The intervertebral disc prevents the vertebrae
from coming together and damps the
compressive forces on the spine. Degeneration of
the intervertebral disc is accompanied by the loss
of vitality of its stem cells, resulting in disc
deformation and instability, which can cause local
pain or even painful, disabling nerve injury.
Treatment options for disc degeneration include
palliative treatment based on medications,
physical therapy, and often require surgery, which
can lead to biomechanical problems and
accelerated degeneration of the adjacent
segments. The intradiscal application of stem cells
is a safe procedure that is minimally invasive, with
long-lasting beneficial effects, which does not
require surgery or hospitalization, and compares
favorably with results obtained with surgical
interventions, such as spinal fusion or disc
replacement, at much lower costs (24- 36).

Apart from the disc, all the other structures that
constitute the anatomy of the spine (muscles,
intervertebral joints, nerve roots, sacroiliac joints,
etc.) are capable of causing pain in the area
involved or to radiate to the lower extremity (37).
In these cases, benefits of local infiltration of stem
cells have already been demonstrated in
controlled clinical trials, a higher risk/benefit ratio
than other conventional alternatives (38,39).

Every day, accumulating evidence show the
benefits of stem cells to treat neuropathic pain,
indicating that this may be a new approach for the
treatment of a condition that deteriorates
patient’s quality of life and for which conventional
medicine has little to offer. Moreover, it has been
shown that, at injury sites, stem cells inhibit the
production of pain-causing substances, while
releasing analgesic substances, correcting the
imbalance between chemical pain mediators and
analgesics, thus constituting a new strategy for
the treatment of pain caused by a wide variety of
diseases (40-44). It is relevant to notice that there
is some evidence regarding intractable pain, in
which stem cells potentiate the analgesic effect of
opioids (45,46).

Ischemic heart disease (angina, infarction) and
cardiomyopathy (heart failure) are among the
leading causes of morbidity and mortality
worldwide despite the significant advances
achieved in technology, surgery, and
cardiovascular pharmacology. Paracrine and
regenerative actions of stem cells, related to the
preservation of cardiac muscle contractility,
stimulation of new vessel formation, and control of
inflammation and fibrosis, have encouraged
preclinical and clinical studies evaluating the role
of these cells in several cardiovascular diseases
(1-3).

Referred as refractory since angina persists even
after several months of standard treatment.
Patients are often not candidates for
revascularization due to the presence of diffuse
coronary lesions or severe comorbidity. Stem cell
therapy is now a valuable resource for the
treatment of these patients and clinical trials
highlight that although available data are not yet
conclusive, due to the lack of therapeutic
alternatives, authors consider stem cell–based
therapy to be a viable option to add to the
conventional treatment of refractory angina; when
comparing patients on conventional treatment
plus stem cells and patients with only optimal
conventional treatment, studies found
improvement of angina indicators and frequency
of attacks, increased exercise time and decreased
all-cause mortality, without an increase in adverse
reactions, among those who received stem cells
(4-6).

Cell death secondary to AMI causes a strong
inflammatory reaction in order to repair the heart
muscle, but that unleashes a process of ventricular
remodeling, and its duration and intensity
determines the prognosis of the infarction.
According to available evidence,
anti-inflammatory and immunomodulatory
activity, on the one hand, and regenerative activity,
on the other, explain why stem cells restore the
balance between inflammation and repair, control
cardiac remodeling and improve the prognosis of
infarction (7). In studies carried out with patients
with AMI who underwent surgery and/or received
conventional medication in a timely manner, stem
cell application is associated with significant
clinical improvement and better indicators of
cardiac function. Although, there are still gaps in
knowledge that must be filled (such as dose, cell
type, time of application), the role of stem cells in
ischemic heart disease is becoming increasingly
clear, to the point where regenerative stem cell
therapy is considered as an option with sufficiently
strong evidence to be advised in AMI treatment
protocols (8-13).

