Highlights

Articles

  1. Home
  2. Digital Cortile
  3. Cortile Spring 2020
  4. The Next Frontier in Health Care: A Review in Regenerative Medicine

Tissue regeneration can be achieved by combining living cells to provide biological functionality and materials to support cell proliferation as scaffolds. Regenerative medicine has brought high hopes for the treatment of many human diseases worldwide. Diseases, such as Parkinson's disease, Alzheimer's disease, osteoporosis, spine injuries or cancer, could be treated with methods to regenerate diseased or damaged tissues in the near future. The perspective of using an off-the-shelf synthetic product to regenerate damaged or non-functional tissues is a driving force for medical science. Today's interest in nanomedicine continues to grow, the application of nanotechnology tools to the development of structures at the molecular level, creates cooperative interactions between material surfaces and biological entities (1). Regenerative medicine aids the body to form new functional tissue to replace lost or defective cells by employing three strategies: 1. inducing the body’s inherent regenerative capacities (such as when we get a cut) through the application of stem cell therapies and/or growth factors; 2. “tissue-engineering”, or creating custom, complex cellular structures in the lab to implant into the patient; and 3. recolonizing damaged tissue structures with patient-derived cells and implanting them into the patient (2). Ultimately, this will help to provide therapeutic treatment for conditions where current therapies are inadequate, or non-existent.

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.

Astonishing Tools: Stem Cells

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).

Potency

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

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.

 

 

Mesenchymal Stem Cells

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.

Embryonic Stem Cells

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; a Giant Leap for Mankind

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).

iPSCs as A Disease Model

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.

Therapeutic Applications

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.

Personalized Medicine

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.

iPSCs and Nanotechnology

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.

Concluding Remarks

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.

