Transient Existence of Circulating Mesenchymal Stem Cells in the Deep Veins in Humans Following Long Bone Intramedullary Reaming

Abstract

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, n = 9, femur using reamer/irrigator/aspirator (RIA), n = 15). PVBs were also taken from early (n = 15) and established (n = 12) rheumatoid arthritis (RA) patients and healthy donors (n = 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 (n = 28). The rare CFU-Fs’ MSC nature was confirmed by phenotypic: CD105+/CD73+/CD90+ and CD19−/CD31−/CD33−/CD34−/CD45−/CD61−, 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 (ACVR2A, p = 0.032 and MSX1, p = 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.

Therapeutic Mesenchymal Stem/Stromal Cells: Value, Challenges and Optimization

“…After being mobilized, these local MSCs are recruited to the site of injury where they participate in the healing process (Xu and Li, 2014). Another hypothesis supports that the very rare presence of MSCs is likely linked to biophysical microdamage rather than the fact that specific molecular cues to a circulatory pool of MSCs are capable of repairing remote organs or tissues (Churchman et al, 2020). Several groups have revealed that MSCs, after infusion, activate complement by unknown mechanisms, leading to their damage and disappearance.…”

Ways to increase the regenerative potential of mesenchymal stromal cells

“…КЛЕТОЧНАЯ БИОЛОГИЯ, ЦИТОЛОГИЯ, ГИСТОЛОГИЯ Как известно, при повреждении тканей МСК способны выходить в системный кровоток для последующей миграции в пораженную область [6,66]. Их мобилизация из депо в периферическую кровь может быть стимулирована путем внутривенного введения гранулоцитарного колониестимулирующего фактора (granulocyte colony-stimulating factor, G-CSF) [67,68], гранулоцитарно-макрофагального колониестимулирующего фактора (granulocyte macrophage colony-stimulating factor, GM-CSF) [69], TGF-β [70], субстанции P [71], VEGF [71].…”

Multipotent Mesenchymal Stromal Cells in Rheumatoid Arthritis and Systemic Lupus Erythematosus; From a Leading Role in Pathogenesis to Potential Therapeutic Saviors?

“…An interesting aspect of the use of culture-expanded MSCs as effector cells for immunomodulation in RA is that these cells are given intravenously. However, there is little evidence for the physiological circulation of MSCs in humans, including patients with RA ( 49 ), which will be discussed further in this review.…”