As mentioned above, ischemic injury and death of
cardiac muscle cells leads to cardiac fibrosis, in
which the damaged tissue is replaced by a fibrous
scar, which is important to prevent ventricular wall
rupture in the infarction zone. However, it expands
over time to non-infarcted areas. which end up
deteriorating cardiac function. Despite optimal
medical and surgical management, many patients
with heart disease are inevitably exposed to this
long process of heart muscle damage, which
reduces its contraction and relaxation capacity.
Which means that current treatment protocols are
unable to prevent the loss of vitality of heart
muscle over time (cardiomyopathy) (14). Under
these circumstances, it was to be expected that
the medical community would want to explore the
potential benefits of stem cells, due to their
anti-inflammatory, anti-fibrotic, angiogenic, and
immunomodulatory properties. In fact, since
2018, several meta-analyses have been published,
including dozens of studies on thousands of
patients with heart failure in which the effect of
stem cell–based therapy was examined. In
general terms, results can be summarized as
follows: compared to controls treated with
conventional management, patients who received
stem cells had a significant improvement in
cardiac function parameters, heart failure severity
classification, 6minute walk distance, quality of
life, and mortality; there was not attendant
increase in serious adverse events or
hospitalization rates (15-24).

Atherosclerosis has a dual inflammatory and
immune nature. Due to their anti-inflammatory,
immunomodulatory, and angiogenic properties
(new blood vessels), stem cells control atheroma
formation and stabilize the formed atheromatous
plaque, decreasing its risk of inflammation,
rupture, and formation of thrombi (25-28). On the
other hand, beneficial and safety results are
already beginning to be reported on the
administration of stem cells in patients with
critical peripheral arterial disease (29,30).

The lung has an extraordinary capacity for
self-repair, but it is exposed to numerous
damaging environmental and endogenous
factors. From the moment it was demonstrated in
human lung tissue cultures that stem cells inhibit
the formation of fibrous tissue and stimulate
repair, numerous studies have been conducted in
a variety of animal models of obstructive,
restrictive and inflammatory lung diseases (such
as pulmonary hypertension, bronchopulmonary
dysplasia, chronic obstructive pulmonary disease
(COPD), pulmonary fibrosis, asthma, obstructive
sleep apnea, acute injury, and infection), with
safety and effectiveness results that have
provided the basis for the beginning of clinical
research.
Different clinical investigations and meta-analyses
have yielded very reliable results in terms of safety
and effectiveness of the use of stem cells in
patients with chronic lung diseases, such as
pulmonary fibrosis (1-6), pulmonary hypertension
(7), COPD and asthma (8-14), among others,
although benefits are limited in advanced stages
of the disease and issues such as optimal source
of cells, dose, route and frequency of
administration have not yet been resolved. Since
the prevalence of these diseases is increasing
worldwide and therapeutic alternatives are so
scarce, there is no doubt that this is one of the
fields in which evidence of benefit will quickly
accumulate.

Although the liver has extraordinary regenerative
capacity, viral infections, drugs, toxins, metabolic
disorders, genetic and immune diseases, among
others, can cause acute liver failure or can lead to
chronic inflammation and cirrhosis, despite
adequate medical and surgical treatment. For
some patients, liver transplantation is not an
accessible option due to the scarcity of donors,
complications related to immunosuppression,
complexity and high costs of surgery.
There is sufficient evidence in preclinical studies
regarding the ability of stem cells to differentiate
into liver cells, attesting to their anti-inflammatory,
anti-fibrotic and immunoregulatory properties
and of their therapeutic effect on acute liver
failure, in different animal models (1). Studies in
humans with hepatopathies have been ongoing
since 2015 (2) and the majority of individual
investigations and meta-analyses, which include
thousands of patients, confirm the benefits in the
treatment of fatty liver, liver cirrhosis of different
causes and acute liver failure, with biochemical,
histological, functional and clinical improvement
(edema, fatigue, anorexia, abdominal distension)
(3-23).
In addition, two recent studies report, on the one
hand, a decrease in the incidence of liver cancer in
terminal stages of liver failure, up to 5 years after
the application of stem cells (24) and, on the other
hand, an increase in survival rates at 3- and
5-years post treatment, in cirrhotic patients who
received stem cells (25).

Inflammatory bowel disease (IBD) is divided into
three types: chronic IBD, ulcerative colitis (UC) and
Crohn’s disease (CD). All of them share an
autoimmune disorder that alters the normal
intestinal flora, and its ability to respond to
pathogenic bacteria, which causes an intense
inflammatory reaction of the intestinal wall;
therefore, treatment focuses on the normalization
of the immune system and control of
inflammation (1-3). However, despite the increase
in anti-inflammatory and immunosuppressive
drugs, up to 30% of patients with IBD do not
respond to the different protocols available, and
up to half of the patients who benefited initially
stop responding over time (3).
The benefit of stem cell treatment of IBD has been
confirmed in numerous clinical trials and
meta-analyses, including severe forms of CD, with
fistula formation (4,5). Reports show that stem
cell-based regenerative medicine is associated
with reduction of autoimmune inflammation
activity and stimulation of the intestinal mucosa
repair process, increasing the duration of
remissions and reducing the frequency of
hospitalizations and surgeries (6-16).
Although studies evaluating potential interactions
between stem cells and conventional drugs have
reached contradictory results and, therefore, the
evidence is not conclusive, everything indicates
that the combination of stem cells with
glucocorticoids or azathioprine (and perhaps
other drugs) enhances its benefits in IBD (3,17).

