Mesenchymal stem cell (MSC) therapy is usually entering a new era

Mesenchymal stem cell (MSC) therapy is usually entering a new era shifting the focus from initial feasibility study to optimization of therapeutic efficacy. and discusses the major findings of their studies, emphasizing the anti-inflammatory function Brequinar distributor and trophic cross-talk mechanisms mediated by HGF and other MSC-derived trophic factors in sustaining the treatment benefits. Identification of multiple functionally synergistic trophic factors, such as HGF and vascular endothelial growth factor, can eventually lead to the development of efficacious cell-free therapeutic regimens targeting a broad spectrum of degenerative conditions. and their perivascular origin in multiple human organs appears certain[3,22,23], it is possible that these prophylactic benefits of poly(I:C) may be mediated through its trophic stimulatory effect on the Brequinar distributor endogenous MSC niches. Therapeutically, MSC trophic factors can be functionally redundant and synergistic, mediating Brequinar distributor immune regulation, cytoprotection, host stem cell activation and mobilization, and extracellular tissue remodeling. MSC also interact with cells of both the innate and adaptive immune systems, leading to immunomodulation of their effector functions[24]. The anti-inflammatory property of MSC was indeed highlighted in the study by Bai et al[5], showing that the therapy reduced the levels of multiple inflammatory cytokines and enhanced the levels of multiple anti-inflammatory cytokines produced by the mononuclear cells from the spinal cords. Along this line, Osiris Therapeutics is currently conducting a Phase III trial of MSC in treating several immune disorders such as graft-versus-host disease and Crohns disease ( Although how HGF might singly modulate the host immune response remains unclear, the authors speculated that HGF might alter the balance of pro- and anti-inflammatory T cells possibly by influencing the function of dendritic cells, which express cMet and therefore can be modulated by HGF. However, the immunomodulatory function of MSC alone does not appear to lead to effective tissue repair as demonstrated in our recent MSC therapy for the failing hamster heart, which shows that while a low-dose MSC regimen suppressed myocardial inflammation, it failed to promote cardiac repair. On the other hand, the low-dose cell therapy combined with poly(I:C) conditioning of MSC, which amplified HGF and other trophic factors, suppressed inflammation and stimulated myocardial regeneration[18]. Another important point regarding the therapeutic use of MSC trophic factors is that these soluble mediators typically exhibit a short half-life. Vascular endothelial growth factor (VEGF), for instance, Sox18 possesses a half-life of about 3 min in circulation[25]. Given a short half-life of HGF[26], the authors raised the question of how this treatment might result in long-term therapeutic benefits. It has previously been found that exogenously administered HGF could result in sustained elevation of endogenous HGF through a positive feedback loop[27]. This obtaining may not be unexpected given that the growth factor network often exhibits a cross-talk mechanism, enabling induction and amplification of more than one growth factor by another. This trophic cross-talk mechanism has been illustrated in our cardiac therapeutic studies based on intramuscular injection of MSC[4,15]. This MSC therapeutic strategy is coupled to the inherent ability of skeletal muscle to produce beneficial trophic factors in response to exercise and injury[28,29]. Although the injected MSC are trapped in the hamstrings, their trophic actions induce mobilization of bone marrow progenitor cells (BMPC) through the SDF-1/CXCR4 axis and promote increased growth factor levels in the quadriceps, liver, and brain[4,15]. We further demonstrate that this mobilized BMPC are also capable of trophic actions[30], contributing to the systemic increase in trophic factors, which may be explored for MS therapy (Physique ?(Figure1).1). Consistent with these preclinical findings, the clinical trials with MS patients revealed comparable benefits mediated by either intrathecal or intravenous MSC with no consensus on the best cell delivery route[31]. Note that intravenous infusion of MSC has been adopted for clinical trials of neurodegenerative and heart diseases[2,32]. Although the intravenously infused MSC are largely distributed to the lungs, their trophic actions underlie the observed therapeutic benefits impartial of MSC stemness. These findings illustrate the significance of formulating a minimally invasive stem cell delivery approach for patient care. Open in a separate windows Physique 1 Current model of mesenchymal stem cell therapy for brain and heart regeneration. Mesenchymal stem cell (MSC) therapies for brain and heart Brequinar distributor repairs have been conducted using either MSC or MSC-derived trophic factors. Successful trials have been obtained based on multiple injection regimens, such as intravenous (for brain and heart), intrathecal (for brain), and intramuscular (for heart) administration routes. Major MSC trophic factors that have been found to be crucial in mediating tissue regeneration include hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), stromal cell derived factor (SDF)-1,.