research & Development, Biogen,
“Mario Negri”, Centro Anna Maria Astori, Science &
Cambridge, MA, USA; Departments of Medicine &
Technology Park Kilometro Rosso Bergamo, Italy
Pathology, University of Washington, Seattle, WA, USA
John F. Bertram Department of Anatomy and Developmental
Klaudyna Dziedzic Pediatric Stem Cell Research Institute,
Biology, School of Biomedical Sciences, Monash University,
Edmond & Lili Safra Children’s Hospital, Sheba Medical
Melbourne, VIC, Australia
Center, Sackler School of Medicine, Tel Aviv University,
M. Jane Black Department of Anatomy and Developmental
Tel Aviv, Israel
Biology, Monash University, Melbourne, VIC, Australia
David A. Ferenbach Renal Division and Biomedical
Joseph V. Bonventre Renal Division and Biomedical Engineering Division, Brigham and Women’s Hospital,
Engineering Division, Brigham and Women’s Hospital, Department of Medicine, Harvard Medical School, Boston,
Department of Medicine, Harvard Medical School, Boston, MA, USA; Centre for Inflammation Research, Queen’s
MA, USA; Division of Health Sciences and Technology, Medical Research Institute, University of Edinburgh,
Harvard-Massachusetts Institute of Technology, Edinburgh, UK
Cambridge, MA, USA; Harvard Stem Cell Institute,
Julia B. Finkelstein Department of Urology, Columbia
Cambridge, MA, USA
University College of Physicians and Surgeons, New York,
Deborah A. Buffington Innovative BioTherapies, NY, USA
Incorporated, Ann Arbor, MI, USA
Paul Goodyer Department of Pediatrics, McGill University,
Kevin T. Bush Department of Pediatrics, University of Montreal, QC, Canada; Department of Human Genetics,
California, San Diego, La Jolla, CA, USA McGill University, Montreal, QC, Canada
Qi Cao Centre for Transplant and Renal Research, L.M. Guay-Woodford Center for Translational Science,
Westmead Millennium Institute, University of Sydney at Children’s National Health System, Washington, DC, USA
Westmead Hospital, Westmead, NSW, Australia
Marc R. Hammerman Renal Division, Departments of
Thomas Carroll Departments of Molecular Biology and Medicine, and Cell Biology and Physiology, Washington
Internal Medicine (Nephrology), University of Texas University School of Medicine, St. Louis, MO, USA
Southwestern Medical Center, Dallas, TX, USA
David C.H. Harris Sydney Medical School – Western
Melanie Cosgrove Department of Experimental Medicine, Centre for Transplant and Renal Research, Westmead
McGill University, Montreal, QC, Canada Millennium Institute, University of Sydney at Westmead
Frank Costantini Department of Genetics and Development, Hospital, Westmead, NSW, Australia
Columbia University, New York, NY, USA Michael J. Hiatt Developmental Biology and Regenerative
Luise Cullen-McEwen Department of Anatomy and Medicine Program, The Saban Research Institute, Children’s
Developmental Biology, Monash University, Melbourne, Hospital Los Angeles, University of Southern California,
VIC, Australia Los Angeles, CA, USA
Alan J. Davidson Department of Molecular Medicine & Wendy E. Hoy Centre for Chronic Disease, University of
Pathology, School of Medical Sciences, Faculty of Medical Queensland, Brisbane, QLD, Australia
Health Sciences, The University of Auckland, Auckland, Michael D. Hughson Department of Pathology, University
New Zealand of Mississippi Medical Center, Jackson, MS, USA
xi
xii CONTRIBUTORS
Jennifer C. Huling Wake Forest School of Medicine, Wake Sanjay K. Nigam Department of Pediatrics, University of
Forest Institute for Regenerative Medicine, Winston-Salem, California, San Diego, La Jolla, CA, USA; Department of
NC, USA; School of Biomedical Engineering and Sciences, Medicine, University of California, San Diego, La Jolla,
Virginia Tech-Wake Forest University, Winston-Salem, NC, CA, USA; Department of Cellular & Molecular Medicine,
USA University of California, San Diego, La Jolla, CA, USA
H. David Humes Innovative BioTherapies, Incorporated, Ryuichi Nishinakamura Department of Kidney
Ann Arbor, MI, USA; The University of Michigan, Ann Development, Institute of Molecular Embryology and
Arbor, MI, USA Genetics, Kumamoto University, Kumamoto, Japan
Benjamin D. Humphreys Renal Division, Brigham and A.K. O’Connor Center for Translational Science, Children’s
Women’s Hospital, Boston, MA, USA; Harvard Medical National Health System, Washington, DC, USA
School, Boston, MA, USA; Harvard Stem Cell Institute, Juan A. Oliver Department of Medicine, Columbia
