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RL1-00658-1: Placental Derived Stem Cells

Recommendation: Not recommended for funding

Public Abstract (provided by applicant)

Diseases that can potentially be cured by the use of stem cell treatment afflict significant number of individuals. Currently, the application of this treatment is limited because of the limited supply of appropriate amounts of stem cells, and because it is necessary to match certain characteristics of the donor’s and host’s immune systems. In addition to the need of massive supply of cells to cure patients, stem cells from diverse genetic backgrounds are required to study the apparent variation in responses to drugs, and to develop individualized medicine. Therefore, more new and well-defined stem cell lines are needed. We have carried out pioneering studies demonstrating that human placenta may be used as a source of these stem cell lines. These cell lines derived from human placenta have the potential to contribute to research in stem cell biology and clinical applications. Furthermore, placentas are readily available from all racial and ethnic groups. As this approach does not require the donation or use of either human embryos or eggs, it will eliminate ethical concerns. Further, it will help to overcome the limitations inherent in obtaining excess human embryos from different populations in our society. We are confident that these stem cell lines will be used in regenerative medicine research and cell replacement therapies, as well as in the development of new treatment approaches. Ultimately, the knowledge and experience produced by the work proposed will contribute to the goal of making stem cell transplantation and new medical approaches available to a much broader group of patients and contribute significantly to CIRM’s goal of providing new cures for human disease.

Statement of Benefit to California (provided by applicant)

Diseases that can potentially be cured by the use of stem cell treatment afflict significant number of individuals in California. The application of this treatment is limited because of the limited supply of appropriate stem cell lines, as it is necessary to match certain characteristics of the donor’s and host’s immune systems. In addition, stem cells from diverse genetic backgrounds are needed to evaluate the apparent variation in responses to drugs and to develop individualized medicine. We have carried out pioneering studies demonstrating that human placenta may be used as a source of such stem cell lines. These cell lines derived from human placenta will contribute to research in stem cell biology and clinical applications. Furthermore, placentas are readily available from all racial and ethnic groups. As this approach does not require the donation or use of either human embryos or eggs, it will greatly reduce the ethical concerns, and may help overcome the limitations inherent in obtaining excess human embryos. As such, we will be able to generate stem cell lines that will reflect the diverse population of California. These stem cell lines will be used in regenerative medicine research and cell replacement therapies as well as the development of new treatment approaches. The enhanced and extended lives of the individuals will represent an evident benefit; the savings to the health care system as a consequence of their cure will straightforwardly benefit all California taxpayers. The use of these stem cell lines from diverse genetic backgrounds, will enable scientists to study the apparent variation in responses to drugs and treatment, and to develop individualized medicine for the diverse population in California. Ultimately the knowledge and experience produced by the work proposed will contribute to the goal of making stem cell transplantation and new medical approaches available to a much broader group of patients, thus greatly extending the benefits to the affected individuals and to the taxpayers of California.

Review

This proposal is focused on the human placenta as a high capacity source of stem cells that can be harvested both for therapeutic applications and for drug discovery approaches. In the first aim, the applicant proposes to harvest large numbers of hematopoietic stem cells (HSC) from human placentas both from normal individuals and from patients with Sickle Cell Disease (SCD), using well described markers and functional assays of these cells. In Aim 2, studies will be performed to derive pluripotent, embryonic stem cell (ESC)-like cell lines from placenta. Experiments in the third Aim will seek to develop drug screens to treat SCD, using the HSC isolated from placentas in Aim1.

The research proposed in this application, if successful, has the potential to establish the placenta, a large, readily available human tissue, as a valuable new (and potentially abundant) source of HSC for transplantation applications. The additional possibility of the placenta as a source of cells with pluripotent stem cell-like properties further adds to the potential significance of the proposed studies. Because of the abundance of placenta, there would be little problem in obtaining material from genetically diverse groups. Whether the placenta can be regarded as a truly viable alternative source of either HSC (with more cells per placenta than per cord, for example) or pluripotent human stem cells will critically depend on the results of studies of the nature described in the current proposal.

The PI is an expert in SCD and has a strong interest in generating bankable stores of HSC from placenta. The applicant group has extensive expertise in HSC research and has access to excellent facilities, they will undoubtedly succeed in isolating these cells from placenta. However, one reviewer expressed concern that despite the experience of the PI, a critical marker of the myeloid lineage was incorrectly presented in the experimental plans. Furthermore, reviewers expressed difficulty in evaluating the proposed screens on HSC because of insufficient experimental detail.

The derivation of pluripotent ESC-like cells from placenta is a worthy goal, although a strong focused approach to achieve this goal (as presented for HSC) was not clearly articulated in the proposal. There is strong evidence in the literature for enrichment of stem cell activity in placenta, such as mesenchymal and hematopoietic stem cells, but there is no published evidence for pluripotent stem cells from placenta. In the studies proposed under Aim 2, it is critical that in characterizing the potential pluripotent properties of cells derived from the placenta, comparisons are made with human (h)ESC cells. However, the reviewers were concerned that expertise in hESC biology methodologies is lacking amongst the investigators assembled for this project, and that the proposed experimental design will not allow the applicant to demonstrate pluripotentiality of the placenta-derived cells. Finally, criticism was raised that the drug screening proposed in the third aim does not include the pluripotent stem cells potentially identified in Aim 2.

The idea of deriving pluripotent stem cells from a placental source is responsive to the RFA, although one reviewer was uncertain based on the preliminary data and the proposed experimental plan whether this proposal will yield pluripotent stem cell lines. Furthermore, and more importantly, the majority of this proposal is relevant to generating and using HSC and derivatives. While isolating HSC from placenta is a clinically-relevant and laudable goal, this part of the research plan is not responsive to the RFA.

The following Working Group members had a conflict of interest with this application and were therefore recused from participating in review of, discussion of, and voting on the application:

• None