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Developmental Biology - CRISPR

CRISPR Makes Stem Cells 'Invisible'

A new technique prevents transplant rejection in the lab, a major advance for stem cell therapies...


University of California San Francisco (UCSF) scientists are using the CRISPR-Cas9 gene-editing system to make the first functionally "invisible," to the immune system, pluripotent stem cells. This is a feat of biological engineering that, in laboratory studies, prevents rejection of stem cell transplants. "Universal stem cells" can be manufactured more efficiently than stem cells tailor-made for each patient. The "individualized approach" dominated earlier efforts in stem cell transplants. However, "universal stem cells" bring the promise of regenerative medicine a step closer to reality.
Scientists often tout the therapeutic potential of pluripotent stem cells, which can mature into any adult tissue, but the immune system has been a major impediment to safe and effective stem cell therapies."

Tobias Deuse MD, the Julien I.E. Hoffman MD, Endowed Chair in Cardiac Surgery at UCSF and lead author of the new study.

The work is published in the journal Nature Biotechnology. Our immune system is unforgiving. It's programmed to eradicate anything it perceives as alien, to protect the body against infectious agents and other invaders that could wreak havoc if given free rein. But this also means that transplanted organs, tissues or cells are seen as a potentially dangerous foreign incursion, invariably provokin a vigorous immune response leading to transplant rejection. When this occurs, donor and recipient are said to be "histocompatibility mismatched."
"We can administer drugs that suppress immune activity and make rejection less likely. Unfortunately, these immunosuppressants leave patients more susceptible to infection and cancer."

Sonja Schrepfer MD, PhD and professor of surgery, the study's senior author and director of the UCSF Transplant and Stem Cell Immunobiology (TSI) Lab at the time of the study.

In the realm of stem cell transplants, scientists once thought the rejection problem was solved by induced pluripotent stem cells (iPSCs), which are created from fully-mature cells - like skin or fat cells - reprogrammed in ways that allow them to develop into any of the myriad cells that comprise the body's tissues and organs. If cells derived from iPSCs were transplanted into the same patient who donated the original cells, the thinking went, the body would see the transplanted cells as "self" and would not mount an immune attack. But in practice, clinical use of iPSCs has proven difficult. For reasons not fully understood, many patients' cells prove unreceptive to reprogramming. It is also expensive and time-consuming to produce iPSCs for each patient who might benefit from stem cell therapy. "There are many issues with iPSC technology, but the biggest hurdles are quality control and reproducibility. We don't know what makes some cells amenable to reprogramming, but most scientists agree it can't yet be reliably done. Most approaches to individualized iPSC therapies have been abandoned because of this."

Deuse and Schrepfer wondered whether it might be possible to sidestep these challenges by creating "universal" iPSCs that could be used in any patient who needed them. In their paper, they describe how after just three genes were altered, iPSCs were able to avoid rejection after being transplanted into histocompatibility-mismatched recipients with fully functional immune systems. "This is the first time anyone has engineered cells that can be universally transplanted and can survive in immunocompetent recipients without eliciting an immune response," Deuse added.

Researchers first used CRISPR to delete two genes essential for the proper functioning of a family of proteins known as major histocompatibility complex (MHC) class I and II. MHC proteins sit on the surface of almost all cells and display molecular signals that help the immune system distinguish a cell as either an interloper or a native. Cells that are missing MHC genes don't present these signals, so they don't register as foreign. However, cells that are missing MHC proteins become targets of immune cells known as natural killer (NK) cells.
Working with Professor Lewis Lanier PhD, study co-author and chair of UCSF's Department of Microbiology and Immunology, an expert in the signals that activate and inhibit NK cell activity - Schrepfer's team found that CD47, a cell surface protein that acts as a "do not eat me" signal against immune cells called macrophages, also has a strong inhibitory effect on NK cells.

Believing that CD47 might hold the key to completely shutting down rejection, researchers loaded the CD47 gene into a virus, which delivered extra copies of the gene into mouse and human stem cells in which the MHC proteins had been knocked out.

CD47 indeed proved to be the missing piece of the puzzle.

When researchers transplanted their triple-engineered mouse stem cells into mismatched mice with normal immune systems, they observed no rejection. They then transplanted similarly engineered human stem cells into so-called humanized mice — mice whose immune systems have been replaced with components of the human immune system to mimic human immunity — and once again observed no rejection.

Additionally, the researchers derived various types of human heart cells from these triple-engineered stem cells, which they again transplanted into humanized mice. The stem cell-derived cardiac cells were able to achieve long-term survival and even began forming rudimentary blood vessels and heart muscle, raising the possibility that triple-engineered stem cells may one day be used to repair failing hearts.
"Our technique solves the problem of rejection of stem cells and stem cell-derived tissues, and represents a major advance for the stem cell therapy field. Our technique can benefit a wider range of people with production costs that are far lower than any individualized approach. We only need to manufacture our cells one time and we're left with a product that can be applied universally."

