The human body has an endogenous system of regeneration and repair by means of stem cells (Figure 1 ((3)), where they can be found in almost all tissues. Stem cells are undifferentiated cells characterized by multipotential differentiation and self-renewal. Self-renewal of stem cells is the consequence of cell division occurring within the microenvironment in which the stem cells (niche) reside. Inside the niche the number of stem cells is kept constant by balancing dormant and activated cells. The division of stem cells could result in a daughter stem cell and a progenitor daughter (asymmetric division), or in two daughters of stem cells (symmetric division) (4). This renewal mechanism was highly developed across evolution, and has granted humans the ability to regenerate cells and grow, restore cellular function, and replace damaged cells. Stem cells hold great promise for translational medicine's future (5).

Despite much interest in stem cell biology however, there are few examples of successful clinical applications to date. Nevertheless, the number of potential clinical applications RM has to offer is vast, and the most fascinating fact is that no idea is too farfetched. From replacing brain cells after a stroke to reconstructing muscles, the

potential is limitless. Furthermore, this could one day render certain types of complex surgeries obsolete, with patients sending tissue samples to the lab and have a simple surgery which would fix long-term tissue damage. This would save hospitals significant amounts of time and money. It is imperative to understand how stem cells are the foundation of RM, and hopefully in this mini review, you will be able to appreciate their incredible potential as a therapeutic treatment in future healthcare.

The maintenance of most cell lineages in many adult organisms is the product of an orderly chain of highly regulated processes involving cell proliferation, migration, differentiation and maturation. The cells responsible for carrying out cellular regeneration are called Stem Cells (SCs), and together with their expensive capacity for self-renewal, SCs have proven to have a high potential for giving rise to diverse cell lines (6). Stem cells can be defined as units of organization of biological systems that are responsible for the regeneration and development of organs and tissues. These cells can also be considered as units of evolution via natural selection (7). Two factors ensure the continuity of a stem cell population: 1. Division of the asymmetric cells: a stem cell divides into one mother cell similar to the original stem cell, and another distinct daughter cell. When a stem cell renews itself, it divides and does not interact with the undifferentiated cell. This self-renewal involves cell cycle regulation as well as multipotency or pluripotency maintenance, which all depends on the stem cell. 2. Symmetric differentiation: the process in which a stem cell undergoes division, giving rise to two daughter cells that are differentiated (8).

Stem cells are characterized by their ability to self-renew and give rise to different types of differentiated cells according to their potency. As evidenced by their potential to generate the variety of cell lineages, they are graded as pluripotent, multipotent, and unipotent. Although pluripotent stem cells (PSCs) in an organism may give rise to all cell types from the three germ layers (except the placenta) multipotent and unipotent stem cells remain restricted to specific tissue or lineages. The potency of these stem cells can be identified along with the evaluation of different molecular markers by using a number of functional tests (9). Whereas multipotent and unipotent stem cells are known to carry limited capacity for self-renewal and differentiate into a particular type of tissue or cell lineage; it is important to note that conversely, the cells originating from a fertilized egg (zygote / blastomere) have the potential to generate both embryonic and extra-embryonic cells; a capacity referred to as totipotency and thus may give rise and entire organism (10). Current developmental theory guides the division of totipotent stem cells to PSCs, PSCs to multipotent stem cells, multipotent stem cells to unipotent stem cells, and eventually mature cells. The cell’s self-renewing ability and differential potential continuously changes based on their transition from totipotent to mature cell status.

Adult stem cells, also known as somatic stem cells, are stem cells which maintain and repair the tissue they find themselves in. For example, blood stem cells from the bone marrow, epithelial from epidermal layers and mesenchymal cells from adipose (fatty) tissue. They can be found in adults and children alike. There are three known accessible sources of autologous adult stem cells in humans: bone marrow, which requires harvesting extraction, that is, bone drilling. Adipose tissue (fat cells) which needs liposuction extraction, and blood, which involves apheresis extraction, where blood is drained from the donor (similar to blood donation) and passed through a system that removes the stem cells and returns other blood parts to the donor.

