Publications by authors named "Grigol Tediashvili"

7 Publications

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Hypoimmune induced pluripotent stem cell-derived cell therapeutics treat cardiovascular and pulmonary diseases in immunocompetent allogeneic mice.

Proc Natl Acad Sci U S A 2021 07;118(28)

Division of Cardiothoracic Surgery, Department of Surgery, Transplant and Stem Cell Immunobiology Laboratory, University of California, San Francisco, CA 94143;

The emerging field of regenerative cell therapy is still limited by the few cell types that can reliably be differentiated from pluripotent stem cells and by the immune hurdle of commercially scalable allogeneic cell therapeutics. Here, we show that gene-edited, immune-evasive cell grafts can survive and successfully treat diseases in immunocompetent, fully allogeneic recipients. Transplanted endothelial cells improved perfusion and increased the likelihood of limb preservation in mice with critical limb ischemia. Endothelial cell grafts transduced to express a transgene for alpha1-antitrypsin (A1AT) successfully restored physiologic A1AT serum levels in mice with genetic A1AT deficiency. This cell therapy prevented both structural and functional changes of emphysematous lung disease. A mixture of endothelial cells and cardiomyocytes was injected into infarcted mouse hearts, and both cell types orthotopically engrafted in the ischemic areas. Cell therapy led to an improvement in invasive hemodynamic heart failure parameters. Our study supports the development of hypoimmune, universal regenerative cell therapeutics for cost-effective treatments of major diseases.
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http://dx.doi.org/10.1073/pnas.2022091118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8285900PMC
July 2021

The SIRPα-CD47 immune checkpoint in NK cells.

J Exp Med 2021 03;218(3)

Department of Surgery, Division of Cardiothoracic Surgery, Transplant and Stem Cell Immunobiology Lab, University of California, San Francisco, San Francisco, CA.

Here we report on the existence and functionality of the immune checkpoint signal regulatory protein α (SIRPα) in NK cells and describe how it can be modulated for cell therapy. NK cell SIRPα is up-regulated upon IL-2 stimulation, interacts with target cell CD47 in a threshold-dependent manner, and counters other stimulatory signals, including IL-2, CD16, or NKG2D. Elevated expression of CD47 protected K562 tumor cells and mouse and human MHC class I-deficient target cells against SIRPα+ primary NK cells, but not against SIRPα- NKL or NK92 cells. SIRPα deficiency or antibody blockade increased the killing capacity of NK cells. Overexpression of rhesus monkey CD47 in human MHC-deficient cells prevented cytotoxicity by rhesus NK cells in a xenogeneic setting. The SIRPα-CD47 axis was found to be highly species specific. Together, the results demonstrate that disruption of the SIRPα-CD47 immune checkpoint may augment NK cell antitumor responses and that elevated expression of CD47 may prevent NK cell-mediated killing of allogeneic and xenogeneic tissues.
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http://dx.doi.org/10.1084/jem.20200839DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7802363PMC
March 2021

The H-Y Antigen in Embryonic Stem Cells Causes Rejection in Syngeneic Female Recipients.

Stem Cells Dev 2020 09 25;29(18):1179-1189. Epub 2020 Aug 25.

Transplant and Stem Cell Immunobiology Lab, Department of Surgery, University of California, San Francisco, California, USA.

Pluripotent stem cells are promising candidates for cell-based regenerative therapies. To avoid rejection of transplanted cells, several approaches are being pursued to reduce immunogenicity of the cells or modulate the recipient's immune response. These include gene editing to reduce the antigenicity of cell products, immunosuppression of the host, or using major histocompatibility complex-matched cells from cell banks. In this context, we have investigated the antigenicity of H-Y antigens, a class of minor histocompatibility antigens encoded by the Y chromosome, to assess whether the gender of the donor affects the cell's antigenicity. In a murine transplant model, we show that the H-Y antigen in undifferentiated embryonic stem cells (ESCs), as well as ESC-derived endothelial cells, provokes T- and B cell responses in female recipients.
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http://dx.doi.org/10.1089/scd.2019.0299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7482111PMC
September 2020

A Cryoinjury Model to Study Myocardial Infarction in the Mouse.

J Vis Exp 2019 09 19(151). Epub 2019 Sep 19.

