title: Perivascular stem cells: a prospectively purified mesenchymal stem cell population for bone tissue engineering.
abstract: Adipose tissue is an ideal source of mesenchymal stem cells for bone tissue engineering: it is largely dispensable and readily accessible with minimal morbidity. However, the stromal vascular fraction (SVF) of adipose tissue is a heterogeneous cell population, which leads to unreliable bone formation. In the present study, we prospectively purified human perivascular stem cells (PSCs) from adipose tissue and compared their bone-forming capacity with that of traditionally derived SVF. PSCs are a population (sorted by fluorescence-activated cell sorting) of pericytes (CD146+CD34-CD45-) and adventitial cells (CD146-CD34+CD45-), each of which we have previously reported to have properties of mesenchymal stem cells. Here, we found that PSCs underwent osteogenic differentiation in vitro and formed bone after intramuscular implantation without the need for predifferentiation. We next sought to optimize PSCs for in vivo bone formation, adopting a demineralized bone matrix for osteoinduction and tricalcium phosphate particle formulation for protein release. Patient-matched, purified PSCs formed significantly more bone in comparison with traditionally derived SVF by all parameters. Recombinant bone morphogenetic protein 2 increased in vivo bone formation but with a massive adipogenic response. In contrast, recombinant Nel-like molecule 1 (NELL-1; a novel osteoinductive growth factor) selectively enhanced bone formation. These studies suggest that adipose-derived human PSCs are a new cell source for future efforts in skeletal regenerative medicine. Moreover, PSCs are a stem cell-based therapeutic that is readily approvable by the U.S. Food and Drug Administration, with potentially increased safety, purity, identity, potency, and efficacy. Finally, NELL-1 is a candidate growth factor able to induce human PSC osteogenesis.
authors.affiliation: Dental and Craniofacial Research Institute, University of California, Los Angeles, USA. 900950-1579, USA.
authors.forename: Aaron W
authors.initials: AW
authors.lastname: James
authors.forename: Janette N
authors.initials: JN
authors.lastname: Zara
authors.forename: Xinli
authors.initials: X
authors.lastname: Zhang
authors.forename: Asal
authors.initials: A
authors.lastname: Askarinam
authors.forename: Raghav
authors.initials: R
authors.lastname: Goyal
authors.forename: Michael
authors.initials: M
authors.lastname: Chiang
authors.forename: Wei
authors.initials: W
authors.lastname: Yuan
authors.forename: Le
authors.initials: L
authors.lastname: Chang
authors.forename: Mirko
authors.initials: M
authors.lastname: Corselli
authors.forename: Jia
authors.initials: J
authors.lastname: Shen
authors.forename: Shen
authors.initials: S
authors.lastname: Pang
authors.forename: David
authors.initials: D
authors.lastname: Stoker
authors.forename: Ben
authors.initials: B
authors.lastname: Wu
authors.forename: Kang
authors.initials: K
authors.lastname: Ting
authors.forename: Bruno
authors.initials: B
authors.lastname: Péault
authors.forename: Chia
authors.initials: C
authors.lastname: Soo
mesh_terms: D050156:Adipogenesis; D052436:Adipose Tissue, White / Q000166:cytology / Q000378:metabolism; D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D001857:Bone Matrix / Q000378:metabolism; D055396:Bone Morphogenetic Protein 2 / Q000378:metabolism / Q000494:pharmacology; D001861:Bone Regeneration; D051929:CD146 Antigen / Q000378:metabolism; D002130:Calcium Phosphates / Q000378:metabolism; D002135:Calcium-Binding Proteins; D018929:Cell Culture Techniques; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D017493:Leukocyte Common Antigens / Q000378:metabolism; D015187:Lipectomy; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010012:Osteogenesis; D020286:Pericytes / Q000166:cytology* / Q000187:drug effects; D011446:Prospective Studies; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology; D044968:Regenerative Medicine / Q000379:methods; D054457:Tissue Scaffolds; D055114:X-Ray Microtomography
chemical_list: D018952:Antigens, CD34; C525718:BMP2 protein, human; D055396:Bone Morphogenetic Protein 2; D051929:CD146 Antigen; D002130:Calcium Phosphates; D002135:Calcium-Binding Proteins; C497902:MCAM protein, human; C104144:NELL1 protein, human; D009419:Nerve Tissue Proteins; D011994:Recombinant Proteins; D017493:Leukocyte Common Antigens; C516769:PTPRC protein, human; C018392:tricalcium phosphate