Many stem cells used for regenerative therapy are usually derived either from the bone marrow of the patient or from adipose tissue. The cells that make up the bone, cartilage, tendons, and ligaments as well as the muscle, neural, and other progenitor tissues can be derived from mesenchymal stem cells (MSCs). These types of cells  have become the main type of stem cell used in the treatment of diseases involving these tissues (Figure 2) (11)).

MSCs are multipotent stromal cells that are used mostly in regenerative therapy to restore function to the musculoskeletal tissues, such as muscle, cartilage and bone formation. These cells despite being multipotent, they retain a significant level of potency throughout their lifespan, and therefore have been at the centre of regenerative medicine research. MSCs have also been found to play an important role in the correct functioning of the immune system, and despite very few clinical trials, they have shown incredible potential in the treatment of auto-immune diseases such as multiple sclerosis and Crohn’s disease (12). The variable differentiation potential is one of the most critical characteristics of MSCs. In addition, different tissue sources affect the differentiation tendency and proliferation capability of MSCs.

Once MSCs are transplanted in the body, they avoid immune detection, secrete a variety of anti-inflammatory and anti-fibrotic mediators and activate resident precursors in a very significant fashion (13). Due to these very favourable characteristics, these cells have been used to treat heart disease and engineer heart tissue. One particular study demonstrated the ability of MSCs to differentiate into cardiac muscle-like when transplanted into damaged myocardial tissue in-vivo (within the organism and not in the lab) (14). Most importantly however, is the fact that these cells aid in the recovery and regeneration of cardiomyocytes (heart cells) via the secretion of angiogenesis (blood vessel creation) and anti-inflammatory factors  (15). If used in a clinical application, this could one day help heart attack and stroke victims recover and potentially regenerate dead or damaged heart cells.

The capacity to repair damaged nerves is lacking in the adult central nervous system (CNS), so  damage to CNS is permanent, and there is actually no effective method for restoring CNS loss in clinical practice. In the field of CNS rehabilitation, MSC-based treatment mainly focuses on two areas: CNS damage or injury caused by severe trauma and chronic neurological disease caused by ischemia and CNS dysfunction (16). MSCs have been used to restore neural cell function both in the lab and in clinical trials (17). Persistent release of specific signal molecules and growth factors, which can facilitate neurogenesis, angiogenesis, and synaptogenesis, creates a favourable microenvironment for angiogenesis or remyelination which has been shown to repair and/or regenerate damaged axons and synapses. These are the neural cells in our brain which form the nervous system “high-ways” from which we send signals from our brain to all our body and vice versa (18). Several clinical trials revealed MSCs-based treatment as a healthy and practical method for spinal cord injury and/or traumatic brain injury patients. MSCs migrated into the cerebral damage region which was affected by haemorrhagic stroke in rats. The cells migrated despite being under hypoxic conditions and notably aided in the development of multiple growth factors to facilitate neurogenesis and neurological regeneration. Despite this technique being relatively novel, the potential regenerative capabilities are very high, and should therefore be investigated further.

One major topic of controversy in regenerative medicine research is the sourcing of embryonic stem cells (ESCs). ESCs (Figure 3 (19)) are pluripotent stem cells which can give rise to any cell type in the body, and therefore are of high interest to researchers. They are derived from the inner cell mass (ICM) of a blastocyst, which develops from a human embryo 4-5 post fertilization and consists of around 50-150 cells. Isolating the cells from the ICM however, destroys the blastocyst; a procedure that has raised several ethical questions about the moral considerations of human embryos (20). I would like to clarify, that in this review I will not be discussing the ethical standpoints and arguments associated with ESCs. Instead, I will be focusing on their potential use in regenerative medicine and tissue engineering, using some clinical examples. However, this should not deter the reader from delving deeper into bioethics and forming their own opinion on ESCs.

