Fujifilm Cellular Dynamics, Inc. (FCDI) is a large scale manufacturer of human cells, created from induced pluripotent stem cells, for use in basic research, drug discovery and regenerative medicine applications.
FCDI iCell Neurons with beta-III tubulin (a neuronal marker) stained red and nuclei stained blue with Hoechst
History
Prior to acquisition, the company then named Cellular Dynamics International, Inc. tendered an initial public offering in July 2013 under the ticker symbol ICEL. On March 30, 2015, Fujifilm Holdings Corporation announced an agreement to acquire Cellular Dynamics International for $307 million or $16.50/share on a fully diluted basis.[2] The company was subsequently renamed Fujifilm Cellular Dynamics, Inc.
Human cells are considered to be a more predictive model and a replacement for other cellular models that serve as proxies, including animal cells, immortalized cell lines, and cadaveric cells.[3]
FCDI offers several terminally differentiated cell types as catalog products: iCell® Cardiomyocytes, iCell Neurons, iCell Endothelial Cells, and iCell Hepatocytes. CDI's MyCell® Products portfolio enables customer-provided donor samples to be reprogrammed, gene edited, and differentiated. The company also has several prototype products derived from pluripotent stem cells, including iCell Cardiac Progenitors, iCell Hematopoietic Progenitors, iCell Astrocytes, and iCell Skeletal Myoblasts.
FCDI corporate headquarters are located in Madison, Wisconsin. In 2013, FCDI was awarded a US$16,000,000 contract from the California Institute for Regenerative Medicine to reprogram and bank iPS cells from 3,000 individuals.[4] The CIRM biorepository is managed by FCDI and housed at a sister company, Fujifilm Irvine Scientific, in Irvine, CA.
As of 2013[update], FCDI has more than 800 patents and licensed technologies as part of their technology portfolio.
FCDI was recognized by The Scientist for having among the year's "Top 10 Innovations" in 2010 for the iCell Cardiomyocyte product,[7] and in 2012 for the MyCell Product.[8] The iCell Cardiomyocyte product was also recognized in 2010 by MIT Technology Review as being among the year's "Top 10 Emerging Technologies".[9] In 2011, the same product received Gold Winner status in The Wall Street Journal's "Technology Innovation Award".[10]
Application areas
Toxicity
FCDI began to develop drug compound safety applications early in the company's product development cycle. Several published studies have used FCDI products to investigate mechanisms of toxicity and have leveraged cellular models to identify toxicity earlier in the drug development process. Unexpected toxicity is one of the leading reasons that drugs are pulled from the market or from late stage clinical trials and toxicity issues greatly increase the cost of drug development.[11]
Drug discovery
FCDI cells enable new strategies for disease modeling and drug discovery work. Because FCDI's MyCell Products are created using custom iPS cell reprogramming and differentiation processes, they provide biologically relevant human cells from donors with specific disease-associated genotypes and phenotypes. The company's iCell and MyCell cells are readily adapted to screening platforms and demonstrate functionality using widely accepted readout technologies.[12] FCDI's products are used in high throughput screens,[13] and have been used as supporting data in Investigational New Drug (IND) submissions to the FDA.[14]
Regenerative medicine
Reprogramming technology enables new ways to study disease mechanisms and modeling. Researchers can reprogram diseased cells of interest to study how a particular disease affects those cell types and to discover methods of repairing the cells.[15] FCDI's iCell and MyCell products are being used to research the development of regenerative medicine approaches, including: regenerative medicine compound screening, allogeneic and autologous cell therapy, tissue engineering, and transplantation. Specifically in the area of tissue engineering, FCDI's iCell and MyCell products are being employed across a variety of technologies, such as implantable devices, de-cellularized organ reconstitution and 3D bioprinting.
Stem cell banking
FCDI is actively engaged in a number of large-scale iPS cell reprogramming and banking projects, with the goal of creating broadly available resources of iPS cells that represent normal human diversity, disease states and adverse drug reactions. In 2013, CIRM awarded FCDI a US$16,000,000 grant to derive 3 iPS cell lines from each of 3,000 donors that represent a multitude of disease states.[4] This project follows a $6.3 million grant awarded by the National Heart, Lung, and Blood Institute to FCDI and the Medical College of Wisconsin to investigate the mechanisms underlying left ventricular hypertrophy.[16][17] FCDI's role in this project is to generate iPS cell lines and cardiomyocytes from 250 donors selected from the Hypertension Genetic Epidemiology Network (HyperGEN) GWAS study.
