







































Abstract: As of today, there are approximately 100,791 individuals waiting for kidney transplants, with a 
new patient added every fourteen minutes.33 Treatments for renal failure and kidney disease are limited 
to dialysis, renal replacement therapy, or transplantation. However, advancements in renal regeneration 
diminish the need for these transplants. Several techniques allow for kidney recovery after development 
of renal disease, including bioengineering mechanisms, stem cell therapies, drug therapeutics, and renal 
regenerative techniques. In this review, the role of induced regeneration will be discussed in relation to renal 
damage. The mechanisms of embryonic kidney development have been elucidated, allowing researchers to 
recreate self-organizing renal tissue and nephrons by using human pluripotent stem cells. Although kidneys 
have a limited regenerative ability, understanding the mechanisms of developmental biology and kidney 
morphology have allowed researchers to identify the process of self-renewing damaged renal tissue. The 
role of regenerative medicine in repairing damaged kidneys serve as a model of hope for the hundreds of 
thousands affected by kidney illnesses.

Aisthesis      Volume 8,  201734

The Regeneration of Renal Tissue
by Hannah Thompson

Introduction and Objectives      
 Renal disease and illness are worldwide public 
health issues due to the shortage of organ donors and 
treatments available.1 These illnesses and diseases 
arise when renal structures, such as nephrons, are 
unable to perform their function. 
 Kidney disease is one of the most common 
illnesses, with an astonishing one in three American 
adults at risk for developing it.5 This illness can lead 
to end-stage renal disease (ESRD), commonly known 
as kidney failure, resulting in a complete loss of renal 
function. Other common illnesses include malignant 
hypertension, diabetes, glomerular disease, tubular 
diseases, and interstitial diseases. 
 The renal system, composed of several organs, 
such as the kidneys, ureters, bladder, and urethra, 
works to maintain homeostasis of the human 
body.2 The kidneys, specifically, are responsible 
for the filtration of bodily fluids and excretion of 
waste in the form of urine.3 The kidneys also serve 
to maintain metabolic (chemical), hemodynamic 
(cardiovascular), immunologic (immunity), and 
endocrinologic (hormone) levels of the body.  
 Each kidney consists of approximately one 
million functional units referred to as nephrons, 
which are responsible for filtering blood through 

two structures, the glomerulus and tubule. 
Glomeruli filter proteins, blood cells, and other large 
molecules from fluid that passes through them; this 
fluid then proceeds to the proximal tubule where 
urine is produced, waste is removed, and minerals 
are returned back to the bloodstream.4 Any illness 
involving these structures (Figure 1) is serious 
and potentially life threatening. Traditionally, the 
treatment for   kidney diseases, such as ESRD, is 
either dialysis or a kidney transplant. However, 
an imbalance exists between patients requiring 
treatment and available treatments. The lack of 
kidneys available for transplant and deficiencies in 
dialysis result in over 89,000 deaths each year. The 
possibility of the regeneration of renal tissue brings 
to light a new possibility in this dreadful reality.
 Renal regeneration allows for the repair and 
regrowth of renal structures, resulting in the 
restoration of function.6, 7 Nephrons form during 
embryonic development, and thus regeneration 
as an adult is impossible. However, animal models 
provide a better understanding of neoneprogenesis, 
a mechanism that results in the formation of new 
nephrons. Identifying these animal models and 
understanding kidney morphogenesis has allowed 



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Aisthesis      Volume 8,  201735

for advancements in the growth of kidney cells 
through human pluripotent stem cells.1, 8, 9, 10 Stem 
cells are currently being explored in both human 
and animal models.  In the future, stem cell therapies 
may be used to halt the progression of disease and 
illness in patients who are diagnosed with other 
renal diseases but have not yet developed ESRD.  
 A common symptom of kidney diseases includes 
the inability of the vasculature to function properly; 
without this efficient blood flow, the renal system is 
unable to maintain homeostasis. Angiogenesis, the 
formation of new blood vessels from preexisting 
ones, allows for the restoration of this crucial 
function of the renal system. Bioengineering uses 
tissue decellularization processes to manipulate 
genetic material and create artificial limbs, tissues, 
or organs. Three dimensional bioprinting, an 
aspect of bioengineering, involves the growth and 
development of bodily structures using biological 
material and engineered systems. 
 This review will discuss renal regeneration in 
three objectives. Objective 1 will discuss the methods 
of embryonic renal development and its application 
to the use of stem cells in regenerating nephrons and 
renal structures. Objective 2 will discuss angiogenesis 
and other techniques used to prevent complete loss 
of renal function. Objective 3 will describe the future 
of renal regeneration, including drug therapeutics 

and bioengineering. These objectives all relate to 
a common goal of renal regeneration, combating 
against renal disease and illness.

