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Bone Tissue Engineering with Perivascular Stem Cells

  • Author(s): James, Aaron Watkins
  • Advisor(s): Adams, John S
  • et al.
Abstract

Historically, mesenchymal stem cells (MSC) have been isolated in laboratory culture after several weeks, being selected from heterogeneous cell suspensions based on their ability to adhere and proliferate. Since 2001, human subcutaneous adipose tissue has been recognized as a rich source of tissue resident MSC. The isolation of perivascular progenitor cells from human adipose tissue by a cell sorting strategy was first published in 2008. Since this time, the interest in using pericytes and related perivascular stem cell (PSC) populations for tissue engineering has significantly increased. Herein, we describe a set of experiments in mouse and rat orthopaedic injury models, which examine the utility and advantages of PSC for bone tissue regeneration. In each model, PSC are compared to an unpurified stromal population taken from the same patient’s sample (termed SVF, or stromal vascular fraction). Next, we examine the effects of several growth and differentiation factors (GDFs) on PSC mediated bone repair, including BMP2 (Bone morphogenetic protein 2), NELL-1, and Wnt signaling ligands. Results showed that adipose-derived PSC are readily obtainable from human lipoaspirate without the need for culture, are able to form bone in vivo without the need for pre-differentiation, and induce superior vascularized bone formation in comparison to unpurified stromal cell populations taken from the same patient sample. PSC have striking functional overlap with other MSC types, including their prominent paracrine function as a rich source of GDFs, but also their ability to directly participate in tissue regeneration. Unlike other MSC types, PSC frequency, viability, and osteogenic differentiation appear unphased in the context of osteoporotic conditions. These observed similarities and differences beg compelling questions regarding the phenotypic overlap between PSC and other MSC types. Finally, several candidate molecules enhance the osteogenic differentiation of PSC. Among these, the novel Wnt signaling regulator NELL-1 stimulates PSC to induce greater vascularized bone than either treatment alone. In aggregate, PSC represent an abundant and uncultured MSC source with significant translational potential for bone tissue repair.

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