Works Cited

  1. Engel E, Michiardi A, Navarro M, Lacroix D, Planell JA. Nanotechnology in regenerative medicine: the materials side. Trends Biotechnol [Internet]. 2008 Jan 1;26(1):39–47. Available from: https://doi.org/10.1016/j.tibtech.2007.10.005
  2. TROMMELMANS L. The Challenge of Regenerative Medicine. Hastings Cent Rep [Internet]. 2010 Feb 25;40(6):24–6. Available from: http://www.jstor.org/stable/40928340
  3. Glendenning Lauren. The next frontier in health care: regenerative medicine. 2019 Jun;2. Available from: https://www.parkrecord.com/news/the-next-frontier-in-health-care-regenerative-medicine-sponsored/
  4. Martino S, D’Angelo F, Armentano I, Kenny JM, Orlacchio A. Stem cell-biomaterial interactions for regenerative medicine. Biotechnol Adv [Internet]. 2012;30(1):338–51. Available from: http://www.sciencedirect.com/science/article/pii/S0734975011000917
  5. Bajada S, Mazakova I, Richardson JB, Ashammakhi N. Updates on stem cells and their applications in regenerative medicine. J Tissue Eng Regen Med [Internet]. 2008 Jun 1;2(4):169–83. Available from: https://doi.org/10.1002/term.83
  6. Minguell JJ, Erices A, Conget P. Mesenchymal Stem Cells. Exp Biol Med [Internet]. 2001 Jun 1;226(6):507–20. Available from: https://doi.org/10.1177/153537020122600603
  7. Weissman IL. Stem Cells: Units of Development, Units of Regeneration, and Units in Evolution. Cell [Internet]. 2000;100(1):157–68. Available from: http://www.sciencedirect.com/science/article/pii/S009286740081692X
  8. Steindler DA. Stem Cells, Regenerative Medicine, and Animal Models of Disease. ILAR J [Internet]. 2007 Oct 1;48(4):323–38. Available from: https://doi.org/10.1093/ilar.48.4.323
  9. Singh VK, Saini A, Kalsan M, Kumar N, Chandra R. Describing the Stem Cell Potency: The Various Methods of Functional Assessment and In silico Diagnostics. Front cell Dev Biol [Internet]. 2016 Nov 22;4:134. Available from: https://pubmed.ncbi.nlm.nih.gov/27921030
  10. Kelly SJ. Studies of the developmental potential of 4- and 8-cell stage mouse blastomeres. J Exp Zool [Internet]. 1977 Jun 1;200(3):365–76. Available from: https://doi.org/10.1002/jez.1402000307
  11. GSCHMEISSNER S. Mesenchymal stem cell, SEM - Stock Image - C037/2463 - Science Photo Library [Internet]. 2019 [cited 2020 Feb 29]. Available from: https://www.sciencephoto.com/media/879146/view/mesenchymal-stem-cell-sem
  12. Sharma RR, Pollock K, Hubel A, McKenna D. Mesenchymal stem or stromal cells: a review of clinical applications and manufacturing practices. Transfusion [Internet]. 2014 May 1;54(5):1418–37. Available from: https://doi.org/10.1111/trf.12421
  13. Golpanian S, Wolf A, Hatzistergos KE, Hare JM. Rebuilding the Damaged Heart: Mesenchymal Stem Cells, Cell-Based Therapy, and Engineered Heart Tissue. Physiol Rev [Internet]. 2016 Jul;96(3):1127–68. Available from: https://pubmed.ncbi.nlm.nih.gov/27335447
  14. Kamihata H, Matsubara H, Nishiue T, Fujiyama S, Tsutsumi Y, Ozono R, et al. Implantation of bone marrow mononuclear cells into ischemic myocardium enhances collateral perfusion and regional function via side supply of angioblasts, angiogenic ligands, and cytokines. Circulation. 2001 Aug;104(9):1046–52.
  15. Williams AR, Hatzistergos KE, Addicott B, McCall F, Carvalho D, Suncion V, et al. Enhanced effect of combining human cardiac stem cells and bone marrow mesenchymal stem cells to reduce infarct size and to restore cardiac function after myocardial infarction. Circulation. 2013 Jan;127(2):213–23.