ESCs have demonstrated to possess a high potential for clinical applications in the treatment of various diseases. Cardiac ischemia, known as myocardial infarction, usually triggers massive cardiomyocyte death. Due to the limited regenerative capacity of the heart, most patients who suffered from permanent ischemia will develop into heart failure. Despite the potential to salvage myocardial ischemia, ischemia reperfusion usually leads to cardiomyocyte (heart cell) dysfunction and worsens heart damage in what is known as ischemia-reperfusion injury. Permanent ischemia significantly changes heart structure and function. In recent years, pluripotent stem cell-based regenerative therapy has shown great promise in heart repair and functional improvement, by using ESCs to develop cardiomyocytes which improve cardiac tissue repair-post transplant and overall cardiac function. The efficacy of this method however is still being debated to this day (21).  ESCs have also been used to develop dopamine-producing cells, and these neurons could be used to potentially treat neurodegenerative diseases such as Parkinson’s (22).

In addition to becoming an effective solution to repair damaged organ tissue, ESCs are also used in the toxicology area, and as cell screens to uncover new chemical entities (NCEs) which can be produced as small molecular drugs. Studies have shown that models of ESC-derived cardiomyocytes are validated to check medication responses and forecast toxicity profiles (23). Lastly, ESCs can be used to repair DNA damage more effectively than somatic cells. ESCs use homology recombination repair (HRR) to repair double stranded DNA breaks, which is a robust repair mechanism which utilizes two sister chromosomes during the cell cycle. Comparatively, other cells use non-homologous end joining, which is known to be an error-prone method during cell cycle stages (24). Despite the advantages offered by ESCs there are usually 3 problems that arise during in-vivo studies, such as: 1) the relative inaccessibility of the mammalian embryo and the difficulty in observing it in real time; 2) the difficulty in manipulating the embryo in the face of maternal control and that of the embryo itself; and 3) many critical steps in development are fleeting and involve a very small number of cells (25).

Induced Pluripotent Stem Cells (iPSCs) are somatic cells which have been converted back into their pluripotent state. Shinya Yamanaka's laboratory in Kyoto, Japan, pioneered the iPSC technique, which demonstrated in 2006 that the addition of four specific genes (named Myc, Oct3/4, Sox2 and Klf4) could turn somatic cells into pluripotent stem cells, and he was awarded the 2012 Nobel Prize (26). iPSC innovation has accelerated research and development in regenerative medicine, providing new cells to investigate pluripotency molecular mechanisms, cancer biology and ageing. Compared to pluripotent embryonic stem cells, a major benefit of human iPSC is that they can be produced from virtually every form of embryonic or adult somatic cell without destruction of human blastocysts. Alternatively, iPSCs can be produced from somatic cells obtained from normal individuals or patients and used as a cellular resource to unravel human development processes and model diseases in a way that was not feasible before (27).

iPSC technology allows the reprogramming of individual cells in the framework of their genetic background, and iPSC's genetic and epigenetic activities have been shown to mimic those of a donor's proper cells. Therefore, iPSCs are considered a great method for modelling human diseases, and if reprogrammed from a patient's cells with genetic variations affecting the disease, iPSCs have the ability to produce cells or tissue-like structures imitating those of the patient affected by the disease of concern (28). Recently, primary cancer cells from different types of human cancer, such as melanoma, gastric cancer, glioblastoma, and pancreatic ductal adenocarcinoma, have been effectively reprogrammed into iPSCs, offering new avenues to research the early stages of cancer development and in-vitro (in the lab) progression (29). iPSCs may be particularly useful for modelling young-age or family-inherited cancers, as these cancers have an early onset that can be initiated by the embryonic development process itself, which is essentially recapitulated during the iPSC differentiation process.

