title: Low Molecular Weight Fraction of Commercial Human Serum Albumin Induces Morphologic and Transcriptional Changes of Bone Marrow-Derived Mesenchymal Stem Cells.
abstract: Osteoarthritis (OA) is the most common chronic disease of the joint; however, the therapeutic options for severe OA are limited. The low molecular weight fraction of commercial 5% human serum albumin (LMWF5A) has been shown to have anti-inflammatory properties that are mediated, in part, by a diketopiperazine that is present in the albumin preparation and that was demonstrated to be safe and effective in reducing pain and improving function when administered intra-articularly in a phase III clinical trial. In the present study, bone marrow-derived mesenchymal stem cells (BMMSCs) exposed to LMWF5A exhibited an elongated phenotype with diffuse intracellular F-actin, pronounced migratory leading edges, and filopodia-like projections. In addition, LMWF5A promoted chondrogenic condensation in "micromass" culture, concurrent with the upregulation of collagen 2α1 mRNA. Furthermore, the transcription of the CXCR4-CXCL12 axis was significantly regulated in a manner conducive to migration and homing. Several transcription factors involved in stem cell differentiation were also found to bind oligonucleotide response element probes following exposure to LMWF5A. Finally, a rapid increase in PRAS40 phosphorylation was observed following treatment, potentially resulting in the activation mTORC1. Proteomic analysis of synovial fluid taken from a preliminary set of patients indicated that at 12 weeks following administration of LMWF5A, a microenvironment exists in the knee conducive to stem cell infiltration, self-renewal, and differentiation, in addition to indications of remodeling with a reduction in inflammation. Taken together, these findings imply that LMWF5A treatment may prime stem cells for both mobilization and chondrogenic differentiation, potentially explaining some of the beneficial effects achieved in clinical trials.
authors.affiliation: Swedish Medical Center, Trauma Research Department, Englewood, Colorado, USA; St. Anthony Hospital, Trauma Research Department, Lakewood, Colorado, USA; Medical Center of Plano, Trauma Research Department, Plano, Texas, USA; Ampio Pharmaceuticals Inc., Englewood, Colorado, USA; New York Blood Center, New York, New York, USA; SomaLogic Inc., Boulder, Colorado, USA dbaror@ampiopharma.com.
authors.forename: David
authors.initials: D
authors.lastname: Bar-Or
authors.affiliation: Swedish Medical Center, Trauma Research Department, Englewood, Colorado, USA; St. Anthony Hospital, Trauma Research Department, Lakewood, Colorado, USA; Medical Center of Plano, Trauma Research Department, Plano, Texas, USA; Ampio Pharmaceuticals Inc., Englewood, Colorado, USA; New York Blood Center, New York, New York, USA; SomaLogic Inc., Boulder, Colorado, USA.
authors.forename: Gregory W
authors.initials: GW
authors.lastname: Thomas
authors.affiliation: Swedish Medical Center, Trauma Research Department, Englewood, Colorado, USA; St. Anthony Hospital, Trauma Research Department, Lakewood, Colorado, USA; Medical Center of Plano, Trauma Research Department, Plano, Texas, USA; Ampio Pharmaceuticals Inc., Englewood, Colorado, USA; New York Blood Center, New York, New York, USA; SomaLogic Inc., Boulder, Colorado, USA.
authors.forename: Leonard T
authors.initials: LT
authors.lastname: Rael
authors.affiliation: Swedish Medical Center, Trauma Research Department, Englewood, Colorado, USA; St. Anthony Hospital, Trauma Research Department, Lakewood, Colorado, USA; Medical Center of Plano, Trauma Research Department, Plano, Texas, USA; Ampio Pharmaceuticals Inc., Englewood, Colorado, USA; New York Blood Center, New York, New York, USA; SomaLogic Inc., Boulder, Colorado, USA.
authors.forename: Elizabeth D
authors.initials: ED
authors.lastname: Gersch
authors.affiliation: Swedish Medical Center, Trauma Research Department, Englewood, Colorado, USA; St. Anthony Hospital, Trauma Research Department, Lakewood, Colorado, USA; Medical Center of Plano, Trauma Research Department, Plano, Texas, USA; Ampio Pharmaceuticals Inc., Englewood, Colorado, USA; New York Blood Center, New York, New York, USA; SomaLogic Inc., Boulder, Colorado, USA.
authors.forename: Pablo
authors.initials: P
authors.lastname: Rubinstein
authors.affiliation: Swedish Medical Center, Trauma Research Department, Englewood, Colorado, USA; St. Anthony Hospital, Trauma Research Department, Lakewood, Colorado, USA; Medical Center of Plano, Trauma Research Department, Plano, Texas, USA; Ampio Pharmaceuticals Inc., Englewood, Colorado, USA; New York Blood Center, New York, New York, USA; SomaLogic Inc., Boulder, Colorado, USA.
authors.forename: Edward
authors.initials: E
authors.lastname: Brody
mesh_terms: D001854:Bone Marrow Cells / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D017326:Clinical Trials, Phase III as Topic; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D006801:Humans; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000187:drug effects*; D008970:Molecular Weight; D010003:Osteoarthritis / Q000473:pathology / Q000628:therapy*; D040901:Proteomics; D012709:Serum Albumin / Q000494:pharmacology*; D015398:Signal Transduction
chemical_list: D012709:Serum Albumin
keywords: Actin; Collagen 2α1; Human serum albumin; Mesenchymal stem cell; Osteoarthritis; PRAS40