Stem Cells and Human Disease
Sharp J, Keirstead HS. 2009. Stem cell-based cell replacement strategies for the central nervous system. Neurosci Lett. 456(3):107-11.
Keirstead HS, Nistor G, Bernal G, Totoiu M, Cloutier F, Sharp K, Steward O. Human embryonic stem cell-derived oligodendrocyte progenitor cell transplants remyelinate and restore locomotion after spinal cord injury. J Neurosci. 2005 May 11;25(19):4694-705.
Cloutier F, Siegenthaler MM, Nistor G, Keirstead HS. 2006. Transplantation of human embryonic stem cell-derived oligodendrocyte progenitors into rat spinal cord injuries does not cause harm. Regen Med. 1(4):469-79.
Dr. Keirstead, you gave a fantastic talk at the Beckman Conference, where you outlined the numerous ways in which you and your labs and companies are using embryonic stem cells to treat human diseases. Can you first tell us a bit about yourself and your career path over the years and what led you to work on Stem Cells? Additionally, based on what I know from your talk, it would be a nice spring board for conversation if you could summarize the list of therapies and approaches you are in the process of developing?
You mentioned in your papers that the number of transplanted cells may have played a role (either beneficial or detrimental) in cell restoration and behavioral outcomes. More specifically, in the Future Medicine paper, you stated that many of the transplanted cells probably did not survive. Have you developed any ways to quantify the number of cells that die, or alternatively, to quantify the number of surviving cells in a ratio to the original number of transplant cells, as another determinant of the effectiveness of your transplants?
You stated that environmental factors characteristic of an injury, such as inflammation, excitotoxicity, secondary degeneration and progressive demyelination, could affect the efficacy of the transplant treatment. Are there ways to reduce these risks?
In the Regenerative Medicine journal paper you highlight the fact that growth factors, such as PDGF, IGF-1 and CNTF, affect the survival and myelinogenic capacity of oligodendrocytes and their progenitors. You suggest that perhaps these factors are either not present or insufficiently expressed following a 50kD injury but are expressed following a more severe 200kD injury. Does this mean that there may be an injury threshold for the release of these factors? If so, what would this threshold possibly depend on?
Yvanka de Soysa
Have you determined when exactly the therapeutic window for spinal cord cell transplant treatment closes? What are the molecular signals that prevent remyelination ten months after spinal cord injury?
Your chronic injury studies (in the 2005 paper) indicate that a potential reason why transplanted hESC-derived OPCs did not remyelinate axons after an SCI was due to the presence of astroglial scarring, yet it worked very well in an acute injury prior to an astroglial response. What further steps would research have to overcome so that this transplant research could become applicable to clinical usage in patients who had SCI in the past and may have already developed astroglial scars?
Currently, what stage are you (or your lab — Geron?) at in terms of conducting clinical trials with human subjects using hESCs for potential therapies for spinal cord injury or other neurodegenerative spinal cord diseases such as spinal muscular atrophy? Are clinical trials with human subjects an interest of yours as a stem cell researcher working with hESCs for the development of therapies for potential use in humans — why or why not?
Could the injection of the human fibroblast cell line induce any residual oligodendrocytes to perform some remylination in the injured animal without adding OPCs? Could you please explain the use of hFbs in this experiment and how they were prepared?
You mentioned in the Neuroscience Letters article that a number of obstacles must be reconciled before hESC therapy can become a common clinical practice. What are some of the major concerns with the use of embryonic stem cells, primarily from a biological or clinical perspective?
At what point do you believe life begins, or at least a life with the right of protection?