Product areas
Cardiac
The company's first product, iCell Cardiomyocytes, have been used extensively in pharmaceutical research and drug development applications. Other stem cell derived Cardiomyocytes are available commercially from GE Healthcare, Cellectis, Reprocell and others. iCell Cardiomyocytes have been found to display electrical properties similar to those of human cardiomyocytes.[15] iCell Cardiomyocytes have also been used for drug safety testing, toxicology testing, drug screening and Investigational New Drug (IND) filings. iCell Cardiac Progenitor Cells (CPCs) are part of the FCDI Cardiac portfolio; these cells launched in 2014 for use in heart failure research.
Neural
iCell Neurons have been used across several different research areas, including Parkinson's disease, toxicity, autism, Alzheimer's disease, and virology FCDI expanded their neural product portfolio by launching iCell Astrocytes and iCell Dopaminergic Neurons. Other manufacturers of stem cell derived neurons include ArunA Biomedical and ReproCell.
Hepatic
iCell Hepatocytes are used in a variety of ways, including prediction of hepatotoxicity in drug development applications. Adverse and unexpected hepatic side effects are one of the most common reasons for drugs to be removed from the market after launch or in late phase clinical trials[11] iCell Hepatocytes are used as a tool for better predicting hepatic toxicity earlier in the drug discovery process. Other companies that provide hepatocytes include Cellectis and Life Technologies.
Vascular and blood
At least 5 of the top 10 Leading Causes of Death in the United States have a vascular component related to their disease.[18]Endothelial cells (cells that line the interior of blood vessels and allow nutrients to pass back and forth to the body's organs and tissues) play an important role in the study of vascular contributions of many leading causes of death. iCell Endothelial cells were launched as a tool to model vascular biology. Other types of endothelial cells are available from ATCC and Life Technologies. iCell Hematopoietic Progenitor Cells are multipotent progenitor blood cells that can give rise to many different types of blood cells that can then be used for a variety of research purposes, including cell therapy, autoimmune disease, and cancer research.
Donor cells
FCDI offers a family of products called MyCell Products that involve custom reprogramming, genetic engineering and differentiation of a customer's own cell samples. The technology driving MyCell Products enables customers to study their disease of interest or correct a genetic disease phenotype using genome editing technology. Studies have shown that disease cell reprogramming can result in cells that display the particular disease morphology, providing an opportunity to study the disease as never before.[19]
↑ Staff (June 12, 2013). "Human cells mimic Alzheimer". European Biotechnology News. Germany: BIOCOM AG. Archived from the original on December 7, 2014. Retrieved March 20, 2014.
In multicellular organisms, stem cells are undifferentiated or partially differentiated cells that can change into various types of cells and proliferate indefinitely to produce more of the same stem cell. They are the earliest type of cell in a cell lineage. They are found in both embryonic and adult organisms, but they have slightly different properties in each. They are usually distinguished from progenitor cells, which cannot divide indefinitely, and precursor or blast cells, which are usually committed to differentiating into one cell type.
Transdifferentiation, also known as lineage reprogramming, is the process in which one mature somatic cell is transformed into another mature somatic cell without undergoing an intermediate pluripotent state or progenitor cell type. It is a type of metaplasia, which includes all cell fate switches, including the interconversion of stem cells. Current uses of transdifferentiation include disease modeling and drug discovery and in the future may include gene therapy and regenerative medicine. The term 'transdifferentiation' was originally coined by Selman and Kafatos in 1974 to describe a change in cell properties as cuticle producing cells became salt-secreting cells in silk moths undergoing metamorphosis.
Embryonic stem cells (ESCs) are pluripotent stem cells derived from the inner cell mass of a blastocyst, an early-stage pre-implantation embryo. Human embryos reach the blastocyst stage 4–5 days post fertilization, at which time they consist of 50–150 cells. Isolating the inner cell mass (embryoblast) using immunosurgery results in destruction of the blastocyst, a process which raises ethical issues, including whether or not embryos at the pre-implantation stage have the same moral considerations as embryos in the post-implantation stage of development.
