Title Fetal stem cell transplantation : Past, present, and future Author(s) Ishii, Tetsuya World Journal of Stem Cells, 6(4), 404-420 Citation https://doi.org/10.4252/wjsc.v6.i4.404 Issue Date 2014-09-26 Doc URL http://hdl.handle.net/2115/56999 Rights(URL) http://creativecommons.org/licenses/by/4.0/ Type article File Information 404.pdf Instructions for use Hokkaido University Collection of Scholarly and Academic Papers : HUSCAP Submit a Manuscript: http://www.wjgnet.com/esps/ World J Stem Cells 2014 September 26; 6(4): 404-420 Help Desk: http://www.wjgnet.com/esps/helpdesk.aspx ISSN 1948-0210 (online) DOI: 10.4252/wjsc.v6.i4.404 © 2014 Baishideng Publishing Group Inc. All rights reserved. REVIEW Fetal stem cell transplantation: Past, present, and future Tetsuya Ishii, Koji Eto Tetsuya Ishii, Office of Health and Safety, Hokkaido University, Kita-ku, Sapporo 060-0808, Hokkaido, Japan Core tip: Based on the history of fetal stem cell trans- Koji Eto, Center for iPS Cell Research and Application, Kyoto plantation since 1928, this article discusses strategies University, Shogoin Yoshida, Sakyo-ku, Kyoto 606-8507, Japan for transplantation, with a focus on donor cells, cell Author contributions: Ishii T investigated the reports on clini- processing, and the therapeutic cell niche, in addition cal trials and wrote the manuscript; Eto K assessed the analysis to ethical issues associated with fetal origin. We de- and revised the manuscript. scribed the stream line to current clinical trials using Supported by JSPS KAKENHI, No. 26460586(TI) fetal and embryonic stem cells based on Clinical. Trials. Correspondence to: Tetsuya Ishii, PhD, Office of Health and gov. Finally, we discussed the perspective of fetal stem Safety, Hokkaido University, Kita8 Nishi5, Kita-ku, Sapporo 060-0808, Hokkaido, Japan. [email protected] cell transplantation. Telephone: +81-011-7062126 Fax: +81-011-7062295 Received: July 7, 2014 Revised: August 26, 2014 Accepted: August 30, 2014 Ishii T, Eto K. Fetal stem cell transplantation: Past, present, and Published online: September 26, 2014 future. World J Stem Cells 2014; 6(4): 404-420 Available from: URL: http://www.wjgnet.com/1948-0210/full/v6/i4/404.htm DOI: http://dx.doi.org/10.4252/wjsc.v6.i4.404 Abstract Since 1928, human fetal tissues and stem cells have been used worldwide to treat various conditions. Al- INTRODUCTION though the transplantation of the fetal midbrain sub- In 1988, an article reported the hopeful results of a clini- stantia nigra and dopaminergic neurons in patients cal trial in which the fetal mesencephalic substantia nigra suffering from Parkinson’s disease is particularly note- was transplanted in patients with Parkinson’s disease worthy, the history of other types of grafts, such as (PD)[1]. In the preceding year, 1987, a Chinese team had those of the fetal liver, thymus, and pancreas, should reported similar findings of fetal tissue transplantation be addressed as there are many lessons to be learnt conducted in August 1985[2]. Following the publication for future stem cell transplantation. This report de- of these reports, similar neural tissue transplantation scribes previous practices and complications that led procedures became widespread. Most notably, a double- to current clinical trials of isolated fetal stem cells and blind, sham surgery controlled study of transplantation embryonic stem (ES) cells. Moreover, strategies for of fetal dopaminergic neurons in PD patients was re- transplantation are considered, with a particular focus [3] on donor cells, cell processing, and the therapeutic cell ported in 2001 , which provided convincing data regard- niche, in addition to ethical issues associated with fetal ing the efficacy of fetal tissue transplantation for treating origin. With the advent of autologous induced pluripo- this condition. Since then, fetal tissue transplantation has tent stem cells and ES cells, clinical dependence on advanced to include the clinical development of isolated fetal transplantation is expected to gradually decline fetal cells, particularly neural stem cells in business enti- due to lasting ethical controversies, despite landmark ties. achievements. Although many review articles have focused on the application of neural tissue and/or cells in fetal tissue © 2014 Baishideng Publishing Group Inc. All rights reserved. transplantation[4-14], the clinical use of fetal cells is not new or simply confined to the field of neurological field. Key words: Fetal tissue; Fetal stem cells; Fetus, Embry- The rationale of fetal tissue transplantation lies in the onic stem cells; Transplantation; Clinical trials potential for fetal cell proliferation and differentiation, WJSC|www.wjgnet.com 404 September 26, 2014|Volume 6|Issue 4| Ishii T et al . Fetal stem cell transplantation In vivo In vitro In vivo Donor cells Cell culture Recovery Recovery of tissue of tissue Transplantation Tissue processing Cytogenetic testing Expansion Final testing Isolation (if necessary) Cadaveric fetus Cryopreservation e.g., (Approx. 