Metabolic syndrome (MS) is a set of
cardiovascular risk factors, which include
abdominal obesity, high triglycerides with or
without high cholesterol, low HDL, high blood
pressure, hyperglycemia, and nonalcoholic fatty
liver. The common denominator of these entities
is a chronic inflammatory state, atherosclerosis,
and insulin resistance. A vicious circle is also
generated in which each of these pathologies
amplifies the damage caused by the others. There
is an accumulation of preclinical and clinical
evidence that stem cells can control several of the
aforementioned components of MS (1-4).
On the other hand, the main damaging event of
type 1 Diabetes Mellitus (T1DM) is autoimmune
destruction of pancreatic -cells (responsible for
producing insulin) (5), while in type 2 Diabetes
Mellitus (T2DM), which is associated with insulin
resistance, there is -cell inflammation, a loss of
-cell maturity and of their ability to produce
insulin (6,7).
The differentiation potential of stem cells and their
anti-inflammatory and immunomodulatory
properties have drawn increased interest in
researchers and clinicians, which generated a
wave of preclinical and clinical studies, whose
purposes range from evaluating the safety and
effectiveness of stem cells in the treatment of MS
and T1 and T2DM, through the definition of
mechanism of action of these cells, as well as their
optimal sources, doses, routes of administration,
dose intervals, etc. Results aim to have abundant
scientific evidence that supports the use of stem
cells as a safe and cost-effective option for the
treatment of these three pathologies.
In fact, according to meta-analyses and systematic
reviews that were published in recent years,
intravenous administration of stem cells is
associated with clinical and quality of life
improvement, better glycemic control, a decrease
in glycosylated hemoglobin and insulin
requirements, as well as an increase in C-peptide
(8-20). Moreover, a recent research with an 8-year
follow-up found an association between stem cells
and a reduced risk of chronic complications of
T1DM, such as nephropathy, retinopathy and
neuropathy (21).

The key pathological mechanisms of CRF are
inflammation and remodeling (replacement of
normal structures by fibrous tissue, and
dysfunction or destruction of blood vessels) (1).
Considering the anti-inflammatory and
anti-fibrotic activity of stem cells, studies
performed in animal models confirmed that these
cells attenuate kidney damage, improving function
and protecting the glomerular and tubular
structure. The next step was to evaluate the
nephroprotective effect of stem cells in humans
with CRF, with positive results, including kidney
injuries secondary to lupus erythematosus,
diabetes and in children with nephrotic syndrome
resistant to conventional treatment (2-13).

Hematopoietic stem cell transplantation (from
bone marrow, peripheral blood, or cord blood) is
indicated for diseases such as leukemia,
lymphomas, and some anemias and immune
disorders, among others. In fact, the highest
prevalence of these diseases in elderly individuals
is caused by aging and dysfunction of their own
hematopoietic stem cell (1).
However, post-transplant mortality rates remain
high, mainly due to recurrence of the primary
disease, infections, and graft-versus-host disease:
(GVHD), which can occur acutely or chronically.
Although some immunosuppressive drugs can
reduce its incidence, it remains high since the
acute form of GVHD, for example, affects between
40% and 80% of transplant patients, which makes
it necessary to investigate new therapeutic
alternatives (2).
GVHD is the result of a complex immune response.
Since stem cells have strong anti-inflammatory
and immunomodulatory activity, the usefulness of
mesenchymal stem cell transplantation (for
example, from Wharton’s jelly) to treat GVHD has
been studied. Although strengthening the
evidence is still necessary, especially with
controlled clinical trials, several investigations
report beneficial effects of stem cells in the
prophylaxis and treatment of acute and chronic
GVHD in children and adults, with increased
survival rates. It is important to highlight that the
benefit extends to patients with steroid-resistant
GVHD (3-14).

Once the immunomodulatory and
anti-inflammatory activity of stem cells had been
demonstrated in in vitro and preclinical studies,
the exploration of the effect of these cells on an
increasing series of autoimmune diseases in
humans started. However, it should be noted that
the therapeutic effect in these cases is not
curative and effectiveness decreases over time,
which suggests that it is still necessary to enhance
different treatment protocols (1,2).

