Sang Young Jeong

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

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 PKCα, 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. Stem Cells 2013;31:2136–2148

Galectin-3 secreted by human umbilical cord blood-derived mesenchymal stem cells reduces amyloid-β42 neurotoxicity in vitro

In this study, we found that expression and secretion of galectin‐3 (GAL‐3) were upregulated by amyloid‐β42 (Aβ42) exposure in human umbilical cord blood‐derived mesenchymal stem cell (hUCB‐MSC) without cell death. Aβ42‐exposed rat primary cortical neuronal cells co‐treated with recombinant GAL‐3 were protected from neuronal death in a dose‐dependent manner. hUCB‐MSCs were cocultured with Aβ42‐exposed rat primary neuronal cells or the neuroblastoma cell line, SH‐SY5Y in a Transwell chamber. Coculture of hUCB‐MSCs reduced cell death of Aβ42‐exposed neurons and SH‐SY5Y cells. This neuroprotective effect of hUCB‐MSCs was reduced significantly by GAL‐3 siRNA. These data suggested that hUCB‐MSC‐derived GAL‐3 is a survival factor against Aβ42 neurotoxicity.

Autocrine Action of Thrombospondin‐2 Determines the Chondrogenic Differentiation Potential and Suppresses Hypertrophic Maturation of Human Umbilical Cord Blood‐Derived Mesenchymal Stem Cells

Previous studies have shown that mesenchymal stem cell (MSC)‐based therapies have varying efficacies for the treatment of various diseases, including cartilage defects. In this study, we demonstrated that the chondrogenic differentiation potential of human umbilical cord blood‐derived MSCs (hUCB‐MSCs) obtained from different individual donors varies, and we investigated the molecular basis for this variation. Microarray gene expression analysis identified thrombospondin‐2 (TSP2) as a candidate gene underlying the interindividual variation in the chondrogenic differentiation potential of hUCB‐MSCs. To assess the association between TSP‐2 and the differentiation potential, we evaluated chondrogenic differentiation of hUCB‐MSCs treated with TSP2 siRNA. In addition, we studied the effect of supplementing exogenous recombinant TSP‐2 on TSP2 siRNA‐treated hUCB‐MSCs. We found that TSP‐2 autocrinally promoted chondrogenic differentiation of hUCB‐MSCs via the Notch signaling pathway, which was confirmed in MSCs from other sources such as bone marrow and adipose tissue. Interestingly, we observed that TSP‐2 attenuated hypertrophy, which inevitably occurs during chondrogenic differentiation of hUCB‐MSCs. Our findings indicated that the variable chondrogenic differentiation potential of MSCs obtained from different donors is influenced by the TSP‐2 level in the differentiating cells. Thus, the TSP‐2 level can be used as a marker to select MSCs with superior chondrogenic differentiation potential for use in cartilage regeneration therapy. Stem Cells 2015;33:3291–3303

Small hypoxia-primed mesenchymal stem cells attenuate graft-versus-host disease

Mesenchymal stem cells (MSCs) are of particular interest for the treatment of immune-related diseases due to their immunosuppressive capacity. Here, we show that Small MSCs primed with Hypoxia and Calcium ions (SHC-MSCs) exhibit enhanced stemness and immunomodulatory functions for treating allogeneic conflicts. Compared with naïve cultured human umbilical cord blood-derived MSCs, SHC-MSCs were resistant to passage-dependent senescence mediated via the monocyte chemoattractant protein-1 and p53/p21 cascade and secreted large amounts of pro-angiogenic and immunomodulatory factors, resulting in suppression of T-cell proliferation. SHC-MSCs showed DNA demethylation in pluripotency, germline, and imprinted genes similarly to very small embryonic-like stem cells, suggesting a potential mutual relationship. Genome-wide DNA methylome and transcriptome analyses indicated that genes related to immune modulation, cell adhesion, and the cell cycle were up-regulated in SHC-MSCs. Particularly, polo-like kinase-1 (PLK1), zinc-finger protein-143, dehydrogenase/reductase-3, and friend-of-GATA2 play a key role in the beneficial effects of SHC-MSCs. Administration of SHC-MSCs or PLK1-overexpressing MSCs significantly ameliorated symptoms of graft-versus-host disease (GVHD) in a humanized mouse model, resulting in significantly improved survival, less weight loss, and reduced histopathologic injuries in GVHD target organs compared with naïve MSC-infused mice. Collectively, our findings suggest that SHC-MSCs can improve the clinical treatment of allogeneic conflicts, including GVHD.

Modeling and Staging of Osteoarthritis Progression Using Serial CT Imaging and Arthroscopy

Objective The objective of this study was to describe in life methods by which osteoarthritis can be staged in order to time therapeutic interventions that are relevant to osteoarthritis (OA) clinical trials Methods Twenty-two sheep underwent arthroscopic meniscal destabilization to induce OA. Serial computed tomography (CT) imaging and arthroscopy were used to monitor osteoarthritis progression at 3-month intervals over 9 months. Eleven sheep received 1 intra-articular injection of hyaluronate 3 months after OA induction and another group of 11 received saline. A linear mixed model was used to define the trajectory of shape change in the medial joint compartment. Ordinal logistic regression was used to investigate the association between morphological changes and sclerosis. Results Three months after meniscal destabilization there were early bipolar chondral lesions in the medial compartment of the knee, as well as osteophytes and bone remodeling. Superficial fissures and cartilage cracks progressed to discrete areas of cartilage thinning and fibrillation on the medial tibial plateau by 6 months that became cartilage erosions by nine months. A linear mixed effect model demonstrated significant change in medial compartment length and width with over time (P < 0.05) for both groups. A significant association between severity of sclerosis and medial compartment morphology was also observed. Conclusions The induction of osteoarthritic lesions with meniscal release model can be followed using noninvasive and minimally invasive procedures allowing for real-time decisions about redosing therapies, or other changes such as extending trial timelines without sacrificing animals to conduct assessments.

Galectin-3 Secreted by Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells Reduces Amyloid-Beta42 Neurotoxicity In Vitro

In this study, we found that expression and secretion of galectin-3 (GAL-3) were upregulated by amyloid-β42 (Aβ42) exposure in human umbilical cord blood-derived mesenchymal stem cell (hUCB-MSC) without cell death. Aβ42-exposed rat primary cortical neuronal cells co-treated with recombinant GAL-3 were protected from neuronal death in a dose-dependent manner. hUCB-MSCs were cocultured with Aβ42-exposed rat primary neuronal cells or the neuroblastoma cell line, SH-SY5Y in a Transwell chamber. Coculture of hUCB-MSCs reduced cell death of Aβ42-exposed neurons and SH-SY5Y cells. This neuroprotective effect of hUCB-MSCs was reduced significantly by GAL-3 siRNA. These data suggested that hUCB-MSC-derived GAL-3 is a survival factor against Aβ42 neurotoxicity.