Discussion
Objective 1: Embryonic Renal Development Applied 
to Stem Cell Use
 Within the past decade, there has been great 
success with the use of stem cell treatments. Varying 
types of stem cells, such as induced pluripotent stem 
cell (iPSC), bone marrow-derived cells (BMDC), 
organ-specific stem cells, and adipose derived stem 
cells (ADMSC), are capable of differentiating into 
kidney cells.7,11 These stem cells have the ability 
to mimic renal embryonic development through 
laboratory conditions similar to the environment 
of an embryo.12 By identifying the processes of 
embryonic renal development and its physical and 
chemical environment, scientists are able to use stem 
cells to form nephrons. 
 Renal development begins with the primitive 
streak, a structure that gives rise to the gastrula and 
forms the mesoderm, which in turn arranges the 
metanephric kidney or final functioning kidney. 
This mesoderm forms several mesonephros, such 
as the ureteric bud, metanephric mesenchyme, and 
mesonephric duct (Figure 2).8 

Figure 1. Depicted in this diagram is the filtering units 
of the kidney, specifically the glomerulus and proximal 
tubule.29

Figure 2. Depicted in this diagram are the mesonephros 
and the process these structures use to transform 
into the metanephric kidney.28 Also depicted is the 
progression in which these mesonephros form the 
metanephric kidney.



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Aisthesis      Volume 8,  201736

The uretic bud is responsible for forming the 
collecting ducts, renal pelvis, ureter, and parts 
of the bladder. The metanephric mesenchyme 
develops into the glomeruli, proximal and distal 
tubules, and loops of Henle. The mesonephric duct 
forms the trigone of the bladder. It also releases the 
mesonephros into the cloacal, where one wall of 
the bladder is assembled. As previously mentioned, 
these structures all compose the renal system and 
contribute to its function in the human body.7,4 

 Signal transduction transfers information from 
the exterior of a cell to its interior using signal 
pathways and growth factors. The differentiation 
of cells then uses this mechanism by expressing 
particular genes. For instance, Wnt signaling 
pathways are responsible for gastrulation (the process 
by which a blastula forms into a gastrula), body axis 
formation, cellular differentiation, and cell migration. 
To function properly, Wnt signaling pathways must 
be activated by a Wnt protein. In addition to signal 
pathways, growth factors in the form of a protein 
or hormone allow for cellular differentiation. 
Bone morphogenetic proteins (BMP) are a type of 
transforming growth factor protein that specialize in 
the formation of bone, the heart, and central nervous 
system. Unlike the name suggests, this protein is 
crucial to the growth, regulation, and maintenance of 
several different cells.7, 13 The expression of BMP7, for 
example, is crucial for the development of the kidney 
and other renal structures. This protein is found in 
high concentrations in cells found in the Bowman’s 
capsule, the distal tubules and collecting ducts of the 
kidney. This protein may decrease in concentration 
or even disappear when disease strikes one’s renal 
structures.32 Nodal is another transforming growth 
factor protein that conducts a signal transfer using 
receptors that regulate gene expression. The binding 
of these receptors transfer information to the 
primitive streak and mesoderm.7,14

