iPSCs and other stem cells
The enthusiasm of using autologous induced pluripotent stem cells (iPSCs) for cell replacement therapy was dampened by a publication 2 years ago in Nature (Zhao et al, 2011), which suggested that even syngeneic (genetically identical) iPSCs could still invoke strong immune rejection because, as the authors in Yang Xu’s lab at UCSD explained, the iPSCs overexpress a number of tumor antigens possibly linked to genomic mistakes acquired during reprogramming. Embryonic stem cells (ESCs), on the other hand, did not show similar rejection problems in the same studies, indicating that the immune responses were due to somatic reprogramming.
If proven true, the iPSC-specific immune rejection would have been the biggest hurdle for any iPSC-inspired clinical plans. Naturally, a number of labs performed series of experiments that were aimed at addressing the concerns raised by Zhao et al. This month in Cell Stem Cell, researchers from Ashleigh Boyd’s lab at Boston University demonstrated that autologous (self) or syngeneic iPSCs or their derivatives were not rejected (Guha et al. 2013). These iPSCs behaved essentially the same as ESCs in transplantation settings. When immunogenicity was measured in vitro by monitoring T cell responses in co-culture, no immune response was observed either. In contrast, cells and tissues from allogeneic (genetically different) iPSCs were rejected immediately.
In light of this new publication and an earlier Nature paper (Araki et al. 2013), Kaneko and Yamanaka have commented that autologous iPSCs still seem to have a very good chance of being used in cell replacement therapy, pending, of course, additional research and trial results. In their Preview article in Cell Stem Cell (Kaneko and Yamanaka 2013) two points were particularly emphasized: 1) autologous iPSCs are preferred because of the lack of immune rejection; 2) iPSCs generated with footprint-free reprogramming technologies are preferred because the problems reported by Zhao et al 2011 might be correlated with the use of retroviral vectors (even though they also used episomal plasmid-reprogrammed iPSCs). We strongly support both of these points and believe that they point out the direction of future stem cell therapies.
However, we do not agree with the last statement by Kaneko and Yamanaka in that article stating that as a result of the cost and time required to generate iPSC lines from each patient in GMP facilities, iPSC lines from HLA homologous donors will be the choice going forward to clinical applications. First of all, HLA-matched iPSCs should be closer to allogeneic than to autologous iPSCs. From what we just learned in the last round of debates, the field should certainly go with autologous. Second, generating foot-print free iPSCs may already not be the rate-limiting step, even in GMP protocols, compared to downstream differentiations that are required using any pluripotent stem cells. We have shown that human fibroblasts can be reprogrammed in a completely feeder-free, xeno-free, passage-free process, using only mRNAs, in just over a week, achieving sometimes “bulk conversion”—converting nearly all cells within a well into iPSCs (Warren et al. 2012). We have drawn up a plan to establish cGMP protocols and to quickly apply autologous, footprint-free iPSCs to clinical programs through partnerships. The field can move at a faster speed, with all due scientific vigor and caution, if the best technology available is chosen for building the foundation.
Zhao, T., Z.N. Zhang, Z. Rong, and Y. Xu, Immunogenicity of induced pluripotent stem cells. Nature, 2011. 474(7350): p. 212-5.
Guha, P., et al., Lack of immune response to differentiated cells derived from syngeneic induced pluripotent stem cells. Cell Stem Cell, 2013. 12(4): p. 407-1
Kaneko, S. and S. Yamanaka, To Be Immunogenic, or Not to Be: That’s the iPSC Question. Cell Stem Cell, 2013. 12(4): p. 385-6.
Araki, R., et al., Negligible immunogenicity of terminally differentiated cells derived from induced pluripotent or embryonic stem cells. Nature, 2013. 494(7435): p. 100-4.
Warren, L., Y. Ni, J. Wang, and X. Guo, Feeder-free derivation of human induced pluripotent stem cells with messenger RNA. Sci Rep, 2012. 2: p. 657.
Allele Biotechnology Initiates Project On Scaled Manufacturing Of Induced Pluripotent Stem Cells And Differentiation With Chinese Academics
Allele Biotechnology has signed an agreement with Jinan University to develop culturing systems of stem cells and differentiation methods for producing skin tissue cells for wound treatment and stem cell therapy.
San Diego, California (I-Newswire) January 16, 2013 – Allele Biotechnology and Pharmaceuticals, Inc., a San Diego based company with a focus on new technology development, announced today that it has signed an agreement with the Biomedical Institute of Jinan University through a focus group to develop culturing systems of stem cells and differentiation methods for producing skin tissue cells for wound treatment. The joint team will also evaluate using stem cell therapy as potential treatment for arthritis, Lupus, and other autoimmune-related diseases.
