The use of stem cells for drug discovery and organ repair

Numerous currently incurable human diseases arise from the loss or malfunction of highly specialized cell types that lack the capacity to regenerate due to diseases (e.g. heart attack, stroke), traumas (e.g. spinal cord injuries by accidents) or aging (e.g. blindness due to age-related macular degeneration, glaucoma). Recent advances in stem cell technologies have made regenerative medicine, once seen only in science fiction, a reachable reality. In this newsletter focusing on ‘Stem Cells’, we have solicited four articles to introduce some fundamental concepts of stem cells and review some of their immediate applications for disease modeling, drug discovery and toxicity screening as well as future possible therapies.

Stem cells, a collective term, are generally categorized according to their function, origin, and presence of specific protein markers. Pluripotent stem cells (PSC) have the ability to divide indefinitely (self-renew) while maintaining the unique potential to become all cell types of the body (pluripotency) including even such non-regenerative lineages such as heart and brain cells. There are two major PSC sub-classes: embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). Despite the promises of human (h) ESCs to provide an unlimited supply of even the rarest non-regenerative human cell types for regenerative therapies, the need of destructing human blastocysts (early embryos) during their isolation [1] also sparked significant ethical and political debates. Bioethical concerns diminished when Shinya Yamanaka reported in 2006 his landmark technique of direct reprogramming of adult somatic (skin) cells to become hESC-like induced pluripotent stem cells (iPSCs) via forced expression of select pluripotency genes [2]. Although a number of technical concerns such as induced somatic coding mutations and immunogenicity have yet to be fully addressed, hiPSCs largely resemble hESCs in terms of their self-renewal and pluripotency, and can therefore serve as a potential unlimited ex vivo source of human derivatives. By contrast, adult stem cells (ASCs; e.g. cardiac resident stem cells, neural stem cells) are endogenously found in the organs where they reside. While they are autologous and immunocompatible (if the donor is also the recipient), ASCs are often limited in their proliferative ability and can become only the cell type(s) of the organ where they come from. As such, ASCs are generally considered less versatile than PSCs.

