Early Translational I
$1 723 048
Spinal cord injury (SCI) is a problem that affects approximately 2 million people worldwide. Chronic health problems for patients suffering partial and complete spinal cord injury impose tremendous emotional and financial burdens on patients, families, health care providers, and the health delivery system. There remains no adequate treatment for SCI, but stem cell and regenerative medicine technologies hold substantial promise. Although a handful of early trials involving the implantation of bone marrow derived mesenchymal stem cells (MSCs) are underway, these studies involve the use of cells that appear to support spinal neuron survival and recovery, but do not replace neurons themselves that were lost due to injury. Much research has focused on generating supportive cells such as oligodendrocytes and glial-like cells which have each been shown to promote the survival and recovery of spinal cord neurons that were not lost due to injury. Unfortunately, the injured spinal cord is an environment that is inhibitory to neurons themselves, and inflammation at the injury site can be hostile to transplanted cells. Recently, however, methods have been developed that hold promise for a strategy in which one type of implanted stem cell may chaperone a second type of stem cell, simultaneously protecting the susceptible cell from the challenging SCI environment while drawing on the strengths of both cells to regenerate the injured spinal cord. Furthermore, if these cells are implanted to the injury site in a tissue-engineered "architectural" matrix that can provide the cells with instructions guiding their behavior towards regeneration, a powerful treatment modality will emerge. This proposal seeks to fabricate such a dual stem cell-seeded implantable matrix, and demonstrate that it is capable of safely improving functional outcome after spinal cord injury.
Statement of Benefit to California:
It is estimated that ten to fifteen thousand new spinal cord injuries (SCI) occur each year, adding to the 2 million chronic sufferers. The physical, emotional, financial, and social burdens of Californians with SCI are tremendous. Because the consequences of SCI, including conditions such as paralysis, are usually lifelong and impact nearly every aspect of a patient's life, the burdens specific to this injury are disproportionately large compared to many chronic health problems. It is the aim of the proposed research to develop a dual stem cell tissue-engineered implant that will improve the recovery of motor function following injury. If successful, the treatment will benefit not only patients, but their families and care givers. By enabling individuals to regain their abilities for activities of daily living (ADLs), a successful treatment would shorten the chronic nature of SCI, reduce the secondary health consequences, and would therefore offer economic benefit to California patients, families, and health care systems. A successful treatment would further benefit the California biotechnology industry by creating jobs that would help bring the technology to clinical reality. Finally, such a treatment modality would create unique learning and career development opportunities for California students and trainees in areas ranging from biomedical research, to physical therapy, bioengineering, and clinical specialties.
The goal of this application is to use dual stem cell (SC) transplantation in tissue engineered scaffolds for the repair of spinal cord injury (SCI). The proposed research builds upon prior work in designing implantable extracellular matrices (ECM) seeded with glial cell populations to promote nerve regeneration. This project investigates whether transplantation of extracellular matrix hydrogels organized by the application of a magnetic field and then seeded with both neurons and mesenchymal stem cells (MSCs) will enhance regeneration in (SCI) models. The applicant intends to use both MSCs and human embryonic stem cells (hESCs) differentiated into motor neurons and to first establish conditions for the growth and maintenance of these cells within the hydrogels. Then, the gels will be organized by exposing the tissue-engineered ECM scaffolds to a magnetic field. The efficacy of these tissue engineered scaffolds on spinal cord regeneration as well as their safety will be assayed in a model of SCI. Efficacy endpoints, including locomotor assessment to determine function, tissue histology, and evidence of organized myelin structure will be evaluated. Safety assays will include an analysis of potential for tumorigenicity and ectopic tissue formation. SCI is a problem that afflicts approximately two million people worldwide. There are currently no adequate treatments for SCI, but SCs and regenerative medicine technologies hold substantial promise. Reviewers agreed that the impact of the proposed research could be substantial if the investigators were successful in solving this complex problem. In addition, one reviewer asserted that the rationale for the proposed guidance of new neurites was sound. Another reviewer found the use of two different cell populations to be a worthwhile strategy, as each cell type could contribute differentially and synergistically to the regenerative process. However, another reviewer pointed out that although the scientific basis of the study is intriguing, the underlying hypothesis has yet to be substantiated. While enthusiastic about the basic idea, reviewers expressed serious concerns about the feasibility of the proposed research. One major concern was related to the logic of using neurons in the tissue scaffolds, since loss of neurons at the site of injury in spinal cord lesions is only a minor component of the pathology. Although the idea of a mixed cell population in the scaffolds was viewed favorably, reviewers suggested that the inclusion of glial precursors would be a much more appropriate and promising approach. This and other features of the proposal raised reviewer concern that the applicant did not have adequate understanding of SCI. Reviewers also found the design and description of the experiments unclear and confusing. Additionally, reviewers questioned the experience and familiarity of the PI with the in vivo model for SCI and expressed concern that collaborators with such expertise were not included in the proposal. Reviewers had serious concerns about the qualifications of the PI and, in particular, found little evidence from his/her publication record to indicate expertise in SC biology or experience in leading substantive research projects. Additionally, appropriate collaborations (e.g. in the area of SCI) were not proposed or developed. The team appears to have access to adequate facilities to complete the proposed studies. In summary, reviewers believed that this proposal could have a potentially substantial impact in the field of SCI. However reviewers had major concerns about the project’s feasibility and the lack of appropriate expertise and experience of the PI.