In a significant number of patients, conventional
therapy for RA is associated with poor response or
intolerance; in such cases, stem cells are emerging
as a novel therapeutic option. In fact, preclinical
evidence regarding safety/efficacy in RA animal
models is considered sufficiently strong and,
evidence of its benefit in patients with poor
response to standard treatment is accumulating,
with decrease in inflammation markers, and
clinical improvement (1-10).

SLE is one of the autoimmune diseases with
greater evidence on benefits and safety of stem
cells in animal models and in humans. Keeping in
mind that clinical evidence is still limited, results of
clinical trials on the safety and efficacy of stem
cells in SLE give us reasons to be optimistic. As
indicated by molecular mechanisms studies,
where stem cells can be beneficial, and by reports
of survival rates, clinical improvement, and
treatment tolerability in patients with several
autoimmune diseases, including SLE (1-3,11-18).

This is a rare autoimmune disease that affects skin
and multiple internal organs and may have a
severe course. Its treatment options are very
limited, and medications that may be useful have a
narrow safety margin. Cell therapy has emerged
as an option, not only safe but capable of
correcting many of the inflammatory and immune
system disorders that characterize SS. Its safety
has been confirmed in individual clinical studies
and reviews and, significant benefits have been
obtained from the application of stem cells in
patients with SS (19-28).

A significant number of patients with psoriasis do
not respond satisfactorily to current therapies.
Since it is an autoimmune disease, in which the
patient’s own stem cells are involved with
excessive and sustained production of
inflammatory substances, a good response to
stem cell therapy was to be expected, due to the
anti-inflammatory and immunomodulatory
actions of these cells. This hypothesis has been
confirmed by several clinical studies (29-33).

Stem cells emerge as a potential strategy to treat
allergic diseases (asthma, rhinitis, dermatitis,
conjunctivitis and anaphylaxis), probably due to
their immunoregulatory and anti-inflammatory
characteristics. This therapeutic potential has
been demonstrated by preclinical and clinical
studies. But atopic dermatitis is the allergic
disease that has the greatest evidence on the
benefit and safety of stem cell treatment
(22,34-37).

Traditionally, several neurodegenerative diseases
(multiple sclerosis, amyotrophic lateral sclerosis,
Alzheimer’s disease, Parkinson’s disease) have
been considered incurable, and current medicine
can only offer palliative treatment, as in the case of
disease-modifying medications, which manage to
control progression of intermittent forms of
multiple sclerosis, but none of them can repair the
existing damage. In recent years, great interest in
determining the role of stem cell therapies in
several neurodegenerative diseases has arisen.
Multiple in vitro and animal model studies have
confirmed the following properties of different
types of stem cells: formation of new myelin,
prolongation of neuronal vitality, reduction of
oxidative stress, immunomodulation, and
formation of new blood vessels, which translate
into neuroprotection. Although evidence on
safety/efficacy, cell type, dose, routes of
administration, etc., require further elucidation
(1-4).

Multiple sclerosis (MS) is caused by the
destruction of myelin, which damages the
electrical activity of neurons, with subsequent loss
of brain function. Its treatment, based on
regenerative medicine, has reached such a level of
evidence, that it has been recommended by
scientific organizations in severe forms of the
disease. In fact, compared with standard
immunotherapy, stem cells have been associated
with stabilization and delay in the progression of
the disease and increased life expectancy, and also
a decrease in activity biomarkers in blood and
cerebrospinal fluid. On the other hand,
safety/efficacy of intrathecal application of stem
cells, such as those from Wharton’s jelly, have
already been widely documented (5-13).

ALS is a disease characterized by destruction of
motor neurons, neurovascular damage and
muscle degeneration, which leads to paralysis,
respiratory failure and death. Stem cell treatment
has been consolidating as a safe procedure and a
promising strategy to protect motor neurons and
slow down ALS progression (14-21).