  16. Han Y, Li X, Zhang Y, Han Y, Chang F, Ding J. Mesenchymal Stem Cells for Regenerative Medicine. Cells [Internet]. 2019 Aug 13;8(8):886. Available from: https://pubmed.ncbi.nlm.nih.gov/31412678
  17. Ma Y-H, Zeng X, Qiu X-C, Wei Q-S, Che M-T, Ding Y, et al. Perineurium-like sheath derived from long-term surviving mesenchymal stem cells confers nerve protection to the injured spinal cord. Biomaterials. 2018 Apr;160:37–55.
  18. van Velthoven CTJ, Kavelaars A, Heijnen CJ. Mesenchymal stem cells as a treatment for neonatal ischemic brain damage. Pediatr Res. 2012 Apr;71(4 Pt 2):474–81.
  19. Winslow Terese. The Benefits of Stem Cell Research [Internet]. 2016 [cited 2020 Mar 3]. p. 1–3. Available from: https://sites.psu.edu/vegliastemcellresearch/
  20. Baldwin T. Morality and human embryo research. Introduction to the Talking Point on morality and human embryo research. EMBO Rep [Internet]. 2009 Apr;10(4):299–300. Available from: https://pubmed.ncbi.nlm.nih.gov/19337297
  21. Yu Y, Qin N, Lu X-A, Li J, Han X, Ni X, et al. Human embryonic stem cell-derived cardiomyocyte therapy in mouse permanent ischemia and ischemia-reperfusion models. Stem Cell Res Ther [Internet]. 2019 Jun 13;10(1):167. Available from: https://pubmed.ncbi.nlm.nih.gov/31196181
  22. Perrier AL, Tabar V, Barberi T, Rubio ME, Bruses J, Topf N, et al. Derivation of midbrain dopamine neurons from human embryonic stem cells. Proc Natl Acad Sci U S A [Internet]. 2004 Aug 24;101(34):12543 LP – 12548. Available from: http://www.pnas.org/content/101/34/12543.abstract
  23. Davila JC, Cezar GG, Thiede M, Strom S, Miki T, Trosko J. Use and Application of Stem Cells in Toxicology This article summarizes in part the Stem Cell Symposium presented at the 42nd Annual Meeting of the Society of Toxicology, Salt Lake City, Utah, March 2003. Toxicol Sci [Internet]. 2004 Jun 1;79(2):214–23. Available from: https://doi.org/10.1093/toxsci/kfh100
  24. Tichy ED, Pillai R, Deng L, Liang L, Tischfield J, Schwemberger SJ, et al. Mouse Embryonic Stem Cells, but Not Somatic Cells, Predominantly Use Homologous Recombination to Repair Double-Strand DNA Breaks. Stem Cells Dev [Internet]. 2010 May 6;19(11):1699–711. Available from: https://doi.org/10.1089/scd.2010.0058
  25. Bachiller D, Klingensmith J, Kemp C, Belo JA, Anderson RM, May SR, et al. The organizer factors Chordin and Noggin are required for mouse forebrain development. Nature [Internet]. 2000;403(6770):658–61. Available from: https://doi.org/10.1038/35001072
  26. Takahashi K, Yamanaka S. Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors. Cell [Internet]. 2006 Aug 25;126(4):663–76. Available from: https://doi.org/10.1016/j.cell.2006.07.024
  27. Bragança J, Lopes JA, Mendes-Silva L, Almeida Santos JM. Induced pluripotent stem cells, a giant leap for mankind therapeutic applications. World J Stem Cells [Internet]. 2019 Jul 26;11(7):421–30. Available from: https://pubmed.ncbi.nlm.nih.gov/31396369
  28. Kumar S, Blangero J, Curran JE. Induced Pluripotent Stem Cells in Disease Modeling and Gene Identification BT - Disease Gene Identification: Methods and Protocols. In: DiStefano JK, editor. New York, NY: Springer New York; 2018. p. 17–38. Available from: https://doi.org/10.1007/978-1-4939-7471-9_2
  29. Marin Navarro A, Susanto E, Falk A, Wilhelm M. Modeling cancer using patient-derived induced pluripotent stem cells to understand development of childhood malignancies. Cell death Discov [Internet]. 2018 Feb 1;4:7. Available from: https://pubmed.ncbi.nlm.nih.gov/29531804