The promise of iPSCs for immunotherapy (Figure 4 (30)) has recently been investigated, with a particular interest in the search for cancer treatment. In particular, iPSCs were used to produce human dendritic cells and macrophages (immune cells) that have a powerful antigen presenting behaviour with the capacity to stimulate T-cells, which play a central role in immune response and particularly in the activation of killer cells; thereby providing a great potential for immunotherapy for cancer (31). These cells could be a source of unrestricted growth of unique T-cell clones, bypassing their site of origin in the thymus gland for creation and maturation. Some groups have also developed human tumour-specific cytotoxic T-cells, and iPSCs may also be programmed to harbour chimeric antigen receptors/CAR attacking cancer cells (32).

In preclinical studies several novel therapeutic methods are currently being tested utilizing iPSC-derived cells for their potential to generate healthy cells capable of replacing compromised or defective tissues for patients. Furthermore, the first clinical trial recorded involving iPSC-derived cells was designed to treat age-related macular degeneration (AMD), a condition that impacts the eye's macula and results in central vision blurring. In 2013, sheets of epithelial retinal pigment (EPR) cells, isolated from iPSCs originating from the patient were transplanted into the eyes of a patient with AMD. The patient's visual treatment acuity was improved six months after transplantation, with no safety-related concerns (33).

In 2018, Kyoto University announced the first clinical trial for the treatment of Parkinson's disease with iPSC-derived dopaminergic neurons to be transplanted to human patients. The goal of this study will be to determine the safety and effectiveness of iPSC-derived dopaminergic neuron transplantation into the brain of Parkinson's disease patients (34). On the oncological sector, the American Company Fate Therapeutics has recently approved the use of natural killer cell-based cancer immunotherapy for the treatment of advanced solid tumours using cells generated from a clonal differentiated iPSC unit. This research is intended to determine the efficacy and tolerability of multiple doses of these cells in participants who have succeeded or failed immune therapy (35). Also, a plan for a landmark clinical trial was accepted in 2018 for the production of cardiomyocytes from iPSCs that surgeons are preparing to implant in the heart of three patients with heart disease (36).

Potential therapeutic application can extend to cover also neurodegenerative ageing diseases. Alzheimer's disease (AD) is a progressive, fatal neurodegenerative condition that has not yet been fully successfully cured. The disease can be categorized by the formation of extracellular amyloid plaques consisting of Aβ (beta-amyloid) fragments of amyloid precursor protein (APP), these lead to a lengthy pathogenesis which can remain undiagnosed for 10 years. Latest analyses of family Alzheimer's disease from human iPSCs also indicate that genetic mutations may be related to disease mechanisms (37). In 2011, Yahata et al. successfully produced forebrain neurons from human iPSC cells, one of the first studies involving iPSCs developed for AD and showed that Aβ development in neuronal cells was detectable and inhibited by certain common secretase inhibitors and modulators. According to a second study, neuronal cells derived from iPSCs produce functional β-and ÿ-secretases involved in the development of Aβ (38). Taken together, these two studies thus represent crucial first steps in the assessment of the capacity of AD iPSCs for modelling AD. The iPSCs could be used as a practical, preclinical screening method for therapeutic compounds, therefore significantly shortening the timeframe to find a possible cure.

However, there are several challenges associated with iPSC-based therapy that need to be overcome before regular clinical applications can begin. The possibility of tumour formation from iPSCs is one concern. Since pluripotent cells are retained in culture for long periods of time, they may develop genetic defects, copy number differences, and heterozygosity loss. Furthermore, prior to therapeutic usage, iPSC-derived drugs must be closely checked for lack of potentially risky genetic alterations and rigorously tested to ensure their safety, consistency and sterility (39). The potential clinical application of iPSCs has allowed researchers to develop novel treatments for previously untreatable diseases and conditions. Despite this being a novel field that has yet to be fully explored, studies have shown that interdisciplinary research can help galvanize further the potential of this incredible field.