Parkinson’s disease (PD) is caused by a progressive
loss of neurons in specific brain areas. Current
treatment approaches aim to improve symptoms
with medications or neurosurgery, but they are
not focused in preventing damage to the neurons
involved, which means that neuroprotective
strategies that provide the possibility of replacing
lost neurons need to be developed (22). Stem
cells’ ability to repair the damage caused by PD
has been demonstrated in vitro, and studies on
safety and efficacy of stem cell-based treatment in
animal models are conclusive. Currently, clinical
evidence from clinical trials and meta-analysis can
be summarized as follows: i) Safety studies of their
application in humans leave no doubt: stem cells
are a therapeutic tool with a very low rate of
undesirable effects and are not associated with
serious adverse events. ii) Evidence from efficacy
studies is getting stronger, and stem cells are
emerging as a therapy associated with
improvement in patient’s clinical condition,
imaging features, and neuropsychological scores.
(23-31).
Regarding the role of stem cells in Alzheimer’s
disease, there is a good theoretical basis for a
potential benefit. Some studies in animal models
confirm this. Evidence in humans is limited but
promising. Since this is a highly prevalent disease
and one of the leading causes of death in the
elderly, it is expected that in the future evidence
on the safety/efficacy of regenerative medicine in
the treatment of this disease will accumulate
rapidly (32-37).
Epilepsy is an electrical disorder of the brain,
characterized by recurrent convulsive seizures,
which cause progressive damage of neurons.
Approximately 70% of patients respond
satisfactorily to existing anti-epileptic agents, but
up to 30% of them are refractory to
pharmacological therapy, which is not exempt
from significant undesirable effects. In these
circumstances, discovery of new therapeutic
options is a priority of neuroscience research. As
potent anti-inflammatory, anti-oxidant,
immunomodulatory and neuroprotective effects
of stem cells have been confirmed, safety/efficacy
evidence has also been consolidated in preclinical
(38-40) and clinical studies, including
drug-resistant forms (39-49). It should be noted
that, in some of the aforementioned studies,
improvement of electrophysiological markers and
neuropsychiatric comorbidity (depression, anxiety)
has also been reported.

Ischemic-hypoxic encephalopathy (IHE) is a
neurological condition with high mortality and
long-term complications, with significant
personal, family, medical and socio-economic
costs. The damage is caused by conditions that
affect blood circulation and oxygenation of
nervous tissue that lead to deprivation of energy
sources and cell death in the affected area. When
IHE is not fatal, a great majority of patients
present neurological deficits, such as hearing and
vision loss, developmental delay, cerebral palsy
and epilepsy. Hypothermia had been established
as the main current therapy, which must be
initiated within the first 6 hours after birth, is not
without risks and, its role is neuroprotective, not
neurorestorative. This devastating scenario
reinforces the urgent need to develop new
strategies to manage IHE. Stem cells in the central
nervous system can sense the microenvironment
in the damaged area and secrete paracrine factors
with reparative functions, which control
phenomena such as inflammation, oxidative
stress, cell death, and fibrosis (1).
Upon gathering sufficient evidence on safety and
efficacy of stem cells in HIE animal models, made
it possible to undertake the corresponding
safety/efficacy clinical trials with promising results.
Although evidence in humans is still limited,
regenerative medicine based on stem cells and
their derivatives has shown clinical and
paraclinical results that were never achieved with
current therapeutic options available (1-5).

Due to its neuroprotection and neuroregeneration
potential, stem cell transplantation has emerged
as a promising therapeutic alternative to improve
performance of several components of brain
injury in children (intellectual disability, global
developmental delay, cerebral palsy), in
conjunction with conventional rehabilitation
programs. Different clinical studies (case series,
controlled clinical trials, and meta-analyses), which
included hundreds of patients between 6 months
and 15 years of age, have confirmed the safety
and efficacy of several types of stem cells
protocols. Although results of these studies are
not unanimous, most have reported positive
responses in areas such as cognition, language,
self-care, motor function, social adaptability and,
quality of life. Adverse events have been minimal
and temporary (6-18).

Autism spectrum disorders (ASD) are a group of
clinical conditions characterized by
communication and social behavior disorders and
repetitive behaviors. Although their
pathophysiology is not clear, evidence suggests
that immune system dysfunction and
neuroinflammation, which begin in the prenatal
period, cause neurodevelopmental damage and
structural alterations of the brain (1,2).
Current treatment options are few and limited to
control some symptoms, hence the need to
explore new treatment strategies. Due to
anti-inflammatory, neuromodulatory, and
neuroregenerative properties of stem cells, a
growing number of individual research and
meta-analysis have investigated the effect of
these cells on patients with ASD. Benefits in
biochemical markers of neuroinflammation and in
scales measuring the severity of ASD symptoms
(such as language, social communication,
repetitive behavior, and hyperactivity) have been
found in patients in the range of 2 years and 15
years of age, while none of the studies reported
serious adverse events related to the intervention
(2-8).