  30. Robinton DA, Daley GQ. The promise of induced pluripotent stem cells in research and therapy. Nature [Internet]. 2012;481(7381):295–305. Available from: https://doi.org/10.1038/nature10761
  31. Zhu H, Lai Y-S, Li Y, Blum RH, Kaufman DS. Concise Review: Human Pluripotent Stem Cells to Produce Cell-Based Cancer Immunotherapy. Stem Cells. 2018 Feb;36(2):134–45.
  32. Brown ME, Rondon E, Rajesh D, Mack A, Lewis R, Feng X, et al. Derivation of induced pluripotent stem cells from human peripheral blood T lymphocytes. PLoS One. 2010 Jun;5(6):e11373.
  33. Guhr A, Kobold S, Seltmann S, Seiler Wulczyn AEM, Kurtz A, Löser P. Recent Trends in Research with Human Pluripotent Stem Cells: Impact of Research and Use of Cell Lines in Experimental Research and Clinical Trials. Stem cell reports [Internet]. 2018/07/19. 2018 Aug 14;11(2):485–96. Available from: https://pubmed.ncbi.nlm.nih.gov/30033087
  34. Takahashi J. Strategies for bringing stem cell-derived dopamine neurons to the clinic: The Kyoto trial. Prog Brain Res. 2017;230:213–26.
  35. Hu Y, Tian Z, Zhang C. Natural Killer Cell-Based Immunotherapy for Cancer: Advances and Prospects. Engineering [Internet]. 2019;5(1):106–14. Available from: http://www.sciencedirect.com/science/article/pii/S209580991830660X
  36. Cyranoski D. “Reprogrammed” stem cells approved to mend human hearts for the first time. Vol. 557, Nature. England; 2018. p. 619–20.
  37. Ballatore C, Lee VM-Y, Trojanowski JQ. Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders. Nat Rev Neurosci [Internet]. 2007;8(9):663–72. Available from: https://doi.org/10.1038/nrn2194
  38. Majolo F, Marinowic DR, Machado DC, Da Costa JC. Important advances in Alzheimer’s disease from the use of induced pluripotent stem cells. J Biomed Sci [Internet]. 2019 Feb 6;26(1):15. Available from: https://pubmed.ncbi.nlm.nih.gov/30728025
  39. Lund RJ, Närvä E, Lahesmaa R. Genetic and epigenetic stability of human pluripotent stem cells. Nat Rev Genet [Internet]. 2012;13(10):732–44. Available from: https://doi.org/10.1038/nrg3271
  40. Jang S-F, Liu W-H, Song W-S, Chiang K-L, Ma H-I, Kao C-L, et al. Nanomedicine-based neuroprotective strategies in patient specific-iPSC and personalized medicine. Int J Mol Sci [Internet]. 2014 Mar 4;15(3):3904–25. Available from: https://pubmed.ncbi.nlm.nih.gov/24599081
  41. Tabassum N, Verma V, Kumar M, Kumar A, Singh B. Nanomedicine in cancer stem cell therapy: from fringe to forefront. Cell Tissue Res. 2018 Dec;374(3):427–38.
  42. Liu G, David BT, Trawczynski M, Fessler RG. Advances in Pluripotent Stem Cells: History, Mechanisms, Technologies, and Applications. Stem cell Rev reports [Internet]. 2020 Feb;16(1):3–32. Available from: https://pubmed.ncbi.nlm.nih.gov/31760627
  43. Trounson A, McDonald C. Stem Cell Therapies in Clinical Trials: Progress and Challenges. Cell Stem Cell. 2015 Jul;17(1):11–22.
  44. Rami F, Beni SN, Kahnamooi MM, Rahimmanesh I, Salehi AR, Salehi R. Recent Advances in Therapeutic Applications of Induced Pluripotent Stem Cells. Cell Reprogram. 2017 Apr;19(2):65–74.
  45. Underhill GH, Khetani SR. Bioengineered Liver Models for Drug Testing and Cell Differentiation Studies. Cell Mol Gastroenterol Hepatol [Internet]. 2017 Dec 6;5(3):426-439.e1. Available from: https://pubmed.ncbi.nlm.nih.gov/29675458
Environment After CoVid 19
Chapter 1: The World Around Us

