Bio

Professional Education


  • MD, Leiden University, Leiden University Medical Center, The Netherlands, Doctor of Medicine (2012)
  • Doctorandus, Leiden University, Leiden University Medical Center, The Netherlands, Master of Science (2011)

Stanford Advisors


Research & Scholarship

Current Research and Scholarly Interests


Nigel Kooreman received his MSc and MD from the Leiden University School of Medicine, the Netherlands, where he was working on identifying risk factors influencing outcome after orthotopic liver transplantation. In 2012 he joined the Wu lab and is currently studying the tumorigenicity and immunogenicity of pluripotent stem cells and their derivatives in a transplant setting.

Publications

All Publications


  • Tracking gene and cell fate for therapeutic gain NATURE MATERIALS Kooreman, N. G., Ransohoff, J. D., Wu, J. C. 2014; 13 (2): 106-109

    View details for DOI 10.1038/nmat3868

    View details for Web of Science ID 000330182700006

    View details for PubMedID 24452344

  • Costimulation-Adhesion Blockade is Superior to Cyclosporine A and Prednisone Immunosuppressive Therapy for Preventing Stem Cells Huber, B. C., Ransohoff, J. D., Ransohoff, K. J., Riegler, J., Ebert, A., Kodo, K., Gong, Y., Sanchez-Freire, V., Dey, D., Kooreman, N. G., Diecke, S., Zhang, W. Y., Odegaard, J., Hu, S., Gold, J. D., Robbins, R. C., Wu, J. C. 2013; 31 (9)

    View details for DOI 10.1002/stem.1501

  • Short Hairpin RNA Gene Silencing of Prolyl Hydroxylase-2 with a Minicircle Vector Improves Neovascularization of Hindlimb Ischemia Human Gene Therapy Lijkwan, M. A., Hellingman, A., Bos, E., van der Bogt, K., Huang, M., Kooreman, N. G., de Vries, M., Peters, H., Robbins, R. C., Hamming, J. F., Quax, P., Wu, J. C. 2013

    View details for DOI 10.1089/hum.2013.110.

  • Preclinical Derivation and Imaging of Autologously Transplanted Canine Induced Pluripotent Stem Cells JOURNAL OF BIOLOGICAL CHEMISTRY Lee, A. S., Xu, D., Plews, J. R., Nguyen, P. K., Nag, D., Lyons, J. K., Han, L., Hu, S., Lan, F., Liu, J., Huang, M., Narsinh, K. H., Long, C. T., de Almeida, P. E., Levi, B., Kooreman, N., Bangs, C., Pacharinsak, C., Ikeno, F., Yeung, A. C., Gambhir, S. S., Robbins, R. C., Longaker, M. T., Wu, J. C. 2011; 286 (37): 32697-32704

    Abstract

    Derivation of patient-specific induced pluripotent stem cells (iPSCs) opens a new avenue for future applications of regenerative medicine. However, before iPSCs can be used in a clinical setting, it is critical to validate their in vivo fate following autologous transplantation. Thus far, preclinical studies have been limited to small animals and have yet to be conducted in large animals that are physiologically more similar to humans. In this study, we report the first autologous transplantation of iPSCs in a large animal model through the generation of canine iPSCs (ciPSCs) from the canine adipose stromal cells and canine fibroblasts of adult mongrel dogs. We confirmed pluripotency of ciPSCs using the following techniques: (i) immunostaining and quantitative PCR for the presence of pluripotent and germ layer-specific markers in differentiated ciPSCs; (ii) microarray analysis that demonstrates similar gene expression profiles between ciPSCs and canine embryonic stem cells; (iii) teratoma formation assays; and (iv) karyotyping for genomic stability. Fate of ciPSCs autologously transplanted to the canine heart was tracked in vivo using clinical positron emission tomography, computed tomography, and magnetic resonance imaging. To demonstrate clinical potential of ciPSCs to treat models of injury, we generated endothelial cells (ciPSC-ECs) and used these cells to treat immunodeficient murine models of myocardial infarction and hindlimb ischemia.

