| Summary: | The biology of mesenchymal stem cells (MSCs) in humans is incompletely understood and a possible role of systemically circulating cells in health and autoimmune disease remains controversial. Physiological movement of bone marrow MSCs to sites of injury would support the rationale for intravenous administration for relocation to damaged organs. We hypothesized that biophysical skeletal trauma rather than molecular cues may explain reported MSC circulation phenomena. Deep-femoral vein (FV) and matched peripheral vein blood samples (PVBs) were collected from patients undergoing lower-limb orthopaedic procedures during surgery (tibia using conventional sequential reaming, <i>n</i> = 9, femur using reamer/irrigator/aspirator (RIA), <i>n</i> = 15). PVBs were also taken from early (<i>n</i> = 15) and established (<i>n</i> = 12) rheumatoid arthritis (RA) patients and healthy donors (<i>n</i> = 12). Colony-forming unit-fibroblasts (CFU-Fs) were found in 17/36 FVBs but only 7/74 PVBs (mostly from femoral RIA); highly proliferative clonogenic cells were not generated. Only one colony was found in control/RA samples (<i>n</i> = 28). The rare CFU-Fs’ MSC nature was confirmed by phenotypic: CD105<sup>+</sup>/CD73<sup>+</sup>/CD90<sup>+</sup> and CD19<sup>−</sup>/CD31<sup>−</sup>/CD33<sup>−</sup>/CD34<sup>−</sup>/CD45<sup>−</sup>/CD61<sup>−</sup>, and molecular profiles with 39/80 genes (including osteo-, chondro-, adipo-genic and immaturity markers) similar across multiple MSC tissue controls, but not dermal fibroblasts. Analysis of FVB-MSCs suggested that their likely origin was bone marrow as only two differences were observed between FVB-MSCs and IC-BM-MSCs (<i>ACVR2A</i>, <i>p</i> = 0.032 and <i>MSX1</i>, <i>p</i> = 0.003). Stromal cells with the phenotype and molecular profile of MSCs were scarcely found in the circulation, supporting the hypothesis that their very rare presence is likely linked to biophysical micro-damage caused by skeletal trauma (here orthopaedic manipulation) rather than specific molecular cues to a circulatory pool of MSCs capable of repair of remote organs or tissues. These findings support the use of organ resident cells or MSCs placed in situ to repair tissues rather than systemic administration.
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