Opinion: A New Perspective on the Environment After CoVid-19

There are ducks in the Barcaccia, dolphins inquisitively approaching Italian harbors and weeds colonizing urban spaces where human feet no longer tread: nature reconquering lost spaces is one of the short-term effects of this pandemic.

By Jan Claus Di Blasio, Gardens and Sustainability Coordinator

Some Notes from Isolation1
Chapter 1: The World Around Us

Some Notes from Isolation

Who else has begun to think of their lives as divided into the BC (Before Covid) and DC (During Covid) eras? Oh, those simple things we took for granted: catching some fresh air during a short afternoon walk in the park. Having a coffee at the corner bar. A long, leisurely weekend lunch with a friend. A spontaneous decision to go and see a movie. For that matter, a spontaneous decision merely to go and pick up milk and laundry soap at the grocery store.

By Moira Egan - Creative Writing Teacher
Loc3 thumb
Chapter 1: The World Around Us

I’m 15 and Quarantined in Italy—You’d Be Surprised What I Miss

I was in Latin class when the Italian government announced the closure of schools two months ago.

By Anthony Avallone '23
romance corona
Chapter 1: The World Around Us

Romance in the Time of Coronavirus

Right-wing populists are romantics. I know; that sounds strange. You probably imagine romantics staring out over misty moors, their hair blowing at an attractive angle, but make no mistake—Orban, Trump, Bolsonaro, Salvini, Le Pen? They’re romantics too.

By Jen Hollis - Former St. Stephen’s IB History Teacher
virus school 4
Chapter 1: The World Around Us

How a Virus Interrupted the Daily Routine at a Day and Boarding School

On Thursday, March 5th 2020, an unusual silence settled into the hallways, classrooms, and dorm rooms of St. Stephen’s School.

By Natalie Edwards '14 - RA and Dean's Office Assistant
poetry
Chapter 2: Creative Writing

Winners of the Keats-Shelley House Poetry Contest

In May, two St. Stephen’s students, Leila El-Zabri and Isabella Todini, won both of the prizes in the Upper School category of the Keats-Shelley Poetry Contest. This year’s judge was Jackie Kay, award-winning poet, author, and the current Scots Makar (the Scottish Poet Laureate). Ms. Kay was extremely impressed with the technical facility and emotional depth of our students’ work.

By Moira Egan - Creative Writing Teacher
creative writing
Chapter 2: Creative Writing

Creative Writing

Ms. Egan is proud to present work that has been done in her Creative Writing Classes in the Fall and Spring Semesters. Enjoy!

red dragon
Chapter 2: Creative Writing

Children of the Red Dragon

By Ilaria Chen, Grade 10
red riding hood
Chapter 2: Creative Writing

The Golden Children

By Sofia Ghilas '21
Norcia3
Chapter 4: Fall Trips 2019

Fall School Trips 2019

Welcome to our interactive Fall trips 2019 photo galleries. Click the albums for a visual journey through our adventures!

hopkins
Chapter 3: Short Stories in Italian | Italian language

Viaggio intorno alle nostre camere

By Rossano Astremo - IB Italian Teacher
trips 2020 cover
Chapter 4: Fall Trips 2019

Why We Take School Trips

When students enter St. Stephen’s as 9th graders, they will attend eight trips in the course of their career. Trips are an integral part of our identity, and one of the most frequently cited distinctions when Head of School Eric Mayer speaks with parents and students.

By Cortile Staff Writer
class4
Chapter 5: Departments | Molecular Genetics

Molecular Genetics, a Flagship Program

The Molecular Genetics program at St. Stephen's was introduced in 2018 in partnership with Adamas Scienze as a five-year initiative. Adamas Scienze is part of the European Molecular Biology Laboratory (EMBL) in Monterotondo, Italy that specializes in bringing university-level science to high school students.

By Fiona Leckie - Science Department Chair, Chemistry Teacher
five senses 2
Chapter 5: Departments | Classics, The Lyceum

An Archaeology for the Five Senses: A Lyceum Evening

On Monday evening, a group of students, teachers, alumni, and friends of St. Stephen’s gathered in the library to explore the sights, sounds, and, most importantly, the smells of Ancient Roman cities with Ann Kolosky-Ostrow, a Professor of Classical Studies at the University of Brandeis and recent Visiting Scholar at the American Academy of Rome.

By Natalie Edwards '14 - RA and Dean's Office Assistant
DC placeholder1
Chapter 5: Departments | International Baccalaureate (IB)

The Benefits of an IB Education

The International Baccalaureate (IB) is well respected and globally recognized as a very intensive, yet highly rewarding academic programme which is offered in high schools, like St. Stephen's. If you wish to pursue higher education in Europe, such as in the UK, Germany, or Finland, then the IB will be incredibly beneficial towards taking your first steps into university.

By David Rosales '16
city of rome
Chapter 5: Departments | Classics

Discovering Our City with the City of Rome Class

One of St. Stephen’s’ signature courses, Roman Topography, got an upgrade this year. The new course is called City of Rome. In the past, students were required to take either Roman Topography or Latin 1. Beginning in Fall 2019, all ninth graders take City of Rome and choose between three classical languages: Latin, Classical Greek, or Arabic.