Transplant and Stem Cell Immunobiology Lab, University Heart Center; Department of Surgery, Transplant and Stem Cell Immunobiology Lab, University of California San Francisco; Cardiovascular Research Center (CVRC) and DZHK German Center for Cardiovascular Research; Cardiovascular Surgery, University Heart Center;

The use of animal models is essential for developing new therapeutic strategies for acute coronary syndrome and its complications. In this article, we demonstrate a murine cryoinjury infarct model that generates precise infarct sizes with high reproducibility and replicability. In brief, after intubation and sternotomy of the animal, the heart is lifted from the thorax. The probe of a handheld liquid nitrogen delivery system is applied onto the myocardial wall to induce cryoinjury. Impaired ventricular function and electrical conduction can be monitored with echocardiography or optical mapping. Transmural myocardial remodeling of the infarcted area is characterized by collagen deposition and loss of cardiomyocytes. Compared to other models (e.g., LAD-ligation), this model utilizes a handheld liquid nitrogen delivery system to generate more uniform infarct sizes.
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http://dx.doi.org/10.3791/59958DOI Listing
September 2019

Hypoimmunogenic derivatives of induced pluripotent stem cells evade immune rejection in fully immunocompetent allogeneic recipients.

Nat Biotechnol 2019 03 18;37(3):252-258. Epub 2019 Feb 18.

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

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.
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http://dx.doi.org/10.1038/s41587-019-0016-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6419516PMC
March 2019

Balloon-based Injury to Induce Myointimal Hyperplasia in the Mouse Abdominal Aorta.

J Vis Exp 2018 02 7(132). Epub 2018 Feb 7.

Transplant and Stem Cell Immunobiology Lab, University Heart Center; Department of Surgery, Transplant and Stem Cell Immunobiology Lab, University of California San Francisco (UCSF); Cardiovascular Research Center (CVRC) and DZHK German Center for Cardiovascular Research; Cardiovascular Surgery, University Heart Center;

The use of animal models is essential for a better understanding of MH, one major cause for arterial stenosis.In this article, we demonstrate a murine balloon denudation model, which is comparable with established vessel injury models in large animals. The aorta denudation model with balloon catheters mimics the clinical setting and leads to comparable pathobiological and physiological changes. Briefly, after performing a horizontal incision in the aorta abdominalis, a balloon catheter will be inserted into the vessel, inflated, and introduced retrogradely. Inflation of the balloon will lead to intima injury and overdistension of the vessel. After removing the catheter, the aortic incision will be closed with single stiches. The model shown in this article is reproducible, easy to perform, and can be established quickly and reliably. It is especially suitable for evaluating expensive experimental therapeutic agents, which can be applied in an economical fashion. By using different knockout-mouse strains, the impact of different genes on MH development can be assessed.
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http://dx.doi.org/10.3791/56477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5912362PMC
February 2018

Vein Interposition Model: A Suitable Model to Study Bypass Graft Patency.

J Vis Exp 2017 01 15(119). Epub 2017 Jan 15.

Transplant and Stem Cell Immunobiology Lab, University Heart Center Hamburg; Department of Surgery, Transplant and Stem Cell Immunobiology Lab, University of California San Francisco (UCSF); Cardiovascular Research Center (CVRC) and DZHK German Center for Cardiovascular Research), partner site Hamburg/Kiel/Luebeck; Cardiovascular Surgery, University Heart Center Hamburg;

Bypass grafting is an established treatment method for coronary artery disease. Graft patency continues to be the Achilles heel of saphenous vein grafts. Research models for bypass graft failure are essential for a better understanding of pathobiological and pathophysiological processes during graft patency loss. Large animal models, such as pigs or sheep, resemble human anatomical structures but require special facilities and equipment. This video describes a rat vein interposition model to investigate vein graft patency loss. Rats are inexpensive and easy to handle. Compared to mouse models, the convenient size of rats permits better operability and enables a sufficient amount of material to be obtained for further diverse analysis. In brief, the inferior epigastric vein of a donor rat is harvested and used to replace a segment of the femoral artery. Anastomosis is conducted via single stitches and sealed with fibrin glue. Graft patency can be monitored non-invasively using duplex sonography. Myointimal hyperplasia, which is the main cause for graft patency loss, develops progressively over time and can be calculated from histological cross sections.
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http://dx.doi.org/10.3791/54839DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5352261PMC
January 2017
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