Cambridge, MA, USA
University College of Physicians & Surgeons, New York,
Roger Ilagan Division of Regenerative Medicine, United NY, USA
Therapeutics Corporation, Research Triangle Park, NC, USA Kenji Osafune Center for iPS Cell Research and
Nine V.A.M. Knoers Department of Medical Genetics, Application (CiRA), Kyoto University, Shogoin, Sakyo-ku,
University Medical Centre Utrecht, Utrecht, The Kyoto, Japan
Netherlands Leif Oxburgh Center for Molecular Medicine, Maine
Raphael Kopan Division of Developmental Biology, Medical Center Research Institute, ME, USA
Cincinnati Children’s Hospital, Cincinnati, OH, USA Joo-Seop Park Division of Pediatric Urology, Cincinnati
Jordan A. Kreidberg Department of Medicine, Boston Children’s Hospital, Cincinnati, OH, USA; Division of
Children’s Hospital, and Department of Pediatrics, Developmental Biology, Cincinnati Children’s Hospital,
Harvard Medical School, Boston, MA, USA Cincinnati, OH, USA
Callie S. Kwartler Departments of Molecular Biology and Anna Peired Excellence Centre for Research, Transfer and
Internal Medicine (Nephrology), University of Texas High Education for the Development of DE NOVO
Southwestern Medical Center, Dallas, TX, USA Therapies (DENOTHE), University of Florence, Florence,
Laura Lasagni Excellence Centre for Research, Transfer and Italy
High Education for the Development of DE NOVO Christopher J. Pino Innovative BioTherapies, Incorporated,
Therapies (DENOTHE), University of Florence, Florence, Ann Arbor, MI, USA
Italy Oren Pleniceanu Pediatric Stem Cell Research Institute,
Elena Lazzeri Excellence Centre for Research, Transfer and Edmond & Lili Safra Children’s Hospital, Sheba Medical
High Education for the Development of DE NOVO Center, Sackler School of Medicine, Tel Aviv University,
Therapies (DENOTHE), University of Florence, Florence, Tel Aviv, Israel
Italy Sharon Presnell Organovo, Inc., San Diego, CA, USA
Melissa H. Little The Institute for Molecular Bioscience, Victor G. Puelles Department of Anatomy and
The University of Queensland, Brisbane, QLD, Australia Developmental Biology, School of Biomedical Sciences,
Weining Lu Department of Medicine, Boston University Monash University, Melbourne, VIC, Australia
School of Medicine, Boston Medical Center, Boston, MA, Susan E. Quaggin Division of Nephrology and
USA
Hypertension, Feinberg School of Medicine, Northwestern
Daniela Macconi IRCCS — Istituto di Ricerche University, Chicago, IL, USA
Farmacologiche “Mario Negri”, Centro Anna Maria Astori, Ton J. Rabelink Department of Nephrology, Leiden
Science & Technology Park Kilometro Rosso Bergamo, Italy
University Medical Center, Leiden, The Netherlands;
Douglas G. Matsell Child and Family Research Institute, Department of Nephrology, Einthoven Laboratory for
British Columbia Children’s Hospital, University of British Experimental Vascular Medicine, Leiden University
Columbia, Vancouver, BC, Canada Medical Center, Leiden, The Netherlands
Andrew P. McMahon Department of Stem Cell Biology and Egon Ranghini Department of Pathology, University of
Regenerative Medicine, Eli and Edythe Broad-CIRM Michigan, Ann Arbor, MI, USA
Center for Regenerative Medicine and Stem Cell Research, Scott Rapoport Division of Regenerative Medicine, United
WM Keck School of Medicine of the University of
Therapeutics Corporation, Research Triangle Park, NC,
Southern California, Los Angeles, CA, USA
USA
Cathy Mendelsohn Departments of Urology, Genetics and Marlies E.J. Reinders Department of Nephrology, Leiden
Development and Pathology, Columbia University, University Medical Center, Leiden, The Netherlands
New York, NY, USA
Giuseppe Remuzzi IRCCS — Istituto di Ricerche
Marcus J. Moeller Department of Nephrology and Farmacologiche “Mario Negri”, Centro Anna Maria Astori,
Immunology, RWTH Aachen University, Aachen, Germany Science & Technology Park Kilometro Rosso Bergamo,
Karen M. Moritz School of Biomedical Science, The Italy; Unit of Nephrology and Dialysis, Azienda
University of Queensland, St Lucia, QLD, Australia Ospedaliera Papa Giovanni XXIII, Bergamo, Italy
CONTRIBUTORS xiii
Sharon D. Ricardo Department of Anatomy and Megan R. Sutherland CHU Sainte-Justine Research Center
Developmental Biology, Monash University, Clayton, VIC, and the University of Montreal, Montreal, QC, Canada
Australia Atsuhiro Taguchi Department of Kidney Development,
Paola Romagnani Excellence Centre for Research, Transfer Institute of Molecular Embryology and Genetics,
