Lessons from human teratomas to guide development of safe stem cell therapies

  title={Lessons from human teratomas to guide development of safe stem cell therapies},
  author={Justine J. Cunningham and Thomas M. Ulbright and Martin F. Pera and Leendert H. J. Looijenga},
  journal={Nature Biotechnology},
The potential for the formation of teratomas or other neoplasms is a major safety roadblock to clinical application of pluripotent stem cell therapies. Preclinical assessment of the risk of tumor formation in this context poses considerable scientific and regulatory challenges, especially because animal xenograft models may not properly reflect the long-term tumorigenic potential of human cells. A better understanding of the biology of spontaneously occurring teratomas and related tumors in… 

Path to the clinic: assessment of iPSC-based cell therapies in vivo in a nonhuman primate model.

The Tumorigenic Potential of Human Pluripotent Stem Cells

Major tumor-associated risk factors entailed in hPSC-based therapy are described, and precautionary and safety measures relevant for the development and application of such therapies are presented.

Overcoming clinical hurdles for autologous pluripotent stem cell-based therapies

This review examines the five hurdles to be overcome in safely moving towards personalised human induced pluripotent stem cell-based therapeutics and evaluates the feasibility of various possible solutions.

Teratoma: from spontaneous tumors to the pluripotency/malignancy assay

The standardized teratoma assay should be directed more to the assessment of EC/malignant cell features than of differentiated tissues, especially after a unique case of human therapy with neural stem cells was found to lead to malignancy.

Technical approaches to induce selective cell death of pluripotent stem cells

A brief overview of recent attempts at selective elimination of undifferentiated hPSCs to decrease the risk of teratoma formation in hPSC-based cell therapy is offered.

Clinical potential of human-induced pluripotent stem cells

The clinical potential of human iPS cells is reviewed and which are the most suitable approaches to overcome or minimize risks associated with the application of iPS cell-derived cell therapies are evaluated.

Neural Differentiation of Human Pluripotent Stem Cells for Nontherapeutic Applications: Toxicology, Pharmacology, and In Vitro Disease Modeling

This review critically examines the various potential nontherapeutic applications of hPSC-derived neuronal lineages and gives a brief overview of differentiation protocols utilized to generate these cells from hESCs and iPSCs.

Assessment of established techniques to determine developmental and malignant potential of human pluripotent stem cells

  • Thomas F. Peter W. Yishai Ivana Nissim Christoph Jennifer Allison Andrews Avior Barbaric Benvenisty Bock BreT. Allison S. Yamanaka
  • Biology
    Nature Communications
  • 2018
EB assays, analyzed after differentiation under neutral conditions and under conditions promoting differentiation to ectoderm, mesoderm or endoderm lineages, are sufficient to assess the differentiation potential of PSCs, and only the teratoma assay offers evidence of malignant potential.



Growth of teratomas derived from human pluripotent stem cells is influenced by the graft site.

It is reported that cells grafted into the liver rapidly produced large tumors containing predominantly immature cells, in contrast, subcutaneous implants were significantly slower growing and eventually formed tumors composed of differentiated tissues.

Differentiation of Human Embryonic Stem Cells After Transplantation in Immune‐Deficient Mice

Evidence for the ability of hESCs to differentiate in vivo is presented and some of the prominent questions that need to be addressed are highlighted if transplantation is to be used as a research tool to study hESC differentiation.

The tumorigenicity of human embryonic stem cells.

Effects of cell number on teratoma formation by human embryonic stem cells

This study used non-invasive reporter gene imaging to investigate the relationship between human ES cell number and teratoma formation in a xenogenic model of ES cell transplantation, and observed a minimum of 1x105 ES cells in the myocardium and 1x104 cells inthe skeletal muscle was observed to be requisite for teratomas development.

CD30 is a survival factor and a biomarker for transformed human pluripotent stem cells

CD30, a member of the tumor necrosis factor receptor superfamily, is expressed on transformed but not normal hES cells, and that CD30 expression protects hES cell–derived grafts against apoptosis.

Highly sensitive biosafety model for stem-cell-derived grafts.

This model will facilitate the generation of homogenous non-tumorigenic cell populations, and will help to integrate standardized safety systems into the application of stem-cell-derived grafts for clinical purposes.

Culture adaptation of embryonic stem cells echoes germ cell malignancy.

Understanding the mechanisms that drive culture adaptation of human embryonic stem cells may also provide insights into the development and progression of germ cell tumours.

Noninvasive de novo imaging of human embryonic stem cell-derived teratoma formation.

By targeting alpha(v)beta(3) integrin, the ability of (64)Cu-DOTA-RGD4 to noninvasively visualize teratoma formation in vivo for the first time is shown.

Human embryonic stem cells are prone to generate primitive, undifferentiated tumors in engrafted human fetal tissues in severe combined immunodeficient mice.

This study is the first report to demonstrate that human ES cells are prone to generate primitive, undifferentiated tumors in human fetal tissue grafts in SCID mice and raises a potential safety concern for using human ES cell-derived cell products in humans.