6-12 wk) Various assays Cytogenetic testing e.g. , Biochemical assay Biochemical assay Immunoassay Immunoassay Quantitative PCR Patient Quantitative PCR DNA microarray Cryopreservation for Miscarriage Pyrosequencing subsequent analysis Administration of Stillbirth immunosuppressive drugs Ectopic pregnancy Rehabilitation Elective abortion Evaluation of symptom Figure 1 Fetal tissue transplantation procedures. Fetal tissue can be obtained from cadaveric fetuses for medical and non-medical reasons in obstetrics and gynecology hospitals. Procured fetal tissue, which was donated with consent for research, is processed in vitro, confirming cell function without contamination and genetic abnormality. After careful examination, donor cells are used for grafts primarily in the form of a cell suspension, which is usually intravenously or intraperitone- ally injected or, otherwise, transplanted into predefined implant sites during surgery. Although fetal tissue cells are less likely to be rejected by transplant recipients, immunosuppressive drugs are administered in some cases. PCR: Polymerase chain reaction. and fetal grafts may be integrated into the host without In this article, the authors offer a discussion of the inducing immune rejection. These features of fetal tis- progression from previous applications of fetal tissue sue are well known, as is the established clinical use of transplantation to current uses of stem cell transplanta- transplants derived from cadaveric fetuses in the history tion. In humans, the product of conception after im- of transplantation therapy. For example, early as 1928, plantation in the uterine wall through the eighth week of a form of fetal tissue transplantation in Italy was docu- development is referred to as the embryo. From the ninth mented in a medical journal as a treatment for diabetes week to birth, the embryo is called a fetus. The authors mellitus[15]. Subsequently, the indications for fetal tissue largely follow this nomenclature. transplantation expanded to other subjects with thera- peutic efficacy in conditions other than diabetes. Since FETAL TISSUE TRANSPLANTATION the early 1960’s, a tremendous number of fetal liver and thymus transplantations have been performed worldwide PROCEDURES to treat immunodeficiency and hematological disorders. Fetal tissue contains a sufficient number of stem cells In order to gain new perspectives on future clinical and progenitor cells for development, making it valuable application of stem cells, it is worth considering the his- for some treatments. Namely, fetal tissue cells are easier tory of fetal tissue transplantation, taking into account to culture and proliferate more readily than comparable an overview of current fetal stem cell research. In this adult tissue cells[16-24], with the exception of pancre- report, the authors examine the history of fetal tissue atic cells[25,26]. Fetal tissue cells are also less likely to be transplantation, as well as many associated complications rejected by transplant recipients, as these cells are less including procuring and processing fetal tissue, select- antigenic, expressing HLA-G for immune tolerance dur- ing appropriate diseases and subjects, developing new ing pregnancy[27]. This fact and the findings of animal transplantation strategies, assessing graft survival and in- experiments suggested a reduced need for an exact tissue tegrity in vivo, providing long-term monitoring of patients match, which is frequently difficult to obtain[28]. Collec- treated with fetal grafts for adverse events. Moreover, tively, the features of fetal tissue cells facilitate engraft- important ramifications of ES cell research are addressed ment in vivo and may provide beneficial effects against and transplantation strategies are considered from the diseases difficult to treat. viewpoint of donor cells, cell processing and the thera- Fetal tissue can be obtained from cadaveric fetuses peutic cell niche, in addition to ethical concerns. Finally, following spontaneous abortion, stillbirth, or surgery due the authors provide future perspectives on fetal stem cell to ectopic pregnancy in obstetrics and gynecology hos- transplantation. pitals (Figure 1). In addition, such tissue may be derived WJSC|www.wjgnet.com 405 September 26, 2014|Volume 6|Issue 4| Ishii T et al . Fetal stem cell transplantation from elective abortions. The obtained fetal tissue is ordi- ful outcomes due to tissue matching, thus controlling narily processed and used for grafts