Thrombospondin-2 secreted by human umbilical cord blood-derived mesenchymal stem cells promotes chondrogenic differentiation

Abstract

Increasing evidence indicates that the secretome of mesenchymal stem cells (MSCs) has therapeutic potential for the treatment of various diseases, including cartilage disorders. However, the paracrine mechanisms underlying cartilage repair by MSCs are poorly understood. Here, we show that human umbilical cord blood-derived MSCs (hUCB-MSCs) promoted differentiation of chondroprogenitor cells by paracrine action. This paracrine effect of hUCB-MSCs on chondroprogenitor cells was increased by treatment with synovial fluid (SF) obtained from osteoarthritis (OA) patients but was decreased by SF of fracture patients, compared to that of an untreated group. To identify paracrine factors underlying the chondrogenic effect of hUCB-MSCs, the secretomes of hUCB-MSCs stimulated by OA SF or fracture SF were analyzed using a biotin label-based antibody array. Among the proteins increased in response to these two kinds of SF, thrombospondin-2 (TSP-2) was specifically increased in only OA SF-treated hUCB-MSCs. In order to determine the role of TSP-2, exogenous TSP-2 was added to a micromass culture of chondroprogenitor cells. We found that TSP-2 had chondrogenic effects on chondroprogenitor cells via PKCa, ERK, p38/MAPK, and Notch signaling pathways. Knockdown of TSP-2 expression on hUCB-MSCs using small interfering RNA abolished the chondrogenic effects of hUCB-MSCs on chondroprogenitor cells. In parallel with in vitro analysis, the cartilage regenerating effect of hUCB-MSCs and TSP-2 was also demonstrated using a rabbit full-thickness osteochondral-defect model. Our findings suggested that hUCB-MSCs can stimulate the differentiation of locally presented endogenous chondroprogenitor cells by TSP-2, which finally leads to cartilage regeneration.

Downregulation of Melanoma Cell Adhesion Molecule (MCAM/CD146) Accelerates Cellular Senescence in Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells

“…Mesenchymal stem cells derived from human umbilical cord blood (hUCB-MSCs) are characterized by self-renewal [1], a potential for differentiation into multiple cell lineages [2], low immunogenicity [3], and paracrine functions [4][5][6], suggesting that they may be beneficial in allogeneic MSC-based therapy. However, enabling MSC-based therapy requires expanding MSCs in large-scale production via long-term in vitro cultivation.…”

A Promyelocytic Leukemia Protein–Thrombospondin-2 Axis and the Risk of Relapse in Neuroblastoma

“…Thus, our study suggests that PML may regulate Schwannian differentiation within neuroblastoma tumors via angiogenesis inhibition or that TSP2 itself may have direct prodifferentiation properties in vivo. In keeping with this, TSP2 has been shown to induce synaptogenesis in the central nervous system (49) and chondrogenic differentiation in the bone (50).…”

Therapeutic effects of umbilical cord blood derived mesenchymal stem cell-conditioned medium on pulmonary arterial hypertension in rats

“…It was previously demonstrated that CM of hUCB-MSCs contain active levels of a number of disease modifying growth factors and cytokines. 21,22 CM of hUCB-MSCs contain sizable levels of angiopoietin, hepatocyte growth factor, interleukin-4, insulin-like growth factor, placental growth factor, vascular endothelial cell growth factor, angiogenin, stem cell factor, and tyrosine hydroxylase. 5,[23][24][25] Our previous studies demonstrated the neuroprotective effects of conditioned media from hADSC and hNSC in rat models of stroke and Huntington's disease.…”