    View details for DOI 10.1074/jbc.M111.235739

    View details for Web of Science ID 000294726800078

    View details for PubMedID 21719696

  • Tumorigenicity of pluripotent stem cells: biological insights from molecular imaging JOURNAL OF THE ROYAL SOCIETY INTERFACE Kooreman, N. G., Wu, J. C. 2010; 7: S753-S763

    Abstract

    Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) have the ability (i) to duplicate indefinitely while maintaining pluripotency and (ii) to differentiate into cell types of all three embryonic germ layers. These two properties of ESCs and iPSCs make them potentially suitable for tissue engineering and cell replacement therapy for many different diseases, including Parkinson's disease, diabetes and heart disease. However, one critical obstacle in the clinical application of ESCs or iPSCs is the risk of teratoma formation. The emerging field of molecular imaging is allowing researchers to track transplanted ESCs or iPSCs in vivo, enabling early detection of teratomas.

    View details for DOI 10.1098/rsif.2010.0353.focus

    View details for Web of Science ID 000284505100007

    View details for PubMedID 20880852

  • Teratoma formation: a tool for monitoring pluripotency in stem cell research. Current protocols in stem cell biology Nelakanti, R. V., Kooreman, N. G., Wu, J. C. 2015; 32: 4A 8 1-4A 8 17

    Abstract

    This unit describes protocols for evaluating the pluripotency of embryonic and induced pluripotent stem cells using a teratoma formation assay. Cells are prepared for injection and transplanted into immunodeficient mice at the gastrocnemius muscle, a site well suited for teratoma growth and surgical access. Teratomas that form from the cell transplants are explanted, fixed in paraformaldehyde, and embedded in paraffin. These preserved samples are sectioned, stained, and analyzed. Pluripotency of a cell line is confirmed by whether the teratoma contains tissues derived from each of the embryonic germ layers: endoderm, mesoderm, and ectoderm. Alternatively, explanted and fixed teratomas can be cryopreserved for immunohistochemistry, which allows for more detailed identification of specific tissue types present in the samples. © 2015 by John Wiley & Sons, Inc.

    View details for DOI 10.1002/9780470151808.sc04a08s32

    View details for PubMedID 25640819

  • Novel codon-optimized mini-intronic plasmid for efficient, inexpensive, and xeno-free induction of pluripotency. Scientific reports Diecke, S., Lu, J., Lee, J., Termglinchan, V., Kooreman, N. G., Burridge, P. W., Ebert, A. D., Churko, J. M., Sharma, A., Kay, M. A., Wu, J. C. 2015; 5: 8081-?

    Abstract

    The development of human induced pluripotent stem cell (iPSC) technology has revolutionized the regenerative medicine field. This technology provides a powerful tool for disease modeling and drug screening approaches. To circumvent the risk of random integration into the host genome caused by retroviruses, non-integrating reprogramming methods have been developed. However, these techniques are relatively inefficient or expensive. The mini-intronic plasmid (MIP) is an alternative, robust transgene expression vector for reprogramming. Here we developed a single plasmid reprogramming system which carries codon-optimized (Co) sequences of the canonical reprogramming factors (Oct4, Klf4, Sox2, and c-Myc) and short hairpin RNA against p53 ("4-in-1 CoMiP"). We have derived human and mouse iPSC lines from fibroblasts by performing a single transfection. Either independently or together with an additional vector encoding for LIN28, NANOG, and GFP, we were also able to reprogram blood-derived peripheral blood mononuclear cells (PBMCs) into iPSCs. Taken together, the CoMiP system offers a new highly efficient, integration-free, easy to use, and inexpensive methodology for reprogramming. Furthermore, the CoMIP construct is color-labeled, free of any antibiotic selection cassettes, and independent of the requirement for expression of the Epstein-Barr Virus nuclear antigen (EBNA), making it particularly beneficial for future applications in regenerative medicine.