By Natalie Edwards '14 - RA and Dean's Office Assistant
cortile sofia peng
Chapter 6: Student Life | Student Ambassador Program

Hi, I'm Sofia Peng, and I am a Student Ambassador!

I think that being a Student Ambassador made me grow so much. As a student, I concentrated mainly on my academics, yet I was never a talkative and outgoing person at school because I thought I wasn't a fluent English speaker. As it is not my first language, I have never really managed to speak comfortably around people other than my friends without feeling nervous about being judged. I always had a hard time dealing with my self-esteem and I doubted myself.

By Sofia Peng '22
lab1
Chapter 6: Student Life | Students Love Tech!

The iLab is the Place to Be at St. Stephen’s!

I think it would be safe to say that the Innovation Lab, the ILab for short, is my favorite place in the entire school. It allows for anyone with an interest in tech, design, or anything similar to enjoy themselves while also learning at the same time and pushing themselves beyond what they thought they were going to be able to do, ever.

By Valerio Pepe '22
life in the fast lane hero
Chapter 6: Student Life | Students Love Tech!, Formula 1

Life in the Fast Lane

When you think of Formula 1, you probably don’t think of engineering, aerodynamics, economics, marketing, and design yet these are just a few of the components that go into building the sleek race cars that characterize the sport.

By Natalie Edwards '14 - RA and Dean's Office Assistant
cortile smalling
Chapter 6: Student Life | Student Clubs, Chris Smalling

Tackling Inequality

AS Roma defender and Manchester United legend Chris Smalling was invited to talk to students of St. Stephen's School about equality in sports, his vegan diet, and, of course, football, on 2 December 2019.

By Laith Zehni '20
writing awards
Chapter 7: Scholastic Writing Awards

The Scholastic Art & Writing Awards, 2020

Again this year, St. Stephen’s Creative Writing teacher Moira Egan is delighted to present the work of her students, who achieved wonderful success in the Scholastic Art & Writing Competition for 2020. This year, students in Grades 9, 10, 11, and 12 garnered 10 Honorable Mentions, 6 Silver Keys, and 2 Gold Keys.

By Moira Egan - Creative Writing Teacher
Grade 9 award
Chapter 7: Scholastic Writing Awards

Scholastic Art & Writing Awards 2020

By Moira Egan - Creative Writing Teacher
Grade 10 award
Chapter 7: Scholastic Writing Awards

Scholastic Art & Writing Awards 2020

By Moira Egan - Creative Writing Teacher
grades 11 12 thumb
Chapter 7: Scholastic Writing Awards

Scholastic Art & Writing Awards 2020

By Moira Egan - Creative Writing Teacher
winter arts show3
Chapter 8: The Arts

Winter Arts Show

Enjoy a visual showcase of our Winter Arts Show highlights.

By Luigi Fraboni - Photography Studio
cortile regenerative medicine 2
Chapter 9: Alumni | Alumni Spotlight

The Next Frontier in Health Care: A Review in Regenerative Medicine

Regenerative medicine (RM) is an emerging and very exiting multidisciplinary field aimed at restoring, maintaining or enhancing tissue and, consequently, organ functions.

By David Rosales '16
Wahiba Sands
Chapter 9: Alumni | Alumni & Friends, Health & Wellness

Alumni & Friends in Oman

Our fearless leader Dr Helen Pope lead in October our 5th edition of Alumni & Friends Trip. A group of 10 alumni followed Dr Pope in Oman, The Land of Frankincense.

By Cortile Staff Writer
NY(5)
Chapter 9: Alumni

DC, NY & Boston Alumni Events

Images from St. Stephen's Alumni events across the North East last Fall.

Painting by Cate Whittemore 1972
Chapter 9: Alumni | Class Notes

Class Notes

Welcome to our first-ever digital 'Class Notes.' Enjoy the posts and images collated by Class Ambassadors from their respective years!