Churchman Sarah M, Jones Elena A, Roshdy Tarek, Cox George, Boxall Sally A, McGonagle Dennis, Giannoudis Peter V
Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds LS9 7TF, UK.
NIHR-Leeds Musculoskeletal and Biomedical Research Center, Chapel Allerton Hospital, Leeds Teaching Hospital NHS Trust, Leeds LS7 4SA, UK.
J Clin Med. 2020 Mar 31;9(4):968. doi: 10.3390/jcm9040968.
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 ( = 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.
人类间充质干细胞（MSCs）的生物学特性尚未完全明确，全身循环细胞在健康和自身免疫性疾病中的潜在作用仍存在争议。骨髓间充质干细胞向损伤部位的生理性迁移，为静脉注射使其重新定位于受损器官提供了理论依据。我们推测，生物物理性骨骼创伤而非分子信号，可能解释了已报道的间充质干细胞循环现象。在接受下肢骨科手术的患者术中采集股深静脉（FV）血样及配对的外周静脉血样（PVBs）（胫骨采用传统顺序扩髓，n = 9；股骨采用扩髓/冲洗/吸引器（RIA），n = 15）。还从早期（n = 15）和确诊（n = 12）的类风湿关节炎（RA）患者以及健康供者（n = 12）中采集了外周静脉血样。在17/36份股深静脉血样中发现了集落形成单位 - 成纤维细胞（CFU - Fs），但在外周静脉血样中仅发现7/74份（大多来自股骨RIA组）；未产生高增殖性克隆细胞。在对照/类风湿关节炎样本（n = 28）中仅发现1个集落。通过表型（CD105/CD73/CD90和CD19/CD31/CD33/CD34/CD45/CD61）及分子谱（39/80个基因，包括成骨、成软骨、成脂及未成熟标志物）证实了罕见CFU - Fs的间充质干细胞特性，这些基因在多个间充质干细胞组织对照中相似，但与真皮成纤维细胞不同。对股深静脉间充质干细胞的分析表明，其可能起源于骨髓，因为股深静脉间充质干细胞与髂嵴骨髓间充质干细胞（IC - BM - MSCs）之间仅观察到两个差异（ACVR2A，p = 0.032；MSX1，p = 0.003）。循环中几乎未发现具有间充质干细胞表型和分子谱特征的基质细胞，这支持了以下假设：它们的罕见存在可能与骨骼创伤（此处为骨科手术操作）引起的生物物理微损伤有关，而非与能够修复远处器官或组织的间充质干细胞循环池的特定分子信号有关。这些发现支持使用器官驻留细胞或原位植入的间充质干细胞来修复组织，而非全身给药。
