Dkk1 Antagonism for Stromal Vascular Fraction (SVF) Mediated Bone Repair
Abstract
Non-healing bone defects remain a significant problem for combat casualties and military veterans. The gold standard for skeletal regeneration is autograft bone, which is limited in supply, and possesses harvest-related complications. As an alternative, mesenchymal stem cells (MSC) have been employed to accelerate bone regeneration. Yet, current MSC sources have significant drawbacks, including: (1) scarce availability, (2) need for culture, and (3) cell heterogeneity with decreased bone-forming efficacy. On the backdrop of these significant limitations, our research group has identified a novel, purified and uncultured stem cell source for improved bone tissue regeneration, known as Perivascular Stem Cells (PSC). PSC are prospectively purified ancestors of culture derived MSC and are identified by their presence around blood vessels. PSC are isolated from adipose tissue by multicolor fluorescence activated cell sorting (FACS). Since the first description of PSC by our research group, we have demonstrated in multiple animal models that PSC induce significantly greater bone regeneration as compared to unpurified stromal cells derived from the same patients adipose sample. Despite the clear cut biologic advantages of PSC for bone regeneration, the level of complexity for cell isolation is high, leading to regulatory challenges in clinical translation. In contrast, a much simpler and more deployable solution from a regulatory standpoint would be to identify those cell signaling components responsible for the poor-bone forming efficacy of SVF or their culture-equivalent (ASC). This advance will allow one to bypass the need for cell purification. Toward this end, whole transcriptome sequencing (RNA Seq) was performed on SVF and PSC from the same patient samples. We screened our transcriptome analysis for extracellular, anti-osteogenic molecules enriched in SVF, and identified the Wnt signaling antagonist DKK1 (Dickkopf-1) as a targetable factor.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jan 01, 2024
- Accession Number
- AD1227969
Entities
People
- Aaron W James
Organizations
- Johns Hopkins University