James Alexander Thomson is an American developmental biologist best known for deriving the first human embryonic stem cell line in 1998 and for deriving human induced pluripotent stem cells (iPS) in 2007.
Cardiomyoplasty is a surgical procedure in which healthy muscle from another part of the body is wrapped around the heart to provide support for the failing heart. Most often the latissimus dorsi muscle is used for this purpose. A special pacemaker is implanted to make the skeletal muscle contract. If cardiomyoplasty is successful and increased cardiac output is achieved, it usually acts as a bridging therapy, giving time for damaged myocardium to be treated in other ways, such as remodeling by cellular therapies.
Induced pluripotent stem cells are a type of pluripotent stem cell that can be generated directly from a somatic cell. The iPSC technology was pioneered by Shinya Yamanaka and Kazutoshi Takahashi in Kyoto, Japan, who together showed in 2006 that the introduction of four specific genes, collectively known as Yamanaka factors, encoding transcription factors could convert somatic cells into pluripotent stem cells. Shinya Yamanaka was awarded the 2012 Nobel Prize along with Sir John Gurdon "for the discovery that mature cells can be reprogrammed to become pluripotent."
Shinya Yamanaka is a Japanese stem cell researcher and a Nobel Prize laureate. He is a professor and the director emeritus of Center for iPS Cell Research and Application, Kyoto University; as a senior investigator at the UCSF-affiliated Gladstone Institutes in San Francisco, California; and as a professor of anatomy at University of California, San Francisco (UCSF). Yamanaka is also a past president of the International Society for Stem Cell Research (ISSCR).
A mesenchymal–epithelial transition (MET) is a reversible biological process that involves the transition from motile, multipolar or spindle-shaped mesenchymal cells to planar arrays of polarized cells called epithelia. MET is the reverse process of epithelial–mesenchymal transition (EMT) and it has been shown to occur in normal development, induced pluripotent stem cell reprogramming, cancer metastasis and wound healing.
Gladstone Institutes is an independent, non-profit biomedical research organization whose focus is to better understand, prevent, treat and cure cardiovascular, viral and neurological conditions such as heart failure, HIV/AIDS and Alzheimer's disease. Its researchers study these diseases using techniques of basic and translational science. Another focus at Gladstone is building on the development of induced pluripotent stem cell technology by one of its investigators, 2012 Nobel Laureate Shinya Yamanaka, to improve drug discovery, personalized medicine and tissue regeneration.
Cell potency is a cell's ability to differentiate into other cell types. The more cell types a cell can differentiate into, the greater its potency. Potency is also described as the gene activation potential within a cell, which like a continuum, begins with totipotency to designate a cell with the most differentiation potential, pluripotency, multipotency, oligopotency, and finally unipotency.
A list of examples of transdifferentiation:
Induced stem cells (iSC) are stem cells derived from somatic, reproductive, pluripotent or other cell types by deliberate epigenetic reprogramming. They are classified as either totipotent (iTC), pluripotent (iPSC) or progenitor or unipotent – (iUSC) according to their developmental potential and degree of dedifferentiation. Progenitors are obtained by so-called direct reprogramming or directed differentiation and are also called induced somatic stem cells.
A neural, cerebral, or brain organoid, describes an artificially grown, in vitro, tissue resembling the brain. A 2022 consensus agreement is to call these neural organoids. Neural organoids are created by culturing pluripotent stem cells, which spontaneously develop into a three-dimensional culture that can be maintained for months. The brain is an extremely complex system of heterogeneous tissues and consists of a diverse array of neurons. This complexity has made studying the brain and understanding how it works a difficult task in neuroscience, especially when it comes to neurodevelopmental and neurodegenerative diseases. The purpose of creating an in vitro neurological model is to study these diseases in a more simple and less variable space. This 3D model is free of many potential in vivo limitations. The varying physiology between human and other mammalian models limits the scope of study in neurological disorders. Neural organoids are synthesized tissues that contain several types of nerve cells and have anatomical features that recapitulate regions of the nervous system. Cerebral organoids are most similar to layers of neurons called the cortex and choroid plexus. With the addition of guidance cues, other regionalized neural organoids resemble structures similar to the retina, meninges, spinal cord and hippocampus. Stem cells have the potential to grow into many different types of tissues, and their fate is dependent on many factors. Below is an image showing some of the chemical factors that can lead stem cells to differentiate into various neural tissues; a more in-depth table of generating specific organoid identity has been published since. Similar techniques are used on stem cells used to grow cerebral organoids.