Tobias Deuse PhD, Department of Surgery, Division of Cardiothoracic Surgery, Transplant and Stem Cell Immunobiology-Lab, University of California San Francisco, San Francisco, CA, USA

Abstract
Autologous induced pluripotent stem cells (iPSCs) constitute an unlimited cell source for patient-specific cell-based organ repair strategies. However, their generation and subsequent differentiation into specific cells or tissues entail cell line-specific manufacturing challenges and form a lengthy process that precludes acute treatment modalities. These shortcomings could be overcome by using prefabricated allogeneic cell or tissue products, but the vigorous immune response against histo-incompatible cells has prevented the successful implementation of this approach. Here we show that both mouse and human iPSCs lose their immunogenicity when major histocompatibility complex (MHC) class I and II genes are inactivated and CD47 is over-expressed. These hypoimmunogenic iPSCs retain their pluripotent stem cell potential and differentiation capacity. Endothelial cells, smooth muscle cells, and cardiomyocytes derived from hypoimmunogenic mouse or human iPSCs reliably evade immune rejection in fully MHC-mismatched allogeneic recipients and survive long-term without the use of immunosuppression. These findings suggest that hypoimmunogenic cell grafts can be engineered for universal transplantation.

Authors
Tobias Deuse, Xiaomeng Hu, Alessia Gravina, Dong Wang, Grigol Tediashvili, Chandrav De, William O. Thayer, Angela Wahl, J. Victor Garcia, Hermann Reichenspurner, Mark M. Davis, Lewis L. Lanier and Sonja Schrepfer.

Conflicts: The authors declare no competing financial interests.


Acknowledgements
The authors thank C. Pahrmann for cell culture work, imaging experiments and overall assistance and L. Li for his assistance. The in vivo BLI experiments were performed at the UCSF Pre-clinical Therapeutics Core (A. Fries; with special thanks to B.C. Hann). Special thanks go to J. Wu (Stanford Cardiovascular Institute, Stanford University School of Medicine) for providing the miPSCs and the help of his laboratory with developing the protocol for hiPSC differentiation into cardiomyocytes. We thank J.-F. Garcia-Gomez (City of Hope, Duarte) for the HLA typing of humanized BLT mice. We also thank E. Maltepe and H. Pektas for providing the syncytiotrophoblast cells. D.W. was supported by the Max Kade Foundation. A.W. received funding from the National Institutes of Health (grant AI123010). J.V.G. received funding from the National Institutes of Health (AI111899 and MH108179). The cardiomyocyte research was partly made possible by a grant from the California Institute for Regenerative Medicine (Grant Number DISC1-09984). Research related to cardiomyocyte immunobiology reported in this publication was supported by National Heart, Lung, and Blood Institute of the National Institutes of Health under award number R01HL140236. L.L.L. is an American Cancer Society Professor funded by NIH AI068129 and in part by the Parker Institute for Cancer Immunotherapy. S.S. and T.D. received funding for the cardiomyocyte research from the California Institute for Regenerative Medicine (Grant Number DISC1-09984) and for the immunobiology work from the National Heart, Lung, and Blood Institute of the National Institutes of Health under award number R01HL140236. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the NIH, CIRM and other agencies of the State of California.

This work was supported by National Institutes of Health grants R01NS095884, EB003392, R01EB016657, R01CA185363, 1S10RR019003-01 and 1S10RR025488-01; National Multiple Sclerosis Society grant 5045A1, and National Science Foundation grant CMMI-1634888.

About UCSF: UC San Francisco (UCSF) is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. It includes top-ranked graduate schools of dentistry, medicine, nursing and pharmacy; a graduate division with nationally renowned programs in basic, biomedical, translational and population sciences; and a preeminent biomedical research enterprise. It also includes UCSF Health, which comprises three top-ranked hospitals - UCSF Medical Center and UCSF Benioff Children's Hospitals in San Francisco and Oakland - as well as Langley Porter Psychiatric Hospital and Clinics, UCSF Benioff Children's Physicians and the UCSF Faculty Practice. UCSF Health has affiliations with hospitals and health organizations throughout the Bay Area. UCSF faculty also provide all physician care at the public Zuckerberg San Francisco General Hospital and Trauma Center, and the SF VA Medical Center. The UCSF Fresno Medical Education Program is a major branch of the University of California, San Francisco's School of Medicine. Please visit http://www.ucsf.edu/news.

Funding: Research was supported by grants from the Deutsche Forschungsgemeinschaft, the Fondation Leducq, the Max Kade Foundation, the California Institute for Regenerative Medicine, the National Institutes of Health and the Parker Institute for Cancer Immunotherapy.


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Feb 20, 2018   Fetal Timeline   Maternal Timeline   News  




Human heart muscle cells derived from triple-engineered stem cells that are “invisible” to the immune system. RED is troponin, a protein that participates in cardiac muscle contraction. Cell nuclei are BLUE. Researchers hope cells like these will eventually be used to treat heart failure.
Image Credit: Xiaomeng Hu.


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