Stem cell drugs: the next generation of pharmaceutical products

Stem cells represent a new treatment option in medicine and pharmacy. Stem cells have been increasingly used for the treatment of many diseases. In fact, they have spurred a new age of medicine called regenerative medicine. In recent years, regenerative medicine has become a new revolution in disease treatment, especially with the use of stem cell drugs. Stem cell drugs refer to live stem cell based products that used as drugs for particular diseases. Unlike autologous stem cell transplantation, stem cell drugs are “off-the-shelf” products that are ready to be used without requirement of any further manipulation. This review aims to summarize some of the approved stem cell drugs, and discuss the revolution of regenerative medicine and personalized medicine. As well, the review will discuss how stem cell drugs have led to a new direction in stem cell therapy, providing a new platform for patient needs.


Introduction
Stem cells are considered as the origin of the growth and development of human beings. The capability and relative of stem cell isolation, proliferation and modification gave rise to the field of stem cell application for disease treatment. Today, there is a huge potential benefit for the use of stem cells in disease treatment (stem cell therapy). To date, there are more than 100 different diseases that have been treated with stem cell transplantation. The first application of hematopoietic stem cells (HSCs) in 1950s by Donald et al. showed that stem cells could be used as drugs to treat diseases (Appelbaum 2007).
Clinical applications of HSCs rapidly increased with more and more diseases treated with HSCs. From 1970s to 2000s, all HSC transplantations (HSCTs) were indicated for hematologic malignancies. In recent years, HSCTs have also been used in solid tumor treatment (Kotloff et al., 2004;Rodenhuis et al., 2003;Tallman et al., 2003).
Human leukocyte antigen (HLA) matching is an important component for successful HSCT (Lee et al., 2007;Petersdorf et al., 1998;Sasazuki et al., 1998). Therefore, in the initial years of HSCT, almost all cases were performed as autologous transplantation of HSCs. The stem cells were collected from bone marrow, umbilical cord blood or peripheral blood. However, autologous HSCT had some limitations, especially with regard to the quality and quantity of HSCs. More importantly, autologous HSCs have some mutations in their genome which limit their use in treating genetic diseases. To overcome these limitations, allogenic HSCT was suggested as a better platform; the use of selected HSC samples with greater quality and quantity can be controlled. In light of the demand for allogeneic HSCT, stem cell banks have been developed in several countries, such US, Japan, Korea, England and Germany (Armson et al., 2015). With greater characterization of HSCs (including HLA typing), stem cells were able to be commercialized as pharmaceutical products for transplantation in the US, beginning in the 2000s. Ducord and HemaCord are two HSC drugs introduced around 2010 in the US. However, since the HLA matching ratio is very low in the human population (about 1/100,000), the business of HSC drugs has only slowly developed.