    View details for DOI 10.1038/srep08081

    View details for PubMedID 25628230

  • Transplanted terminally differentiated induced pluripotent stem cells are accepted by immune mechanisms similar to self-tolerance NATURE COMMUNICATIONS de Almeida, P. E., Meyer, E. H., Kooreman, N. G., Diecke, S., Dey, D., Sanchez-Freire, V., Hu, S., Ebert, A., Odegaard, J., Mordwinkin, N. M., Brouwer, T. P., Lo, D., Montoro, D. T., Longaker, M. T., Negrin, R. S., Wu, J. C. 2014; 5

    View details for DOI 10.1038/ncomms4903

    View details for Web of Science ID 000337504100006

  • Short Hairpin RNA Gene Silencing of Prolyl Hydroxylase-2 with a Minicircle Vector Improves Neovascularization of Hindlimb Ischemia HUMAN GENE THERAPY Lijkwan, M. A., Hellingman, A. A., Bos, E. J., van der Bogt, K. E., Huang, M., Kooreman, N. G., de Vries, M. R., Peters, H. A., Robbins, R. C., Hamming, J. F., Quax, P. H., Wu, J. C. 2014; 25 (1): 41-49

    Abstract

    Abstract In this study, we target the hypoxia inducible factor-1 alpha (HIF-1-alpha) pathway by short hairpin RNA interference therapy targeting prolyl hydroxylase-2 (shPHD2). We use the minicircle (MC) vector technology as an alternative for conventional nonviral plasmid (PL) vectors in order to improve neovascularization after unilateral hindlimb ischemia in a murine model. Gene expression and transfection efficiency of MC and PL, both in vitro and in vivo, were assessed using bioluminescence imaging (BLI) and firefly luciferase (Luc) reporter gene. C57Bl6 mice underwent unilateral electrocoagulation of the femoral artery and gastrocnemic muscle injection with MC-shPHD2, PL-shPHD2, or phosphate-buffered saline (PBS) as control. Blood flow recovery was monitored using laser Doppler perfusion imaging, and collaterals were visualized by immunohistochemistry and angiography. MC-Luc showed a 4.6-fold higher in vitro BLI signal compared with PL-Luc. BLI signals in vivo were 4.3×10(5)±3.3×10(5) (MC-Luc) versus 0.4×10(5)±0.3×10(5) (PL-Luc) at day 28 (p=0.016). Compared with PL-shPHD2 or PBS, MC-shPHD2 significantly improved blood flow recovery, up to 50% from day 3 until day 14 after ischemia induction. MC-shPHD2 significantly increased collateral density and capillary density, as monitored by alpha-smooth muscle actin expression and CD31(+) expression, respectively. Angiography data confirmed the histological findings. Significant downregulation of PHD2 mRNA levels by MC-shPHD2 was confirmed by quantitative polymerase chain reaction. Finally, Western blot analysis confirmed significantly higher levels of HIF-1-alpha protein by MC-shPHD2, compared with PL-shPHD2 and PBS. This study provides initial evidence of a new potential therapeutic approach for peripheral artery disease. The combination of HIF-1-alpha pathway targeting by shPHD2 with the robust nonviral MC plasmid improved postischemic neovascularization, making this approach a promising potential treatment option for critical limb ischemia.

    View details for DOI 10.1089/hum.2013.110

    View details for Web of Science ID 000329848600007

    View details for PubMedID 24090375

  • Second Generation Codon Optimized Minicircle (CoMiC) for Nonviral Reprogramming of Human Adult Fibroblasts. Methods in molecular biology (Clifton, N.J.) Diecke, S., Lisowski, L., Kooreman, N. G., Wu, J. C. 2014; 1181: 1-13

    Abstract

    The ability to induce pluripotency in somatic cells is one of the most important scientific achievements in the fields of stem cell research and regenerative medicine. This technique allows researchers to obtain pluripotent stem cells without the controversial use of embryos, providing a novel and powerful tool for disease modeling and drug screening approaches. However, using viruses for the delivery of reprogramming genes and transcription factors may result in integration into the host genome and cause random mutations within the target cell, thus limiting the use of these cells for downstream applications. To overcome this limitation, various non-integrating techniques, including Sendai virus, mRNA, minicircle, and plasmid-based methods, have recently been developed. Utilizing a newly developed codon optimized 4-in-1 minicircle (CoMiC), we were able to reprogram human adult fibroblasts using chemically defined media and without the need for feeder cells.

