Multiple lines of evidence suggest that human adipose-derived stromal cells (hASCs) hold promise for future use in craniofacial skeletal regeneration. Human ASCs are easily harvested by simple liposuction procedures and are readily expandable as compared to bone marrow mesenchymal cells. Moreover, human ASCs undergo rapid osteogenic differentiation. In our laboratory, we have observed convincingly that ASCs, whether derived from mouse or human origin, contribute to osseous healing of mouse calvarial defects. For example, a surgical defect in the mouse parietal bone (4mm in diameter) shows no healing when untreated even up to 16 weeks post injury. Upon direct hASC application with an osteoconductive scaffold, significant bony healing is observed in as little as 4 weeks post injury. Perhaps most exciting are those applications of hASCs to the human patient. In small pilot studies, defects of the cranium, maxilla, and mandible have been either healed or enabled to heal faster with the use of hASCs. The current understanding of ASC identity and function, however, remains insufficient to allow larger clinical trials and applications as they are a highly heterogeneous population of cells. While surface antigen expression is an important component to this understanding, it is likely that more in depth analysis will be required to fully characterize hASCs.
We aim to provide this analysis through completion of the Specific Aims described in this proposal. We expect the results of these studies to move the field forward by providing a new understanding of the transcriptional diversity within hASCs. We anticipate that the findings from our innovative approach will help to define the relationship between transcriptional activity and cell surface markers on a single cell level. This understanding will allow us to more specifically enrich for a population of cells ideal for craniofacial skeletal regeneration.
Successful re-ossification of craniofacial defects is more robust in immature animals and young children. Conversely, skeletally mature animals and adult humans demonstrate an impaired ability to heal skull defects. While a plethora of strategies have been developed over the past century for treating adult calvarial defects, the myriad of methods currently available reflects the inadequacies of each therapeutic technique. By combining advances in developmental biology, organogenesis, stem cell biology, bioengineering, and material sciences, however, a new paradigm for calvarial bone tissue engineering has emerged - Regenerative Medicine. Despite accumulating evidence demonstrating the utility of human adipose derived stromal cells (hASCs) in regenerative applications, little is known about the heterogeneity that exists within the hASC population. By applying an information theoretic approach to cluster individual cells based on similar transcriptional profiles, it becomes possible it systematically interrogate a heterogeneous group of cells, such as hASCs, for functionally distinct subpopulations such as an osteoprogenitor population. This enriched population would be ideal to use for cell-based strategies for craniofacial skeletal regenerative medicine.
| Flacco, John; Chung, Natalie; Blackshear, Charles P et al. (2018) Deferoxamine Preconditioning of Irradiated Tissue Improves Perfusion and Fat Graft Retention. Plast Reconstr Surg 141:655-665 |
| Blackshear, Charles Philip; Rector, Michael Anthony; Chung, Natalie Narie et al. (2018) Three-Dimensional Ultrasound Versus Computerized Tomography in Fat Graft Volumetric Analysis. Ann Plast Surg 80:293-296 |
| Chan, Charles K F; Gulati, Gunsagar S; Sinha, Rahul et al. (2018) Identification of the Human Skeletal Stem Cell. Cell 175:43-56.e21 |
| Ko, Sae Hee; Nauta, Allison C; Morrison, Shane D et al. (2018) PHD-2 Suppression in Mesenchymal Stromal Cells Enhances Wound Healing. Plast Reconstr Surg 141:55e-67e |
| Murphy, Matthew P; Quarto, Natalina; Longaker, Michael T et al. (2017) * Calvarial Defects: Cell-Based Reconstructive Strategies in the Murine Model. Tissue Eng Part C Methods 23:971-981 |
| Tevlin, Ruth; Seo, Eun Young; Marecic, Owen et al. (2017) Pharmacological rescue of diabetic skeletal stem cell niches. Sci Transl Med 9: |
| Blackshear, Charles P; Flacco, John S; Vistnes, Stephanie M et al. (2017) Cell-Based Soft Tissue Reconstruction in a Hydrogel Scaffold. Ann Plast Surg 79:618-622 |
| Brett, Elizabeth; Chung, Natalie; Leavitt, William Tripp et al. (2017) A Review of Cell-Based Strategies for Soft Tissue Reconstruction. Tissue Eng Part B Rev 23:336-346 |
| Marshall, Clement D; Zielins, Elizabeth R; Brett, Elizabeth A et al. (2017) Rapid Isolation of BMPR-IB+ Adipose-Derived Stromal Cells for Use in a Calvarial Defect Healing Model. J Vis Exp : |
| Brett, Elizabeth; Zielins, Elizabeth R; Chin, Monica et al. (2017) Isolation of CD248-expressing stromal vascular fraction for targeted improvement of wound healing. Wound Repair Regen 25:414-422 |
Showing the most recent 10 out of 49 publications