and High Education for the Development of DE NOVO Kumamoto University, Kumamoto, Japan
Therapies (DENOTHE), University of Florence, Florence, Yiping Wang Centre for Transplant and Renal Research,
Italy; Pediatric Nephrology Unit, Meyer Children’s
Westmead Millennium Institute, University of Sydney at
Hospital, University of Florence, Florence, Italy
Westmead Hospital, Westmead, NSW, Australia
Rizaldy P. Scott Division of Nephrology and Hypertension, Stefanie Weber Pediatrics II, University Children’s Hospital
Feinberg School of Medicine, Northwestern University, Essen, Essen, Germany
Chicago, IL, USA
Angela J. Westover Innovative BioTherapies, Incorporated,
Maria Luisa S. Sequeira Lopez University of Virginia Ann Arbor, MI, USA
School of Medicine, Charlottesville, VA, USA
Takashi Yokoo Division of Nephrology and Hypertension,
Benjamin Shepherd Division of Regenerative Medicine, Department of Internal Medicine, The Jikei University
United Therapeutics Corporation, Research Triangle Park, School of Medicine, Tokyo, Japan
NC, USA
James J. Yoo Wake Forest School of Medicine, Wake Forest
Kieran M. Short Department of Biochemistry and Molecular Institute for Regenerative Medicine, Winston-Salem, NC,
Biology, Monash University, Melbourne, VIC, Australia USA
Ian M. Smyth Department of Biochemistry and Molecular Jing Yu Department of Cell Biology, Child Health Research
Biology, Monash University, Melbourne, VIC, Australia; Center, the Center for Immunity, Inflammation and
Department of Anatomy and Developmental Biology, Regenerative Medicine, University of Virginia School of
Monash University, Melbourne, VIC, Australia Medicine, Charlottesville, VA, USA
Katalin Susztak Renal Electrolyte and Hypertension
Division, Perelman School of Medicine, University of
Pennsylvania, Philadelphia, PA, USA
Foreword
According to ancient Greek mythology the Titan Prometheus was punished by Zeus for stealing fire from
the gods and handing it over to mortal humans. His punishment consisted of being chained to the Caucasus
mountains, where he had to suffer an eagle feasting daily on his liver, which would then regenerate overnight.
Out of this mythology arose the great hope that all organs, if damaged, could regenerate. Unfortunately, in
humans the enormous regenerative capacity of the liver seems to be the exception rather than the rule. None-
theless, all organs, including the kidney, have some ability to regenerate or repair injured renal structures. In
nephrology this is most obvious in the case of acute tubular injury. The limitations for renal regeneration may
be imposed by the very complicated intrinsic anatomical structure of the nephron and the functional intercon-
nection of its different components as the basic building blocks of the kidney. Therefore, and in spite of some
regeneration of damaged nephron segments, the overall renal function declines in many forms of renal injury.
This leads to progression of injury and chronic kidney disease (CKD), which remains a major problem with
unfortunately a dearth of effective therapeutic interventions. It is because of this that possible regenerative ther-
apeutic approaches, whether to prevent or slow down progression of CKD or even for replacement of destroyed
nephrons, are increasingly attracting interest. In this context one has to recall that such regenerative therapeutic
interventions will draw on the basic understanding of normal embryonic developmental of the kidney, and that
understanding the molecular basis of these processes will be the key to the development of regenerative thera-
pies for chronic renal disease.
In this book Professor Melissa Little has successfully undertaken the very difficult task of bringing together and
editing texts encompassing the vast amount of information, ranging from basic embryology of the kidney all the way
to exploring potential ways of using this basic knowledge to repair or regenerate parts or even entire nephrons or
their function. The list of authors reads like a “Who’s who” of experts for all aspects of kidney development, injury
response, cell differentiation and de-differentiation, repair processes, their signaling processes and the specific cells
involved, and the various types of stem cells and their biology, with special emphasis on the potential therapeutic
use of renal and non-renal adult and embryonic stem cells.