From 2012 till now, stem cell drugs have advanced with mesenchymal stem cell (MSC) based products. Similar to HSCs, in the first clinical applications of MSCs, the MSCs were administered as autologous transplantation. Indeed, HLA matching as well as immune rejection are taken into consideration before transplantation. Some allogenic transplantations of MSCs have used immunosuppressive drugs to prevent or reduce the immune rejection of grafted cells in the host. However, increasing studies have confirmed that MSCs exhibit strong immune modulation capacity that can regulate the host's immune system; as well, they exhibit low immunogenicity compared to HSCs and other cells (Ankrum et  This review aims to summarize and discuss the development and growth of stem cell drugs in medicine and pharmacy. Stem cell drug has now become a new and potentially important member of regenerative medicine (Fig. 1). What are stem cell drugs?
A drug is defined as any substance other than food that when inhaled, injected, smoked, consumed, absorbed via a patch on the skin or dissolved under the tongue causes a physiological change in the body. In pharmacology, a drug (or pharmaceutical drug) is a substance used to treat, cure, prevent or diagnose a disease or to promote well-being. According to this definition, a drug must satisfy some criteria, such as having indication to treat any disease and is an offthe-shelf product. Therefore, by definition stem cell drugs are off-the-shelf products based on stem cells that are indicated to treat, cure, prevent or diagnose a disease or to promote well-being.
As off-the-shelf products, stem cell drugs are used in the allogeneic setting in stem cell transplantation. There are key differences between allogenic stem cell transplantation and stem cell drugs. The biggest difference between them is that the stem cell drug is a product, while allogenic stem cell transplantation is a procedure using the stem cell drug. Moreover, the former is approved as a drug and the latter is approved as a medical device. The details of the main differences are listed in Table 1.  Personalized medicine is a medical procedure that separates patients into different groups-with medical decisions, practices, interventions and/or products being tailored to the individual patient based on their predicted response or risk of disease. Stem cells offers a new approach in personalized medicine. Indeed, the definition of "personalized medicine" using stem cells has become a popular term in the last 10 years. To date, there are at least 2 approaches using stem cells in personalized medicine, as presented in Fig. 2.
In this review, we mainly discuss the application of stem cells in stem cell therapeutic transplantation. In stem cell transplantation, autologous stem cells from a patient are used to treat his or her disease. However, the reduction in quality and quantity of stem cells due to aging is a major limitation of this approach. However, after Yamanaka's success with induced pluripotent stem cell production from skin fibroblasts (Takahashi and Yamanaka, 2006), scientists hoped that personalized medicine would lead to greater clinical applications using autologous reprogrammed stem cells (Fig. 3). To date, this approach has faced many limitations and proven to be quite difficult. Even if all the technical difficulties and limitations related to this approach could be solved in the near future, the high price of this procedure would remain a challenge. Indeed, the process of fibroblast isolation, culture and reprogramming for clinical applications is very complex, time-consuming and expensive.
Stem cell drug for universalized medicine has become a new option in stem cell therapy. Stem cell drugs can overcome all the major limitations of autologous stem cells. Particularly, the quality, quantity and price can be controlled. While personalized medicine requires more time for development and is, in some ways, a form of medicine for the "future", universalized medicine is more "real" in that the "off-the-shelf", allogeneic stem cell drugs can be used for many patients.