A Muse cell is an endogenous non-cancerous pluripotent stem cell. They reside in the connective tissue of nearly every organ including the umbilical cord, bone marrow and peripheral blood. They are collectable from commercially obtainable mesenchymal cells such as human fibroblasts, bone marrow-mesenchymal stem cells and adipose-derived stem cells. Muse cells are able to generate cells representative of all three germ layers from a single cell both spontaneously and under cytokine induction. Expression of pluripotency genes and triploblastic differentiation are self-renewable over generations. Muse cells do not undergo teratoma formation when transplanted into a host environment in vivo. This can be explained in part by their intrinsically low telomerase activity, eradicating the risk of tumorigenesis through unbridled cell proliferation. They were discovered in 2010 by Mari Dezawa and her research group. Clinical trials for acute myocardial infarction, stroke, epidermolysis bullosa, spinal cord injury, amyotrophic lateral sclerosis, acute respiratory distress syndrome (ARDS) related to novel coronavirus (SARS-CoV-2) infection, are conducted by Life Science Institute, Inc., a group company of Mitsubishi Chemical Holdings company. In february 2023, however, Mitsubishi Chemical Group decided to discontinue the development of a regenerative medicine product (CL2020) using Muse Cells. Physician-led clinical trial for neonatal hypoxic-ischemic encephalopathy was also started. The summary results of a randomized double-blind placebo-controlled clinical trial in patients with stroke was announced.
Gordon M. Keller is a Canadian scientist recognized for his research on applying developmental biology findings to in vitro pluripotent stem cell differentiation. He is currently a Senior Scientist at the Ontario Cancer Institute, a Professor at the University of Toronto and the director of the McEwen Centre for Regenerative Medicine.
Directed differentiation is a bioengineering methodology at the interface of stem cell biology, developmental biology and tissue engineering. It is essentially harnessing the potential of stem cells by constraining their differentiation in vitro toward a specific cell type or tissue of interest. Stem cells are by definition pluripotent, able to differentiate into several cell types such as neurons, cardiomyocytes, hepatocytes, etc. Efficient directed differentiation requires a detailed understanding of the lineage and cell fate decision, often provided by developmental biology.
Regeneration in humans is the regrowth of lost tissues or organs in response to injury. This is in contrast to wound healing, or partial regeneration, which involves closing up the injury site with some gradation of scar tissue. Some tissues such as skin, the vas deferens, and large organs including the liver can regrow quite readily, while others have been thought to have little or no capacity for regeneration following an injury.
Jeffrey D. Macklis is an American neuroscientist. He is the Max and Anne Wien Professor of Life Sciences in the Department of Stem Cell and Regenerative Biology and Center for Brain Science at Harvard University, Professor of Neurology [Neuroscience] at Harvard Medical School, and on the Executive Committee and a Member of the Principal Faculty of the Neuroscience / Nervous System Diseases Program at the Harvard Stem Cell Institute.
Kristin K. Baldwin is an American scientist who is a professor at the Department of Genetics and Development at Columbia University. Her research focuses on using reprogrammed and induced pluripotent stem cells to identify mechanisms and therapies related to human genetic risk for neurologic and cardiovascular disease. Her lab also studies how disease and aging affect the genome; they have used cloning to produce the first complete genome sequence of a single neuron and helped assess the effect of aging on induced pluripotent stem cells that may be used for cell therapies. They also design bespoke neuronal cells in a dish to understand brain function and disease. Baldwin's earlier work included being the first to clone a mouse from a neuron and being one of three groups to first produce an entire mouse from a skin cell by generating induced pluripotent stem cells. epigenetic changes of the genome and the brain.
Experimental models of Alzheimer's disease are organism or cellular models used in research to investigate biological questions about Alzheimer's disease as well as develop and test novel therapeutic treatments. Alzheimer's disease is a progressive neurodegenerative disorder associated with aging, which occurs both sporadically or due to familial passed mutations in genes associated with Alzheimer's pathology. Common symptoms associated with Alzheimer's disease include: memory loss, confusion, and mood changes.
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