In order to connect these various aspects into a logical and understandable framework the initial chapters are
devoted to the basics of renal development. They expand to illustrate the similarities and differences between
developmental processes and those recapitulated during renal injury and repair using various model systems. This
includes aspects of genetics and epigenetics during development as well as in disease processes. Having described
this for the entire kidney, subsequent chapters explore these aspects for specific nephron segments, from the glom-
erulus down to the collecting tubule and upper urinary tract, and also for the renal vasculature and stroma. For each
nephron segment, diseases resulting from genetic and environmental developmental abnormalities are discussed in
terms of their molecular and cellular pathogenesis. Finally, mechanisms and limitations of repair and/or regenera-
tion of specific cell types along the nephron are critically analyzed.
In this context, the use of lineage tracing has been critical to differentiate regeneration from intrarenal versus bone-
marrow derived progenitor cells. Furthermore, it appears that instead of a single type of kidney stem cell to replace
lost or damaged kidney tissue, there are nephron segment-specific progenitor cells which give rise to new cells
within each kidney compartment. Equally important is the identification of pathways that govern the proliferation
and differentiation of regeneration-competent cells, and the signals that inhibit their activity after injury. In addition
to the possibility of intra-renal repair and regeneration of nephrons, the possibilities of growing entirely new struc-
tural and functional nephrons or even kidneys are discussed and the creation of bio-engineered kidneys or partial
replacement of kidney functions are addressed.
The authors point out the potential for the application of many of these novel regenerative approaches, but
also caution about the many remaining hurdles. These include problems of adequately identifying renal stem
cell populations and assessing their therapeutic potential. Also the unique architecture of the kidney compli-
cates the anatomical and functional integration of stem cell–derived nephrons. This may apply even more to the
functional capacity of a bioengineered organ to partially or completely replace the endogenous kidney. In spite
of these difficulties, the road ahead for regenerative therapy is exciting and many obstacles may be overcome
based on the enormous strides forward achieved in genetics, molecular and cell biology, and especially stem
cell biology.
xv
xvi FOREWORD
Taken together this book provides a state of the art compendium of our present knowledge and of future perspec-
tives for all aspects of regenerative kidney repair and therapy. As such it represents a pioneering and gigantic step
forward in this exciting new field. Just as Prometheus brought fire to mortal humans, the authors of this excellent text
bring light and hope to all of us nephrologists dwelling in the present penumbra surrounding the therapy of acute
and chronic kidney injury.
Detlef Schlöndorff
Detlef Schlöndorff, MD is currently visiting professor of medicine at the Icahn School of Medicine at Mount Sinai
in New York, USA, and Editor-in-Chief of Kidney International. He is Professor Emeritus of the Ludwig Maximilians
University of Munich, Germany.
Acknowledgments
The kidneys, from the perspectives of functional diversity and cellular complexity, are one of the most remark-
able organs in our body. This has undoubtedly contributed to the challenge of replacing renal function. Indeed, at a
point in history where chronic renal disease is rapidly increasing in prevalence, the need for alternative approaches
to ensuring ongoing renal function is acute. Fully understanding the organ itself is surely the basis upon which
such solutions will arise. My personal foray into the biology of the kidney commenced as an Honours student in
Physiology examining the rate of production and degradation of angiotensinogen in a rat model. Serendipitously, I
moved from this to a research position in childhood cancer, focussing on the molecular basis of the childhood kidney
cancer, Wilms’ tumour, at a time just before the WT1 gene was identified. As a postdoctoral researcher in the United
Kingdom, under the mentorship of Professor Nicholas Hastie (then of the MRC Human Genetics Unit, Edinburgh)
we began to unravel the link between WT1 and kidney/gonad development and dysmorphogenesis, identifying
mutations in the developmental anomaly syndrome, Denys Drash syndrome. This piqued my interest in how the
development of this fascinating organ was controlled. What followed was not only a journey through kidney biol-
ogy, but one that ranged across developmental molecular biology, through systems biology, experimental nephrol-
ogy and ultimately stem cell biology and regenerative medicine. Hence, bringing together this collection of stories
is a reflection of my own scientific journey. For the first time in one location, the reader can bridge that spectrum
from how the kidney forms, what can go wrong, how the organ attempts to cope with injury and finally how we
might build on this knowledge to recreate structure and function. The end product is the work of many. As always,
my family deserves special mention for their endless patience with my obsession for work. Having their love and
support makes me human and the interspersed chaos and joy of normal life brings the light and colour that makes
the rest worth it. I particularly thank my son, Nathaniel Rhoades, who helped me with production of graphic plates.
