Shining a Spotlight on Stem Cells and Regenerative Medicine Research
Stem cell and regenerative medicine is a high-impact research field, that has grown exponentially over the last two decades. Researchers work predominantly in academia, but also in the Pharma Industry and biotechnology sectors; focusing on a range of areas that include studying human development pathways, understanding disease mechanisms, drug development, and clinical validation of stem cell therapies.
Stem cells form the foundations of development in living organisms. They are so defined as they can self-renew and differentiate. These attributes confer unique properties for research and clinical applications. Embryonic stem cells (ESC’s) are stem cells derived from the undifferentiated inner mass cells of an embryo. These cells are pluripotent, meaning they can differentiate into all 200+ cell lineages of the adult body if they are specified to do so. In addition to their pluripotency, ESC’s are also able to replicate indefinitely under defined conditions.
Developments in the last decade have allowed the derivation of pluripotent cells without the use of cells taken from an embryo. Use of ESC’s for research is subject to strict regulation in most countries, to ensure ethical use. In 2006, Shinya Yamanaka and his colleagues at Kyoto University made the remarkable discovery that mature adult cells could be reprogrammed to become pluripotent like ESC’s, with the addition of defined transcription factors[1]. The research used mature mouse fibroblasts that were transformed into, what are now known as induced pluripotent stem cells, or iPSC’s for short. The work was replicated in human cells and several labs worldwide have established protocols to differentiate iPSC’s into many different cell lineages, with the addition of small molecules and other factors. Yamanaka received a Nobel prize in 2012 for his discovery[2]. iPSC’s have since been used extensively as research tools for scientists, due to their ESC-like properties, enabling further progress in the stem cell field.
Adult stem cells have been found to exist in several tissues and organs, including the brain, bone marrow, gut, liver, and skin, to name a few. Examples include hematopoietic stem cells (HSC’s) in bone marrow, neural stem cells in the brain, and epidermal stem cells in the skin. These cells are thought to reside in a specific area of each tissue, called a stem cell niche. They normally differentiate into a cell lineage found in the organ where they are located. However, there has been some research findings that show they are able to transform into other cell lineages, a process known as transdifferentiation.
In this article, we’ll look at some of the leading research areas that investigators are working in worldwide, in stem cells and regenerative medicine labs.
Examples of stem cell research focus areas
- iPSC’s and disease modeling
Several global research groups are now working with iPSC’s to enable their research, as they provide an unlimited supply of pluripotent cells. One application is to use patient cells to create iPSC’s that can then be used to understand underlying disease mechanisms and drug treatments.An example of research groups that have taken the latter approach is Kevin Eggan’s Lab at Massachusetts Institute of Technology (MIT), Boston, and also Justin Ichida’s Lab in University of South California (USC). They use iPSC’s combined with differentiation to provide a model of Motor Neurone Disease (MND), known as Amyotrophic Lateral Sclerosis (ALS) in the US. Skin cells from patients with MND are used to create iPSC’s and then differentiated into motor neurons - the cells that degenerate and are adversely affected by the disease. These can be examined and compared to cells from normal patients to investigate disease mechanisms. Drug treatments can also be screened for effectiveness against these cultured cells.
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- Stem cell differentiation pathways
The elucidation of how normal developmental pathways are regulated is crucial to progress in the stem cell field. This also allows parallel work on how their disruption contributes to disease. An example of a research group using these approaches is George Daley’s Laboratory, at Harvard Medical School. One area that the Daley Lab are focusing on is the molecular and genetic basis of how ESC’s and pluripotent cells differentiate into HSC’s. The latter cells give rise to blood cells of the myeloid and lymphoid lineages. This research has applications in the modeling of hematopoietic disease, malignant and genetic blood disorders.There are many researchers worldwide researching adult stem cells. Areas of interest include how they remain in an undifferentiated state until adulthood and factors that control their proliferation and differentiation. Two groups currently concentrating on the field of adult stem cells in the skin are Professor Fiona M. Watts laboratory, Kings College London and Professor Elaine Fuchs' group at the Rockefeller University. Current projects in the Watts laboratory center on self-renewal and lineage selection of epidermal stem cells. Professor Fuchs’ work covers how skin stem cells generate and repair tissues, and how this process changes in aging and cancer.
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- Stem cell transplantation clinical therapies
There are many unapproved clinics offering stem cell therapies, that have no scientifically confirmed benefit to patients. At present, there are only a handful of transplantation therapies that have been clinically proven to work and are approved by global regulatory bodies, like the Food and Drug Administration (FDA) in the US.One such therapy includes the intravenous transplantation of hematopoietic progenitor stem cells for use in patients who have diminished blood production, for example in multiple myeloma. These stem cells generate red blood cells, white blood cells and platelets in the bone marrow to help restore blood counts. The patient’s own stem cells can be used, or alternatively, stem cells sourced from umbilical cord blood are also used. Brand names for the latter therapy include Allocord, Hemocord, and Duocord. The procedure is not without complications though, and patients need constant monitoring for potential adverse reactions. These include a risk of infection and graft versus host rejection.
There are some other limited uses for tissue transplantation in the skin, and stem cell therapies are still being tested for approved use in macular degeneration with extremely mixed results to date. In 2014, Masayo Takahashi’s group at the RIKEN Centre for Developmental Biology in Kobe, Japan started the first human trial of an iPSC-based therapy for retinal disease. Retinal pigment epithelium cells were produced from iPSC’s for transplantation. The first trial was promising, with Takahashi’s group reporting a halt to the macular degeneration and brightened vision. However, further tests showed some genetic changes in the cells transplanted. The trial was halted as a caution. Recent work in 2017, at the same lab in RIKEN by Dr. Michiko Mandai showed promise for tolerance of transplantation in one patient, however, the authors urged caution due to the small sample size.
Further small-scale preliminary trials have been carried since, looking at the use human embryonic stem cells, rather than iPSC derived therapies, for age-related macular degeneration and macular dystrophy. These have been run to evaluate tolerance and safety in the first instance, rather than therapeutic effect. Examples of academic research groups that have been involved in this area to date include those led by Professor Pete Coffey at UCL in London and Professor Banin Eyal at Hadassah Medical Centre in Jerusalem.
All the trials up to now have had disparate results, some showing vision stabilization others, including a recent trial in Florida, showing deleterious effects. Of those that showed promise, there is still a need for them to be repeated for clear therapeutic potential and clinically validated.
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Summary
The field of stem cell research and regenerative medicine has grown rapidly over the last few decades[3], offering new and diverse career opportunities to researchers. Due to the relatively high impact of research - there has been ongoing investment in governmental funding, markedly in the Japan, USA, UK, Singapore, and Israel, who are also leading the way for publication rates in the field[4]. The discovery of iPSC’s has contributed heavily to new research, specifically relating to disease mechanisms and drug discovery[4]. Whilst covering all the research areas is beyond the scope of this article, applications in the field hold a great deal of potential for elucidating the pathophysiological mechanisms of disease and their treatments.
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