Stem cell drugs: Drug mechanisms and properties
Stem cell drugs are mainly produced from HSCs and MSCs (Table 3). However, another kind of stem cell (limbal stem cells) can also be used to produce some products for corneal regeneration. The mechanisms of action of these stem cell drugs are different. While HSC based drugs can regenerate the hematopoietic system in treated patients (via homing and differentiation to functional cells), MSC based drugs typically target the immune system and facilitate healing at injured sites by paracrine or endocrine factors.

Hematopoietic stem cell based drugs
HSCs are stem cells that can produce blood cells, including white blood cells, red blood cells and platelets, through the process of hematopoiesis. In adults, HSCs are located in the bone marrow and maintain the blood system in the body. The definition of HSC has evolved since the time HSCs were first discovered in 1961 (Till and Mc, 1961). The hematopoietic tissue contains cells with long-term and short-term regeneration capacities as well as committed multipotent, oligopotent and unipotent progenitors. Nowadays, HSCs are found in and mostly isolated from bone marrow, peripheral blood and umbilical cord blood. The first successful bone marrow derived HSC transplantation was performed in 1950s by E. Donnall Thomas at Fred Hutchinson Cancer Research Center (Washington, USA); his work was later recognized with a Nobel Prize in Physiology or Medicine. Thomas infused bone marrow cells to repopulate the bone marrow and produce new blood cells. Furthermore, the first physician to perform a successful human bone marrow transplant for a disease other than cancer was Robert A. Good at the University of Minnesota in 1968. To date, HSCTs have been evaluated in a variety of malignant and non-malignant diseases ( Table 2).
The roles of HSCs in both malignant and non-malignant diseases were determined by homing and differentiation of HSCs at bone marrow to form a new hematogenesis system. However, HSCs exert strong immunogenicity on the host immune system. Therefore, HLA matching is critical prior to HSCT. The requirement of HLA matching, however, restricts the development and advancement of HSC based stem cell drugs since there is extremely low HLA matching in the human population. Moreover, it is difficult to induce stem cell proliferation in vitro to increase cell quantity. Although umbilical cord blood seems like a good candidate for an unlimited source of HSCs, it too has challenges which limit its application, including the high cost and time for umbilical cord blood cell collection, enrichment and characterization (e.g. HLA typing).   cells has been observed in HSC transplantation and, in some cases, in autologous MSC transplantation. Indeed, in MSC transplantation more than 50% of grafted cells typically die in the recipient from rejection by the immune system and selection in the microenvironment. Autologous transplantation or HLA matching, therefore, are necessary to overcome the kinds of challenges.
Autologous stem cells, however, cannot be produced to mass (industrial) scale and thus stem cell based drugs are highly advantageous. As aforementioned, one important component of stem cell based drugs is the capacity for industrial scale production with similar quality from batch to batch. In most cases, MSCs were used as the source for stem cell based drugs. The two main mechanisms of therapy mediated by stem cell drugs are immune modulation and paracrine/ endocrine effects. Immune modulation is the most common mechanism of commercialized stem cell drugs generated nowadays; about 80% of stem cell drug products act via immune modulation. This means that the host immune system can be regulated by either indirect or direct interactions between stem cells and host immune cells.  Exosomes from stem cells can also affect other systems and organs, such as the cardiovascular system, kidney, liver, nervous system and musculoskeletal system. In the cardiovascular system, exosomes have been suggested as cardioprotective agents (Lai et al., 2010); they have been shown to have proangiogenic effects (Bian et al., 2014) and involvement in reduction of apoptosis and cardiac fibrosis (Feng et al., 2014). Arslan et al. (2013) showed that a single intravenous administration of exosomes was effective in enhancing cardiac function and geometry after myocardial infarction due to bioenergetics re-establishment (increased ATP production), oxidative stress reduction and prosurvival signaling activation (enhanced PI3K/Akt signaling) ( Li et al., 2013). In some diseases of the musculoskeletal system, exosomes can trigger differentiation of MSCs into osteoblasts (Narayanan et al., 2016) and stimulate skeletal muscle regeneration by enhancing myogenesis and angiogenesis (Nakamura et al., 2015). In the nervous system, MSC derived exosomes have been evaluated in the treatment of neurological and neurodegenerative diseases; they have been shown to enhance angiogenesis and neurogenesis, reduce inflammation and improve spatial learning and sensorimotor function (Kim et al., 2016;Zhang et al., 2015).
Taken together, the aforementioned discoveries suggest the dawn of a new era of stem cell therapy, i.e. stem cell drugs. Here, components (mRNA, protein and peptides) from stem cells, in microvesicles or exosomes, can be effective over whole stem cells. Certainly, the advantages of stem cell drugs include reduction of immunogenicity and easy processing, storage and delivery. Stem cells free drugs may play a potentially important and emerging role in regenerative medicine.

Conclusion
Stem cell drugs are new members of pharmaceutical medicines that are produced from stem cells. From 2012 to now, more than ten stem cell drugs have been approved in various countries for clinical applications. These products may contain live hematopoietic stem cells or mesenchymal stem cells. With their advantages such as decreased immunogenicity and ease of processing, stem cell drugs have emerged as a promising new platform in the field stem cell therapy around the world. As a new product of pharmaceutical medicine, it is anticipated that stem cell drugs will significantly contribute to both the pharmaceutical and medical industries in the near future. In clinical applications, besides the stem cell drugs which contain live and whole stem cells, new stem cell drugs containing components from stem cells (such as extracts, exosomes and vesicles) are in development and expected to be launched soon.