No effective treatment is available for conditions
associated with death of neurons and glial cells,
since nerve regeneration capacity is very weak.
Therefore, one of the focuses of attention of the
scientific and clinical community is directed
toward reduction of permanent damage, promote
the reconstruction of nervous tissue, and recover
its structure and function after any type of injury.
Stroke is the most common neurological disorder
in adults, and its incidence has increased mainly
due to population aging and the increased
prevalence of cardiovascular disease. In addition,
current measures to overcome an acute injury
reduce stroke mortality. However, many patients
present residual cognitive, sensory, and/or motor
disabilities. Thus, interventions aimed at
preventing and treating the acute phase and
sequelae of stroke are urgently needed, and cell
therapy represents a new option to reduce the
disability caused by stroke.
Safety and functional improvement associated
with angiogenesis, neurogenesis and
inflammation control in animal models of ischemic
stroke has already been confirmed (1). Evidence in
humans has rapidly accumulated and, in 2020 a
meta-analysis, which included 13 clinical studies
with 704 patients, found benefits in daily activities,
neurological damage and mortality of patients
with ischemic stroke treated with different types
of stem cells, in different doses and by different
routes of administration (2). Since then, evidence
on safety of stem cell transplantation in acute and
chronic ischemic stroke and its association with
improvement of neurological function, in
follow-up trials for durations of up to several
years, has become even stronger (3-14). It should
be noted though that evidence of risk/benefit of
stem cells in hemorrhagic stroke is still very poor,
although results in animal models allow us to be
optimistic (15,16).

Regarding potential benefits of stem cells in
central nervous system (CNS) traumas, it should
be noted that several in vitro and preclinical trials
have found that these cells: a) can differentiate
into various types of nervous system cells; b)
secrete neuroprotective substances; c) stimulate
myelin formation and neuronal development; d)
inhibit scar formation (1).
In head trauma, practically all types of stem cells
have been evaluated in preclinical and clinical
trials, on the acute, subacute, or chronic phase of
trauma, with or without biomaterials that serve as
an extracellular matrix, and showed significant
reduction in neurological deficits and cognitive
sequelae. Nevertheless, several problems still
need to be solved before stem cell–based therapy
becomes part of conventional protocols for clinical
management of head trauma (2-5).
When a spinal trauma occurs, a cascade of
events is unleashed, known as “secondary injury”,
consisting of hemorrhage, ischemia-reperfusion
injury, oxidative stress, neuroinflammation and
degeneration of nervous tissue. Most patients
present permanent disabilities such as motor
dysfunction, spasticity, sensory and urinary
disorders and neuropathic pain. Conventional
therapies have very limited scopes.
Due to their biological properties (regenerative,
anti-inflammatory, immunomodulatory,
antifibrotic, neuroprotective and analgesic), stem
cells have been clinically assessed and have
emerged as a therapeutic option for spinal trauma
with increasing scientific support; to the point that
their use in brain and spinal trauma has already
been authorized by the FDA under the figure of
“experimental therapy with expanded access”
(6-18).

Female infertility, which is the inability to achieve
pregnancy with regular sexual intercourse for at
least 12 months, has multiple causes, and its
treatments vary according to the type of infertility.
Premature ovarian failure (POF: ovaries stop
working before the age of 40) and endometrial
disorders are two common forms of infertility in
which the safety and efficacy of stem cells have
been studied. The mechanism of action in POF is
not clear, but experiments conducted in vitro have
shown that different types of stem cells stimulate
the growth, maturation, and viability of cultured
mouse follicles (1-3).
On the other hand, in some uterine diseases,
intrauterine application of stem cells improves
endometrium thickness and quality and increases
implantation and probability of pregnancy (4). In
summary, from a clinical perspective, stem cells
have been beneficial in restoring fertility among
women with infertility due to several causes
(5-15). Although clinical experience is relatively
scarce, some authors consider that, according to
current evidence, cell therapy has proven to be the
most efficient way to treat POF, compared to other
therapeutic options (16).