In recent decades, nanotechnology has attracted major interest in the delivery of medicines and disease treatment schemes, such as cancer, neurodegenerative diseases, and metabolic disorders. Nanotechnology provides an opportunity for nanoparticles (NP) or molecules to be delivered to the target sites, thus reducing toxicity and increasing drug bioavailability. A large number of nanostructured particles/vehicles have now been discovered, including polymeric nanoparticles, lipid-based nanoparticles, and silicon nanoparticles (40). iPSCs are considered useful tools for the development / screening of drugs and for disease modelling. Recently, personalized medicines have been attracting considerable interest, demonstrating how the application of nanotech and iPSCs can improve research and therefore treatments for various diseases. Typically speaking, personalized medicine is a medical approach providing a customized treatment / cure tailored to a particular patient based on their own genetic data. Consequently, the combination of nanomedicine and iPSCs in transplantation medicine may potentially be very effective weapons for pathologies with no available cure.

While nanoparticle-based drug delivery systems have been extensively investigated, particularly in cancer therapies, the application of NPs in patient-specific iPSCs has not received much attention. The potential, however, has been noted and I believe more research and funding is required to enable us to fully unlock it. Nonetheless, based on the nanoscale structure and huge surface area, it has been observed that NPs can be a powerful tool in both reprogramming disease-specific iPSCs and drug screening methods performed on the disease-specific iPSCs that have been obtained. For example, mesoporous silica nanoparticles (MSNs) have a smaller chance of being rejected by our bodies, and their high surface area allows high drug loading, making MSNs an ideal drug delivery and drug screening platform (38). Nanomedicine can also potentially be used to target specific cells, such as tumour cells in combination with specific cancer stem cells via targeted drug delivery (Figure 5(41)). This could serve as an alternative for chemotherapy, which causes significant damage to other healthy tissues in the body.

Perhaps what is most fascinating about the advancements in regenerative medicine is that despite the significant developments in the knowledge of stem cells and their clinical application, we are only scratching the surface when it comes to their potential therapeutic use. The main aims of stem cell research are regenerative medicine applications, disease modelling, drug screening, and human developmental biology. In recent years, reprogramming technology for generating iPSCs has been progressing gradually towards these aims. This technology expands on multiple fronts but has a prominent application in neuroscience to treat SCIs, brain damage, Alzheimer's disease, PD and also in cancer treatment. This has many benefits, including addressing cell shortages due to readily accessible forms of cells (e.g., fibroblasts from biopsied skin or urine samples), being reprogrammed in culture, and being optimized for clinical use, thereby eliminating or minimizing the need for immunosuppressive therapy and any related risks (42). Clinical use in patients is the main objective of stem cell research. There are many ongoing clinical trials of stem cells around the world including studies in bone / cartilage, heart, neurological, immune / autoimmune, kidney, lung, liver, gastrointestinal disease, and metabolic disease. HESC-and iPSC-derived drug studies based on SCI, PD, macular degeneration, type 1 diabetes mellitus, and serious heart failure are especially of interest (43). Organ transplantation is considered the final treatment for organ failure because there is a significant shortage of donors of organs, so transplantation requires matches between donor and recipient. Thus, an alternative cell and tissue source, such as iPSCs, may help solve these challenges. 3D stem cell structures designed with biomaterials and bio-printing technology can allow for future organ reconstruction (44). While complete, functional organs have yet to be reconstructed, parts of organs including partial livers, vasculature, and bones have been reconstructed (45).

Despite their undenied potential, stem cell research (especially embryonic stem cells) is currently limited in Europe and the US. Due to the highly controversial nature of the source of ESCs, they are incredibly difficult to obtain, and therefore research is equally problematic. Nevertheless, iPSCs have proven time and time again both their clinical and therapeutic applications in vastly different fields of medicine. It is vitally important to keep funding this highly specialized form of research, not only to further our understanding of the underlying molecular and genetic mechanisms which govern pluripotency, but also to extend and possibly one day allow this incredibly revolutionary technology to be readily available as a cure for multiple diseases.

David Rosales is an alumnus of St. Stephen's School, Rome, Italy. He graduated in 2019 with a BSc Hons in Biotechnology from the University of Manchester.

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