Cell surface markers for mesenchymal stem cells related to the skeletal system: A scoping review

Abstract

Multipotent mesenchymal stromal cells (MSCs) have been described as bone marrow stromal cells, which can form cartilage, bone or hematopoietic supportive stroma. In 2006, the International Society for Cell Therapy (ISCT) established a set of minimal characteristics to define MSCs. According to their criteria, these cells must express CD73, CD90 and CD105 surface markers; however, it is now known they do not represent true stemness epitopes. The objective of the present work was to determine the surface markers for human MSCs associated with skeletal tissue reported in the literature (1994-2021). To this end, we performed a scoping review for hMSCs in axial and appendicular skeleton. Our findings determined the most widely used markers were CD105 (82.9%), CD90 (75.0%) and CD73 (52.0%) for studies performed in vitro as proposed by the ISCT, followed by CD44 (42.1%), CD166 (30.9%), CD29 (27.6%), STRO-1 (17.7%), CD146 (15.1%) and CD271 (7.9%) in bone marrow and cartilage. On the other hand, only 4% of the articles evaluated in situ cell surface markers. Even though most studies use the ISCT criteria, most publications in adult tissues don't evaluate the characteristics that establish a stem cell (self-renewal and differentiation), which will be necessary to distinguish between a stem cell and progenitor populations. Collectively, MSCs require further understanding of their characteristics if they are intended for clinical use.

Keywords: Bone; Bone marrow; Cartilage; Cell surface marker; Mesenchymal stem cell (MSCs).

Fig. 1

Article selection. Literature search was performed in three databases Medline (PubMed), Scopus, and Web of Science obtaining a total of 2871 articles. After a revision performed by 18 observers, 152 articles were selected.

Fig. 2

Percentage of articles evaluating cell surface markers in vitro. The most frequently used markers agree with those proposed by ISCT 2006: CD105 (82.9%), CD90 (75.0%), CD73 (52.0%), followed by CD44 (42.1), CD166 (30.9%), CD29 (27.7%), STRO-1 (17.8%), CD146 (15.1%) and CD271 (7.9%).

Fig. 3

Summary of cell surface markers in bone marrow and cartilage. Percentage of articles evaluating cell surface markers in vitro. Inner circle: bone marrow (BM) and articular cartilage (AC). Middle circle describes cell surface markers for BM and AC. Outer circle describes anatomical sites where markers were identified to characterize possible MSCs. Abbreviations: BM: Bone marrow, AC: Articular cartilage, ND: Not described, IC: Iliac crest, F: Femur, H: Hip, K: Knee.

Fig. 4

Possible MSCs-cell/extracellular matrix interactions based on cell surface markers. Using STRING database interactions among cell surface markers and cells expressing them were established. CD44 is a receptor that associates with bone extracellular matrix proteins (osteopontin and collagen Type I, hyaluronic acid). In association with ERB-B2 it plays a function in hematopoiesis. CD166: expressed by stromal cells it interacts with CD6 in T cells to sustain their proliferation and activation. CD29: Receptor in association with ITG-alpha-3 binds to fibronectin, laminin and collagen type I. In association with ITGAV binds to fibronectin and laminin. CD146: Plays a role in cell adhesion to vascular endothelium when co-expressed with KDR. WNT5A is co-expressed with CD146 that could be associated with chondrogenesis. CD271: Stromal cells expressing CD271 are in direct contact with CD34 positive HSCs. CD271 can be associated with RTN4R, whose function is to bind to chondroitin sulfate. STRO-1: Is a protein that binds to CD34 HSCs cells. Abbreviations: ERBB2: Receptor tyrosine-protein kinase erbB-2; HMMR: Hyaluronan mediated motility receptor; MMPs: matrix metalloproteinases, ITG-alpha-3: Integrin alpha-3; ITGAV: Integrin alpha-V; KDR: Vascular endothelial growth factor receptor 2; WNT-5A: Wingless Protein Wnt-5a, RTN4R: (Reticulon-4 receptor) chondroitin sulfate receptor; HSC: Hematopoietic stem cell.