As age advances, there is an inevitable and
progressive loss of the ability to maintain
biological balance, with an increase in prevalence
of debilitating and painful chronic diseases. Thus,
aging and its associated diseases represent an
increased burden on the family, society, and health
systems. Therefore, identification of mechanisms
responsible for aging and the development of new
therapeutic strategies aimed at making aging
more bearable is essential. This is why the World
Health Organization is committed to promoting
measures that ensure the so-called “healthy aging”
(https://www.who.int/es/initiatives/decade-of-heal
thy-ageing).
Although chronological age correlates with several
clinical conditions, it is not always a faithful
reflection of an individual’s functional capacity,
well-being, or their risk of mortality. On the
contrary, biological age provides better
information about the state of health, and
indicates how rapidly or slowly a person ages.
Currently, construction of biological-mathematical
models to estimate the biological age is under
investigation (1).
On the other hand, frailty syndrome is
characterized by reduced muscle volume, tone,
and strength; slowed mobility and, reduced
physical activity, weight loss, fatigability, decline in
physiological functions, and elevation of molecular
markers of inflammation which predispose elderly
individuals to falls, disabilities and hospitalizations.
Although timely health care (exercise, nutrition,
drugs) improves quality of life and costs of patient
care, there is no specific treatment for the
management of frail elderly adults (2).
Since stem cells have biological properties that
could be useful to control or reverse many of the
signs and symptoms of frailty, regenerative
medicine has aroused interest as a therapeutic
option, especially when it has been demonstrated
that, as stem cells become senescent, they begin
to secrete degenerative factors that negatively
affect young stem cells and lose their therapeutic
virtues (3). Regenerative capacity, modulation of
chronic inflammation, reduction of biochemical
markers of senescence, restoration of
mitochondrial function (power production plants
of cells) from the senile patient’s own stem cells,
control of immunosenescence (aging of the
immune system) and loss of muscle tone and
mass (sarcopenia) (4-8), are promising stem cell
actions, not only for the treatment of frailty but
also of other clinical conditions frequently
associated with it, such as chronic lung disease,
cardiovascular disease, diabetes, osteoarthritis,
osteoporosis, among others. Regenerative
medicine based on allogeneic stem cells, from a
young donor or umbilical cord, has the additional
advantage that safety and tolerability has already
been validated in several preclinical and clinical
studies.
Even though results of preclinical researches (in
vitro or in animals) cannot be automatically
applied to humans; some published papers are
still interesting and promising. For example: i) mice
that received stem cells experienced an increase in
life expectancy compared to that of a group of
control mice (9); ii) in old mice, application of stem
cells from other old mice, but not those from
young mice, was associated with worsening of
physical dysfunction (walking speed, grip strength,
daily activities and endurance) (10); iii) it has been
confirmed, in animal models, that stem cells are
able to slow down the aging process and restore
the metabolic balance from a catabolic state
(protein destruction) to an increase in protein
synthesis (protein anabolism). This finding gives
hope for the control of diseases associated with
aging, such as osteoporosis and sarcopenia (loss
of muscle mass) (11); iv) stem cells from young
macaques were applied intravenously to old
macaques and their serum protein expression
profiling related to senility was compared, before
and four months after the application of the cells.
Protein expression profiling in macaques that
received stem cells tended to resemble that of
young macaques, in the sense of decreasing or
increasing the expression of senescence or
anti-aging marker proteins, respectively (12); v)
some patients who have survived certain
anti-cancer treatments suffer a process of brain
deterioration similar to that related to aging. Nasal
administration of stem cells has been reported to
prevent this cognitive deficit syndrome in mouse
models (13).
Although scientific literature on therapeutic
effects of stem cells on frailty is still limited,
regenerative medicine represents a promising
therapeutic strategy to treat this syndrome in
humans. In 2017, two clinical trials conducted in
frail elderly treated with allogeneic stem cells were
published, in which the safety of the procedure
and, improvement in six-minute walking distance,
pulmonary function tests, cognition and physical
component of quality of life were confirmed, and
concentrations of some markers of inflammation
were reduced (14,15). In the following years,
results of several reviews and clinical studies
conducted in patients with frailty have been
published, showing that allogeneic stem cells have
a wide margin of safety and improve physical
performance, markers of inflammation and other
signs and symptoms of frailty (16-25).

The therapeutic potential of stem cells and growth
factors has been widely studied in a variety of skin
diseases and injuries caused by chronic
inflammation, infection, trauma, burns, surgery,
neuropathies, and vascular insufficiency, with
variable results (1).

Intralesional application of stem cells for the
treatment of scars is simple, safe, and effective,
not only in clinical but also in histological terms. In
fact, prophylactic intradermal application of stem
cells in surgical wounds prevents formation of
post-surgical hypertrophic scars, with
preservation of the normal structure and function
of the skin (2,3).
Different reviews and meta-analyses of clinical
trials that studied effects of stem cells for
treatment of ulcers and chronic skin wounds
confirm that stem cell therapy is a safe procedure
that is associated with significant improvement in
conditions such as venous ulcers, diabetic foot
ulcers and those with secondary to severe
ischemic disease, resulting in a reduction in the
rate of amputations. Thus, many experts consider
cell therapy as a novel and effective therapeutic
option when accompanied by adequate medical
and surgical measures (4-15).