The dedicated work of my own team of researchers (past and present), not only in generating some of the science
discussed within these pages but continuing to deliver in response to my tireless enthusiasm, definitely needs
acknowledgement. I thank Jeff Rossetti and Edward Taylor for calmly overseeing the project as timelines walked
into the distance. Most of all, I am indebted to the spectacular scientists who wrote the component chapters. You are
also my heroes, colleagues and mentors, and I thank you for your contributions to the book in the face of the many
clinical, scientific and personal demands on your own lives. I particularly thank Lisa Guay-Woodford and Weining
Lu who accepted either more than was first anticipated or were brought in late with short timelines. In building this
book, I have learnt much from the individual chapters and the perspective of each set of authors on their particular
areas of expertise. To see it complete reinforces my conviction that it was time to marry together these seemingly
disparate areas of research around the commonality of the clinical challenge that is kidney failure. Revealing, but
exciting, is what there is yet to understand and what might be achieved in the coming decades.
Professor Melissa H Little
NHMRC Senior Principal Research Fellow
Murdoch Children’s Research Institute & Department of Pediatric
University of Melbourne
Australia
xvii

S E C T I O N I
DEVELOPMENT
A functioning kidney is vital for life. While most are familiar with the excretory functions of the kidney, this com-
plex organ also modulates fluid volume, blood pressure, red cell count and bone density, thereby acting as a central
regulator of homeostasis. While a fundamental understanding of normal organ morphogenesis is clearly relevant
for the interpretation of congenital anomaly, there is a growing appreciation that normal kidney morphogenesis is
crucial for long term renal function. In humans, as in most mammals, nephron formation is a fetal event with final
nephron number set before or near birth. Evidence in humans for a 10 fold variation in nephron number between
individuals, no capacity to form new nephrons after birth and a clear inverse relationship between nephron number
and renal disease, has refocussed our attention on how the kidney forms and what determines an optimal outcome.
In all amniotes, three excretory organs formed during embryogenesis. The permanent kidney in humans (and
all mammals) is the third of these structures to form; the metanephros. Despite this, there are lessons to be learnt
even from the non-mammalian kidney. The molecular paradigms described in pronephric development in the fish
show remarkable parallels with those used for the elaboration of the much more complex mammalian metanephros.
Chapter 1 will describe the differences in approach to nephron endowment, repair and response to growth that exist
in fish. The developmental origin of these excretory structures is addressed in Chapter 2. Studies on metanephric
development have focussed on mammalian models such as mouse, rat, sheep, pig and baboon. Of these, mouse is
the most amenable to genetic manipulation, including lineage tracing to investigate cellular ontogeny as well
as compartment specific gene deletion or activation. The accessibily of such model organisms, together with the
simplicity of genetic manipulation and visualisation, has allowed us to acquire much information about morpho-
genesis in simpler excretory organs. While studies of kidney morphogenesis in mouse have significantly improved
our knowledge of the pathways involved in kidney morphogenesis, a mouse is not a human. Indeed, substantial
differences exist in the histological structure or kidneys between different mammals. Chapter 3 will address human
kidney morphogenesis and how this differs from morphogenesis in other model organisms. Understanding these
differences may also inform us about approaches to modify development or repair in the human.
The metanephros is generated from four major progenitor populations that give rise to the branching collecting
duct tree (ureteric bud), the nephrons (cap mesenchyme), interstitial elements, including the mesangium and pericytes
(stroma) and the vasculature (vascular progenitors). Chapter 4 discusses the regulation of patterning of the ureteric
epithelium. The challenge in studying morphogenesis in all mammalian species remains the size and cellular
complexity. Chapter 5 begins to address this in the mouse, illustrating both what level of quantitative morphoge-
netic analyses might be possible as well as highlighting what we have missed to date. The nephrons arise from the
cap mesenchyme. Our understanding of what specifies this population and how the balance between self-renewal
and commitment to nephron formation is regulated is discussed in Chapters 6 and 7. The nascent nephron has to
undergo substantial elongation, patterning and segmentation to generate the required functional compartmentalisa-
tion essential for nephron function (Chapter 8). Regulation of nephron number in the human is discussed in Chapter
9. Most critical for nephron function is the differentiation of a vascularised glomerulus with podocytes and
endothelial cells forming a functional glomerular basement membrane. The molecular regulation of this process
will be discussed in Chapter 10. Chapter 11 then discusses how different segments of these elongating and maturing
nephrons are directed to the appropriate location to form the final organ. The influence of the surrounding stroma on
this process is covered by Chapter 12. Finally, our current understanding of how the vasculature of the kidney arises
will be presented in Chapter 13.