    View details for DOI 10.1007/978-1-4939-1047-2_1

    View details for PubMedID 25070322

  • Costimulation-Adhesion Blockade Is Superior to Cyclosporine A and Prednisone Immunosuppressive Therapy for Preventing Rejection of Differentiated Human Embryonic Stem Cells Following Transplantation STEM CELLS Huber, B. C., Ransohoff, J. D., Ransohoff, K. J., Riegler, J., Ebert, A., Kodo, K., Gong, Y., Sanchez-Freire, V., Dey, D., Kooreman, N. G., Diecke, S., Zhang, W. Y., Odegaard, J., Hu, S., Gold, J. D., Robbins, R. C., Wu, J. C. 2013; 31 (11): 2354-2363

    Abstract

    Rationale: Human embryonic stem cell (hESC) derivatives are attractive candidates for therapeutic use. The engraftment and survival of hESC derivatives as xenografts or allografts require effective immunosuppression to prevent immune cell infiltration and graft destruction. Objective: To test the hypothesis that a short-course, dual-agent regimen of two costimulation-adhesion blockade agents can induce better engraftment of hESC derivatives compared to current immunosuppressive agents. Methods and Results: We transduced hESCs with a double fusion reporter gene construct expressing firefly luciferase (Fluc) and enhanced green fluorescent protein, and differentiated these cells to endothelial cells (hESC-ECs). Reporter gene expression enabled longitudinal assessment of cell engraftment by bioluminescence imaging. Costimulation-adhesion therapy resulted in superior hESC-EC and mouse EC engraftment compared to cyclosporine therapy in a hind limb model. Costimulation-adhesion therapy also promoted robust hESC-EC and hESC-derived cardiomyocyte survival in an ischemic myocardial injury model. Improved hESC-EC engraftment had a cardioprotective effect after myocardial injury, as assessed by magnetic resonance imaging. Mechanistically, costimulation-adhesion therapy is associated with systemic and intragraft upregulation of T-cell immunoglobulin and mucin domain 3 (TIM3) and a reduced proinflammatory cytokine profile. Conclusions: Costimulation-adhesion therapy is a superior alternative to current clinical immunosuppressive strategies for preventing the post-transplant rejection of hESC derivatives. By extending the window for cellular engraftment, costimulation-adhesion therapy enhances functional preservation following ischemic injury. This regimen may function through a TIM3-dependent mechanism. Stem Cells 2013;31:2354-2363.

    View details for DOI 10.1002/stem.1501

    View details for Web of Science ID 000327025600007

  • Validation of the donor risk index in orthotopic liver transplantation within the Eurotransplant region. Liver transplantation Blok, J. J., Braat, A. E., Adam, R., Burroughs, A. K., Putter, H., Kooreman, N. G., Rahmel, A. O., Porte, R. J., Rogiers, X., Ringers, J. 2012; 18 (1): 112-119

    Abstract

    In Eurotransplant, more than 50% of liver allografts come from extended criteria donors (ECDs). However, not every ECD is the same. The limits of their use are being explored. A continuous scoring system for analyzing donor risk has been developed within the Organ Procurement and Transplantation Network (OPTN), the Donor Risk Index (DRI). The objective of this study was the validation of this donor risk index (DRI) in Eurotransplant. The study was a database analysis of all 5939 liver transplants involving deceased donors and adult recipients from January 1, 2003 to December 31, 2007 in Eurotransplant. Data were analyzed with Kaplan-Meier and Cox regression models. Follow-up data were available for 5723 patients with a median follow up of 2.5 years. The mean DRI was remarkably higher in the Eurotransplant region versus OPTN (1.71 versus 1.45), and this indicated different donor populations. Nevertheless, we were able to validate the DRI for the Eurotransplant region. Kaplan-Meier curves per DRI category showed a significant correlation between the DRI and outcomes (P < 0.001). A multivariate analysis demonstrated that the DRI was the most significant factor influencing outcomes (P < 0.001). Among all donor, transplant, and recipient variables, the DRI was the strongest predictor of outcomes.

    View details for DOI 10.1002/lt.22447

    View details for PubMedID 21987454

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