In the review article by Marco Zarbin [3], the author reviews specific promises and hurdles faced in the development of hESC/iPSC-based therapies for treating age-related macular degeneration and other retinal degenerative diseases associated with abnormalities in the retinal pigment epithelium (RPE) and/or photoreceptors. Some of the issues discussed such as immunogenicity, phenotype stability, tumor formation, functional integration, cytokine effect, microenvironment and niche, among others, are indeed common considerations that also apply for other organ systems. As an alternative to the cell-based approach for sight restoration by transplanting limbal epithelial progenitor into the damaged retina for corneal reconstruction, Wright et al. discusses the use of biomaterial substrates in the treatment of corneal blindness caused by limbal stem cell deficiency, a prevailing disorder worldwide [4]. Conventional amniotic membrane and various hydrogels such as fibrin, collagen, silicone, alginate, gelatin, chitosan and other emerging forms are discussed and compared. Collectively, PSC and new biomaterials offer novel viable options to numerous traditionally incurable conditions.
The primary function of the heart is to mechanically pump blood, with regular rhythms governed by tightly coordinated electrical events. Bu and colleagues provide a summary of how iPSCs/hESCs and their differentiation into cardiac progenitor cells (CPCs) have contributed to our understanding of normal and pathophysiological human heart development by examining the signals that maintain, expand and regulate CPC migration and differentiation [5]. Therapeutic insights are also discussed in relation to hostile transplantation microenvironments, paracrine factors, extracellular matrix support, among others. Taken collectively, the two eye articles and the CPC review underscore critical considerations for clinical translations that are common even in two vastly different organ systems.
The most well-established stem cell therapy, bone marrow transplantation of hematopoietic stem cells, has been in clinical practice for over 40 years [3]. While there is every reason to optimistically believe that PSC-based therapies such as those mentioned above will become available, the process is likely to be lengthy due to complex regulatory and other non-scientific considerations. In the article by Lilian Hook [6], the author reviews the potential of using stem cells to revolutionize drug discovery and toxicity screening which could potentially immediately benefit the community. State-of-the-art high-throughput platforms such as robotic screening, combinatorial approaches, microarray and microfluidic systems are described.
In summary, we live in a revolutionary new era of stem cell and regenerative medicine. Scientists are now in an excellent position to think what were previously considered unthinkable. Interested readers are strongly encouraged to look into additional sources for stem cell-related topics (e.g. another thematic issue from Drug Discovery Today: Disease Models provides an additional collection of 11 articles that review various latest developments for the use of hESC/iPSC for modeling various heart, neural and blood diseases as well as the associated considerations [5, 7–17]). Not only will human stem cell research lead to a better understanding of our own species but a successful translation of basic discoveries will also be beneficial to the well-being of our rapidly aging populations. It is with great optimism that as a result of these endeavors, novel therapies for currently incurable conditions will become available for our and future generations.
Dr Ronald Li received his B.S. in Biochemistry/Biotechnology, on the Dean’s Honor list, and PhD in Cardiology/Physiology, from the University of Waterloo and University of Toronto in Canada in 1994 and 1999, respectively. Subsequently, he joined the Johns Hopkins University (JHU) School of Medicine to undertake a post-doctoral fellowship in Cardiac Electrophysiology. In 2002, he was promoted to Assistant Professor of Medicine at JHU. During his tenure at JHU, he was the two-time recipient of the Top Junior Faculty Research Award from JHU Dept of Medicine (2002 & 2004), and has also received such honors as the Young Investigator Award from the Heart Rhythm Society (2002), Career Development Award from the Cardiac Arrhythmias Research & Education Foundation (2001), Top Prize for Young Investigator Basic Research from JHU School of Medicine (2001), etc. In light of California’s Proposition 71 for stem cell research, he was recruited in 2005 to the University of California, Davis where he led the Human Embryonic Stem Cell Consortium as a tenured Associate Professor with cross appointments in Biomedical Engineering, Biophysics, Genetics, Physiology and Cell Biology.
Dr Ronald Li has cross appointments at the University of Hong Kong (HKU) and the Mount Sinai School of Medicine (MSSM). As S.Y. and H.Y. Cheng Professor in Stem Cell Biology & Regenerative Medicine, Dr. Li runs the Stem Cell & Regenerative Medicine Consortium at HKU. Concurrently, he co-directs with Dr. Kevin Costa the Section of Cardiovascular Cell and Tissue Engineering at the Cardiovascular Research Center of MSSM. Dr. Li’s research focuses on electrophysiology and construction of ‘custom-tailored’ human heart cells. Their work on cardiac differentiation has been recognized by the American Heart Association as Best Basic Study of 2005, Ground-Breaking Study of 2006, and Late-breaking studies of 2003, 2004 and 2007. His lab receives funding from the National Institute of Health, California Institute of Regenerative Medicine, American Heart Association, Research Grant Council, etc. Dr Li has served as a panel member or reviewer for a number of funding agencies, including the National Institutes of Health, American Heart Association, Association Francaise contre les Myopathies, United States-Israel Binational Science Foundation, Research Grant Council of Hong Kong, Stem Cell Consortium, A*STAR/Biopolis of Singapore, Wellcome Trust and MRC of the United Kingdom, etc.
1.             Thomson et al. (1998) Embryonic stem cell lines derived from human blastocysts. Science 282, 1145–1147
2.             Takahashi K, Yamanaka S. (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663–676
3.             Zarbin, M. (2012) The promise of stem cells for age-related macular degeneration and other retinal degenerative diseases. Drug Discovery Today: Therapeutic Strategies. (
4.             Wright, B. et al.(2012) Towards the use of hydrogels in the treatment of limbal stem cell deficiency. Drug Discov. Today
5.             Lui, KO et al. Human pluripotent stem cell-derived cardiovascular progenitors for heart regeneration. Drug Discov. Today: Disease Models
6.             Hook, L. (2012) Stem cell technology for drug discovery and development. Drug Discov. Today 17, 336
7.             Li, R.A. (2012) The use of induced pluripotent stem cells for disease modeling: What are the promises and hurdles? Drug Discov. Today: Disease Models
·         8.             Chow, HCH et al.(2012) The use of human induced pluripotent stem cells (hipsc) for modelling blood disorders. Drug Discov. Today: Disease Models
·         9.             Hinson, JT, Nakamura K, Wu SM. (2012) Induced pluripotent stem cell modeling of complex genetic diseases. Drug Discov. Today: Disease Models
·         10.           Huang, C, Wu, JC. (2012) Epigenetic modulations of induced pluripotent stem cells: Novel therapies and disease models. Drug Discov. Today: Disease Models
11.           Juopperi TA, Song H, Ming G. Using human induced pluripotent stem cells for modelling schizophrenia, a psychiatric disorder. Nature 473, 221–225
·         12.           Lieu, KD et al. Engineered human pluripotent stem cell-derived cardiac cells and tissues for electrophysiological studies.Drug Discov. Today: Disease Models DOI:
·         13. Lui, KO et al. (2012). Induced pluripotent stem cells as a disease model for studying inherited arrhythmias: Promises and hurdles. Drug Discov. Today: Disease Models
·         14.           Muller, GA et al.(2012) Human esc/ipsc-based ‘omics’ and bioinformatics for translational research. Drug Discov. Today: Disease Models
15.           Stillitano, F. et al. (2012) Preclinical animal models for testing ipsc/esc-based heart therapy.
16.           Tso, GH et al.  Engineering the immune system for hesc- and ipsc-derived grafts.
17.           Turnbull, IC et al. (2012) Cardiac tissue engineering using human stem cell-derived cardiomyocytes for disease modeling and drug discovery. Drug Discov. Today: Disease Models

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