 Using combinations of BMP, nodal protein, 
and signal transduction pathways, scientists have 
successfully used human pluripotent stem cells to 
develop the primitive streak.30 Animal studies have 
suggested varying combinations of the growth 
factors and signal transduction pathways to develop 
this structure.12 For instance, rats injected with 
mesenchymal stem cells showed a decrease in 
further renal damage as well as decreased symptoms 

of hyperglycemia (excess of glucose in the body) and 
glycosuria (excess of sugar in waste).15,31 Different 
stem cells, such as hematopoietic stem cells (which 
result in blood cells), bone marrow derived stem 
cells, and mesenchymal stem cells (stromal cells), 
can be used to prompt the response of a biological 
mechanism, which in turn can lead to the success of 
renal cell replacement (Figure 3).                        
 Stem cells can be induced using either 
intravenous transplantation or intrarenal 
transplantation. Intravenous transplantation 
introduces the stem cells into veins, whereas 
intrarenal transplantation introduces the stem cells 
into renal structures. The damage to the nephron is 
caused by illnesses and diseases that lead to the loss 
of renal function. Although the specifics of media 
conditions vary, they all recognize that they must 
mimic the processes of forming the primitive streak 
in embryonic development in order to form it using 
stem cells. Through the process of stem cell induction 
and biological mechanisms, renal function can be 
restored.7,14,15,31 
 The structures and signal transduction methods 
mentioned are all components of the early development 
of an embryo. However, some components of the 
fully developed kidney are not expressed until later 
development. For the metanephric kidney to form, 
the final interactions between the nephric duct and 
metanephric mesenchyme must occur (Figure 2). 
These interactions allow the formation of the ureters 
through the migration of the nephric duct to the 
bladder. This is the final stage in embryonic renal 
development; when stem cells are used, this will also 
be the concluding step.16

 Humans are unable to perform neonephrogenesis, 
the process by which organisms create new nephrons 
from their own cells after renal injury or damage has 

Figure 3. A variety of media conditions and processes 
can be used for renal cell replacement in mice.7 



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Aisthesis      Volume 8,  201737

occurred. However, animal models, such as zebrafish, 
can. The genomes of humans and zebrafish are quite 
similar. Over seventy percent of human genes have 
a similar gene sequence to that of zebrafish.17 These 
genes are referred to as Orthologs and recognize that 
genes from different species evolve from common 
ancestors, but differentiate through speciation. Due 
to these similarities, zebrafish are a fitting model 
for studying renal regeneration in application to 
humans. This model has led to advancements in the 
research of the growth and production of human 
nephrons. 
 Zebrafish perform neonephrogenesis in two 
stages. The first stage involves the expeditious 
regeneration within existing nephrons that in turn 
replace the damaged nephrons. In the second stage, 
entirely new nephrons are created using renal 
progenitors.18 Zebrafish are capable of regenerating 
nephrons that have been damaged by diseases, 
such as acute kidney injury (AKI).18,19 To duplicate 
the conditions of AKI in humans, scientists 
administered nephrotoxins to the embryos of several 
zebrafish. This drug exposure created symptoms 
similar to AKI, including the loss of function in 
the proximal tubule.17 As a result, zebrafish created 
entirely new nephrons to replace those damaged 
by the nephrotoxins. Researchers identified that 
4-(phenlythio)-butanoic acid was produced when 
stimulated by the nephrotoxins. This acid increased 
the abundancy of renal progenitors that initiate 
the development of new nephrons. These renal 
progenitors were transplanted to secondary and 
tertiary recipients to confirm that progenitors have 
the ability for self-renewal. From this study, further 
research is being performed to determine if the 
induced treatment of 4-(phenlythio)-butanoic acid 
in human pluripotent stem cells serves any function 
in regeneration.9, 17, 19 Scientists also identified 
that when a zebrafish experiences renal injury, 
mesenchymal stem cells (MSCs) emerge from renal 
progenitors. These MSCs restore the structure and 
function of damaged renal cells. When these cells 
divide, the resulting cells differentiate into nephrons 
and have function as well (Figure 4). 
 Scientists have been able to identify the pro-
regenerative agents and chemical elements that 
initiate regeneration. These discoveries make it 
possible for the conditions of nephron renewal 

in zebrafish to be replicated in humans.9, 17, 18, 19 

Further research of embryonic renal development, 
neonephrogenesis in animals, and the use of human 
pluripotent stem cells will be required to successfully 
regenerate nephrons.
       