Minoxidil and finasteride are the only drugs that
are currently approved for the treatment of
androgenic alopecia, but their effectiveness is
limited, and they have frequent undesirable
effects. Thanks to the regenerative mechanisms
of stem cells and the fact that they release factors
that promote hair growth, hair regeneration has
become a target of regenerative medicine, with
several beneficial results and minimal adverse
events, which makes stem cell therapy one of the
most promising and potentially effective
treatments for different causes of alopecia
(16-20).

The skin has a high renewal capacity, but as it is
continuously exposed to adverse environmental
conditions, its vitality decreases over time, and its
aging is inevitable, although it can be slowed
down. Regenerative medicine has become a new
strategy for facial rejuvenation, filling of furrows
and expression lines, and elimination of scars,
acne and vitiligo lesions, among others (21-31).

All cells have the ability to secrete biologically
active molecules into their surrounding
environment to help repair damages and maintain
their own vitality or that of other organs (paracrine
activity). One mechanism to optimize this function
is to release hundreds of active molecules, packed
in vesicles covered by membranes similar to the
cell membrane. Proteins, lipids, nucleic acids and
other biologically active factors are transported
inside these vesicles, which can be transferred into
other recipient cells, in order to modify their
functional state. Therefore, these vesicles are
considered to play pivotal role in the paracrine
activity of cells and in cell-to-cell communication
(1).
These vesicles have been classified based on their
size and the cellular compartment that originates
them. Exosomes range in size from 30 nm to 120
nm; microvesicles (or ectosomes) have a diameter
of 50 nm to 1 μm, while apoptotic bodies range in
size from 50 nm to 2 μm. Apart from their size,
their differences also lie in the type of biologically
active molecules, which depends on the
intracellular site from which they are derived and
the activation state of the cell. This explains the
fact that thousands of proteins, lipids and nucleic
acids have been identified inside EVs. However,
mechanisms for EVs secretion are much more
complex and new vesicles are discovered
continuously; in addition, isolation techniques are
not sufficiently developed to ensure isolation of
homogeneous fractions. Thus, to classify vesicles
into these three categories is imprecise, and the
use of the generic term of “extracellular vesicles”
(EVs) has been proposed (1,2).
Although they are released by all types of cells, this
section refers only to EVs derived from stem cells,
since they exhibit biological characteristics similar
to their source cells, such as the ability to replicate
practically all the therapeutic activity
demonstrated with stem cells. In fact, growing
evidence shows that EVs share the regenerative,
cytoprotective and immunomodulatory potential
of parental stem cells (1), confirming that they can
be used with the same therapeutic indications, in
the broad spectrum of diseases mentioned in this
booklet.
Additionally, EVs possess some advantageous
characteristics in relation to cells from which they
are derived. Thanks to their small size and their
membrane’s physicochemical properties, they are
able to overcome several biological barriers and
distribute successfully throughout the body,
reaching organs that are difficult to access, such
as the brain (3); Furthermore, because of their
small size and because their low immunogenicity,
they can avoid destruction by the patient’s
immune system. They are not living organisms,
they cannot self-replicate and cannot induce
tumors, overcoming many ethical-legal issues of
the use of living cells; they can easily be modified,
they are stable and can be stored for longer
periods (4,5).
This emerging role of EVs allows us to envision
them as a new generation of regenerative therapy,
making them an attractive and novel option (6).
However, medical scope of EVs goes much
further: their promising use to transport and
deliver drugs in tissues that are, otherwise, unable
to reach the target organ cannot be ignored. On
the contrary, they can be distributed to organs
where they could cause damage (1); as drug
delivery systems, EVs are less immunogenic and
more biocompatible than synthetic particles
conventionally used for drug transport in the body
(7). Finally, since any cell is capable of producing
EVs, they can serve as biomarkers for early
diagnosis of several diseases, including cancer and
neurodegenerative diseases (8).
Although the use of EVs as therapeutic
instruments is very promising, this strategy still
faces many challenges and limitations, which
include the availability of an adequate source of
stem cells, difficulties in identification, isolation
and purification methods; storage conditions to
preserve their biological activity, definition of
doses and routes of administration, as well as
confirmation of their safety/efficacy through
clinical studies (1,9-11).