Scientists from Allele Biotechnology recently described an important advance in the generation of stem cells capable of producing all the different tissues of the human body. Using messenger RNA molecules and without the need of viral vectors, animal products or feeder cells, this new method can be used to reprogram human fibroblasts into induced pluripotent stem cells (iPSCs). The efficiency is significantly improved over previously reported reprogramming results and the time required to complete reprogramming is slashed in half under optimal conditions.
The Biomedical Institute at Jinan University, a leading comprehensive research university in South China, has focused on translational research in the areas of epidemic diseases and autoimmune diseases. It has broad collaboration with partners and close connections to the biotech industry in China. It was known to have launched (licensed) a number of new biologics in China, and contributed to the understanding and diagnostics of the SARS epidemic in 2003. The institute has also been entitled as the national engineering research center of biopharmaceutics since 2005.
This collaboration will last for at least 2 years, and will go beyond the R&D stage with selected candidates moving into clinical trials, first in China, then in other countries. If the project reaches clinical trials it will be funded jointly by industry and academic partners in the range of $10 million USD.
American CryoStem Corporation (OTCQB:CRYO), announced the launch of its newest adult stem cell and adipose tissue collection center in Bellevue, Washington
A public company doing business of preparing and providing adipose (fat) tissue and adipose derived adult stem cells, American CryoStem Corporation (OTCQB:CRYO), announced the launch of its newest adult stem cell and adipose tissue collection center in Bellevue, Washington. Dr. Fredric Stern will officially launch the new Stern Center Stem Cell Collection Service as the first to provide Adult Stem Cell and Tissue Banking services to the general public in the Seattle, Washington area.
“Having successfully worked with American CryoStem in the past we are truly excited about the official launch of these adipose tissue based services to the general public in Washington. I look forward to working with American CryoStem on educating my patients about the Regenerative Medicine benefits of “bio-banking” and the latest fat transfer cosmetic services now available at the center. I chose to affiliate my practice with American Cryostem because of their thorough scientific approach to stem cell banking and strict adherence to aseptic technique and FDA guidelines,” said Dr. Fredric Stern, the founder of The Stern Center and a plastic surgeon.
John S. Arnone, CEO said, according to a company news release, “We are excited to have a surgeon with Dr. Stern’s abilities and reputation associated with American CryoStem in the Seattle, WA area and look forward to a productive relationship with the entire Stern Center team. We remain committed to our “Gold Standard” clinical laboratory processing and storage reputation and strive to provide the best physician and patient services in the U.S. The newest stem cell collection center in our network represents our commitment to associate with leading physicians in the Regenerative Medicine Industry.”
Mesenchymal stem cells (MSCs) are typically the products of adipose tissue-isolated stem cells for regenerative medicine or, in this case cosmetic surgeries. The mesenchymal stem cells can also be isolated from bone marrow or embryos. They secret hormones once introduced into human bodies and help balance cytokines in the blood. It is reported that MSCs help reduce several disease symptoms and, in some countries, are used as “youth fountains” in anti-aging treatment. MSCs can be produced fairly easily, in our hands at least, from induced pluripotent stem cells (iPSCs). iPSCs, like embryonic stem cells, can be expanded indefinitely, differentiated into MSCs and all other cell types, and are being tested in various cell therapies including those that are mediated through the MSC stage.
Geron, spinal cord injury
ViaCyte, diabetes, US$10.1 million from CIRM
Blubird Bio, beta-thalassemia, US$9.3 million from CIRM
StemCells, Alzheimer’s US$20 million from CIRM; spinal cord injury US$20 million from CIRM, stocks rise 148% this year.
Osiris, graft-vs.-host disease (GvHD) in children, approved by Canadian regulator Health Canada
Pluristem Therapeutics, aplastic bone marrow, IPO $30 million, shares up 44%.
Cardio3 BioSciences therapy, heart failure, Phase III in Belgium permitted.
TiGenix, cartilage repair in the knee, commercial production; autoimmune, Crohn’s disease Phase III; quarterly revenue up 152% as reported in Oct, 2012.
Advanced Cell Technology, degenerative eye condition, advancing clinical trials in the US and EU.
New Products to be released at next month’s ASCB annual conference in San Francisco: human mRNA-iPS cells, iPSCs with fluorescent markers, neural pregenitors derived from mRNA-iPSCs.
Monday Sir John B. Gurdon and Shinya Yamanaka shared this year’s Nobel Prize for physiology or medicine for work that revolutionized the understanding of how cells and organisms develop.
“By reprogramming human cells, scientists have created new opportunities to study diseases and develop methods for diagnosis and therapy.”
This is the 3rd time that a Nobel Prize is awarded on a technology that we chose as our area of research and made contributions to the field. The other two are RNA interference (2005) and fluorescent proteins (2008).
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