Objective 2: Regenerative Techniques Used to Prevent 
Complete Loss of Function in Early-Stage Patients
 Regenerative medicine can be used to halt the 
progression of illness in patients who have not 
developed ESRD, but have been diagnosed with more 
temperate diseases. Chronic kidney disease (CKD) is 
one of these diseases, in which patients progressively 
lose kidney function over several months or years. 
By using stem cell therapies, scientists can regenerate 
nephrons. Scientists have identified three different 
types of optimal cells capable of renal cellular repair. 
These ideal target cells include vessels, stroma, and 
nephron epithelia.10,20

 Once these target cells were determined, 
scientists determined the type of stem cell they 
would use to promote regeneration.10,20 Through a 
variety of experiments, scientists found that tissue-
specific stem cells were the best source for cellular 
regeneration in early-stage patients.10,20 Tissue-
specific stem cells can generate a large supply of cells 
without the risks of affecting other cells of the body. 
These stem cells can be obtained and isolated from 
embryos or adult organisms.10,20

 Two processes can be used to reprogram 
the renal progenitors that will produce the new 
nephrons.10 One process involves reprogramming 
adult cells back into a pluripotent condition and then 

Figure 4. Renal progenitors release MSCs upon renal 
injury of a zebrafish. These cells repair the structure 
of the renal cell, as shown above, once signaled by the 
injury.9 



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Aisthesis      Volume 8,  201738

differentiating them again into renal progenitors. 
This indirect process is much more time consuming 
and difficult in comparison to a more direct process. 
Alternatively, another process automatically 
reprograms the ideal target cells, such as the stroma 
and nephron epithelia, into induced renal progenitor 
cells. Unlike the indirect process, this more direct 
process avoids reprogramming to the earliest state 
and instead reverts to the particular cellular state 
required to instigate renal regeneration.10 These 
processes can be used to replace the damaged cells in 
patients with chronic kidney disease. While current 
studies are using these processes in kidney tissue, 
they have yet to be performed in human patients. 
 Many patients diagnosed with kidney diseases 
experience the inability of their vasculature to 
function properly. Proper blood flow is necessary for 
the renal system to maintain hemodynamic levels of 
the body and, in turn, homeostasis. The restoration 
of blood flow is possible with angiogenesis, the 
formation of new blood vessels from ones that already 
exist in the body. This induced vascular growth can 
reduce the symptoms of patients diagnosed with 
kidney diseases.  
 There are several different types of angiogenesis 
that will occur, depending on the severity of vascular 
damage. These processes are possible due to the 
formation of angioblasts, the tissue that produces 
blood vessels. Sprouting angiogenesis results in the 
addition of blood vessels to tissues that lack properly 
functioning blood vessels. This method occurs when 
there is a complete loss of function. Suggested by its 
name, sprouting angiogenesis is categorized by the 
sprouting mechanism through which endothelial 
cells grow towards a stimulus. This stimulus is a 
reaction site where the formation of new blood 
vessels occurs.21 In comparison, intussusceptive 
growth is a splitting process where an existing blood 
vessel is cleaved and split into two blood vessels. This 
is used in cases where the existing blood vessels have 
maintained some function but require a larger supply 
of vascular tissue. Intussusceptive growth increases 
the number of blood vessels and capillaries; however, 
it does not increase the number of endothelial cells 
as sprouting angiogenesis does.22 It is important to 
distinguish the difference between vasculogenesis 
and angiogenesis. While angiogenesis forms blood 

vessels from preexisting ones, vasculogenesis is the 
process of creating entirely new blood vessels (Figure 
5). This can occur embryonically or can be replicated 
through the use of stem cells.
 Endothelial cells are affected when blood flow 
is restricted. Some endothelial cell progenitors, 
such as the CD133+, CD34+, and KDR+ cells, have 
the ability to differentiate into cells that promote 
endothelial cellular repair. Growth factors, such as 
the vascular endothelial growth factor, are induced 
to promote the process of replication and its speed 
and accuracy.20 
 Using stem cells and regenerative processes, 
scientists have discovered mechanisms that 
successfully result in the production of healthy 
nephrons to replace diseased ones found in early-
stage patients. Angiogenesis has resulted in the 
ability to restore blood flow and the hemodynamic 
levels of the natural body. All of these processes can 
be used to restore homeostasis in patients with early-
stage kidney diseases.21, 22, 23

Objective 3: The Future of Renal Regeneration 
 Advancements made in renal regeneration 
within the past ten years have mainly concerned 
the use of stem cells. However, that is not the only 
option for renal regeneration. Scientists have 
recently discovered drug therapeutics and developed 
bioengineering mechanisms that can be applied to 
regenerative renal construction. These discoveries 
have the potential to lead to a revolution in organ 
regeneration.

