The unifying hypothesis of this proposal is that the use of biomaterial scaffolds is critical to the development of successful therapies for spinal cord injury. In the absence of a biomaterial scaffold that can help bridge the injury site, the lack of regeneration promoting substrates in the injured spinal cord limits the efficacy of current drug delivery and cell transplantation approaches. We hypothesize that the biomaterial scaffolds can be used to direct the differentiation of embryonic stem cell-derived progenitor motor neurons (pMNs), present growth factor trophic cues and deliver drugs to overcome the inhibitory nature of the adult spinal cord. Through the use of a biomaterial scaffold we hypothesize that we will be able to present combination therapies necessary to achieve significant regeneration following spinal cord injury. This hypothesis will be tested systematically by addressing the following specific aims, all of which are necessary to achieve the goal of spinal cord regeneration.
The aims of this proposal are: (1) to test the hypothesis that growth factor delivery from a fibrin-based biomaterial scaffold will enable the survival and differentiation of embryonic stem cell-derived progenitor motor neurons (pMNs) into motoneurons in an in vitro setting at levels comparable to or better than that observed with traditional differentiation protocols. (2) To test the hypothesis that growth factor delivery from a fibrin-based biomaterial scaffold will enable enhanced survival and differentiation of embryonic stem cell-derived motoneuron progenitors (pMNs) into motoneurons compared with pMN transplantation alone (no scaffold) in the in vivo setting of sub-acute (14 day) spinal cord injury. (3) To test the hypothesis that the combination of a biomaterial scaffold (with growth factor delivery), cell transplantation, and delivery of drugs to overcome the inhibitory cues of the adult spinal cord, will provide a combination therapy that is able to achieve regeneration following sub-acute (14 day) spinal cord injury.
Spinal cord injury is a major clinical problem. In the United States, about 12,000 people per year join the population of approximately 200,000 traumatic spinal cord injury patients. Spinal cord injuries typically occur in young patients (average age of 32, 55% of injuries occur at ages 16 to 30) and the impact of these injuries on the quality of life and productivity of these individuals is dramatic. In addition, the average cost of caring for a patient during the first year following spinal cord injury is $307,847(58). Therapeutic approaches to be developed and the mechanistic knowledge gained in this study may contribute to future clinical therapies for spinal cord injury patients. Approaches for the transplantation of motoneurons developed in this project may also be useful for neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS).
|Iyer, Nisha R; Wilems, Thomas S; Sakiyama-Elbert, Shelly E (2017) Stem cells for spinal cord injury: Strategies to inform differentiation and transplantation. Biotechnol Bioeng 114:245-259|
|Iyer, Nisha R; Huettner, James E; Butts, Jessica C et al. (2016) Generation of highly enriched V2a interneurons from mouse embryonic stem cells. Exp Neurol 277:305-316|
|Xu, Hao; Sakiyama-Elbert, Shelly E (2015) Directed Differentiation of V3 Interneurons from Mouse Embryonic Stem Cells. Stem Cells Dev 24:2723-32|
|Wilems, Thomas S; Pardieck, Jennifer; Iyer, Nisha et al. (2015) Combination therapy of stem cell derived neural progenitors and drug delivery of anti-inhibitory molecules for spinal cord injury. Acta Biomater 28:23-32|
|Xu, Hao; Iyer, Nisha; Huettner, James E et al. (2015) A puromycin selectable cell line for the enrichment of mouse embryonic stem cell-derived V3 interneurons. Stem Cell Res Ther 6:220|
|Wilems, Thomas S; Sakiyama-Elbert, Shelly E (2015) Sustained dual drug delivery of anti-inhibitory molecules for treatment of spinal cord injury. J Control Release 213:103-11|
|McCreedy, D A; Wilems, T S; Xu, H et al. (2014) Survival, Differentiation, and Migration of High-Purity Mouse Embryonic Stem Cell-derived Progenitor Motor Neurons in Fibrin Scaffolds after Sub-Acute Spinal Cord Injury. Biomater Sci 2:1672-1682|
|Sakiyama-Elbert, Shelly E (2014) Incorporation of heparin into biomaterials. Acta Biomater 10:1581-7|
|Brown, Chelsea R; Butts, Jessica C; McCreedy, Dylan A et al. (2014) Generation of v2a interneurons from mouse embryonic stem cells. Stem Cells Dev 23:1765-76|
|McCreedy, Dylan A; Brown, Chelsea R; Butts, Jessica C et al. (2014) A new method for generating high purity motoneurons from mouse embryonic stem cells. Biotechnol Bioeng 111:2041-55|
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