Figure 5. The basic types of vascular growth are 
illustrated in this diagram. Angioblasts develop into 
blood vessels. New blood vessels can be formed in 
two processes: Vasculogenesis and Angiogenesis. The 
mechanisms of these processes are illustrated above.21



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Aisthesis      Volume 8,  201739

 Specific drug delivery systems have been 
shown to foster the growth of several renal tubules 
when grown between layers of polyester fleece. 
For instance, in a recent study, Minuth, Denk, and 
Glashauser isolated and cultured renal cells in a 
serum-containing medium.24 Cells were then coated 
with extracellular matrix proteins that promote the 
growth of tubules. However, the study found that this 
coating leads to substantially low levels of respiratory 
gas exchange. Researchers determined that for the 
development of tubules to occur, they must first 
replicate the environment required by stem cells. To 
do this, they created an artificial interstitium, the 
space between a biological structure, out of polyester 
fleece. They sandwiched the cells and isolated 
embryonic material between layers of the fleece. 
This material fostered the exchange of respiratory 
gas and nutrition (Figure 6). Next, they placed this 

sample in a perfusion culture container maintained 
at 37°C for thirteen days. Within this period, the 
tubules matured and were capable of function. These 
scientists are currently studying the possibility of 
implanting this biomaterial. The growth of these 
tubules was dependent on the serum-containing 
material and polyester fleece and its growth factors.24 
Upon the success of this experiment, one may 
expect to see drug therapeutics used more often to 
create artificial biological structures with the goal of 
eventual implantation.24 
 Bioengineering involves the process of 
decellularization where the extracellular matrix is 
separated from its cells. By manipulating genetic 
material, artificial limbs, tissues, and organs can be 
created.25 Three dimensional bioprinting uses stem 
cells or cells isolated from a patient. These cells are 
placed in a growth medium where they replicate in 
laboratory settings. Once replication has occurred, 
the cells are placed in a cartridge. This resulting 
product has been coined bioink. The bioprinter ejects 
the bioink into specific layers that are immersed with 
hydrogel, a substance that acts as a temporary mold 
around the cells. Once the printing is complete, 
the tissue continues to mature until the hydrogel is 
removed. After these processes have occurred, the 
tissue has complete function.26 
 These processes are relatively new, and as 
a result, more findings are becoming available 
each day. Recently, Homan et. al described the 
ability to bioprint 3D renal proximal tubules using 
perfusable chips.27 Although it may be several years 
until the regeneration of renal tissue through drug 
therapeutics and bioengineering is optimized, it 
seems to be within the future grasp of the scientific 
community.

Conclusion
 An imbalance exists between treatments available 
and patients requiring treatment for kidney illnesses 
and diseases. By understanding the processes of 
embryonic renal developments, scientists have been 
able to apply this knowledge to renal regeneration 
using human pluripotent stem cells. The model of 
neonephrogenesis has also been used to promote 
the use of stem cells. While some patients require 
newly constructed renal structures or nephrons, 
others require revival and replacement of damaged 

Figure 6. This figure illustrates the coating of cells 
using extracellular matrix proteins (a) in comparison 
to using the polyester fleece interstitium (b).24 The cells 
coated with extracellular matrix proteins are unable to 
exchange respiratory gas and lack the space required to 
fully develop. The small arrows on part a represent the 
low gas exchange levels, whereas the large arrows on 
part b represent the spatial development and exchange 
of gas.24  



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Aisthesis      Volume 8,  2017

nephrons. Using angiogenesis, blood function can be 
restored in patients suffering from kidney conditions. 
To prevent complete loss of function in early-stage 
patients, scientists must be able to distinguish the 
mechanism needed to restore function and structure. 
The future of renal regeneration seems promising 
with the use of drug therapeutics and other 
mechanisms of bioengineering. Perhaps one day, 
those diagnosed with kidney illnesses will undergo 
renal regenerative therapies, restoring a vigorous life. 

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