Short-Term Rapamycin Preconditioning Diminishes Therapeutic Efficacy of Human Adipose-Derived Stem Cells in a Murine Model of Multiple Sclerosis

Abstract

Human adipose-derived stem cells (ASCs) show immense promise for treating inflammatory diseases, attributed primarily to their potent paracrine signaling. Previous investigations demonstrated that short-term Rapamycin preconditioning of bone marrow-derived stem cells (BMSCs) elevated secretion of prostaglandin E2, a pleiotropic molecule with therapeutic effects in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS), and enhanced immunosuppressive capacity in vitro. However, this has yet to be examined in ASCs. The present study examined the therapeutic potential of short-term Rapamycin-preconditioned ASCs in the EAE model. Animals were treated at peak disease with control ASCs (EAE-ASCs), Rapa-preconditioned ASCs (EAE-Rapa-ASCs), or vehicle control (EAE). Results show that EAE-ASCs improved clinical disease scores and elevated intact myelin compared to both EAE and EAE-Rapa-ASC animals. These results correlated with augmented CD4+ T helper (Th) and T regulatory (Treg) cell populations in the spinal cord, and increased gene expression of interleukin-10 (IL-10), an anti-inflammatory cytokine. Conversely, EAE-Rapa-ASC mice showed no improvement in clinical disease scores, reduced myelin levels, and significantly less Th and Treg cells in the spinal cord. These findings suggest that short-term Rapamycin preconditioning reduces the therapeutic efficacy of ASCs when applied to late-stage EAE.

Adipose-Derived Stem Cell Exosomes Inhibit Hypertrophic Scaring Formation by Regulating Th17/Treg Cell Balance

“…ADSC-mediated effects on T cells proliferation and differentiation depend on several mechanisms, including cell-to-cell contact and secretion of soluble factors [ 50 , 51 ]. Accumulated evidence has proved that ADSC-Exos, carrying complex biological information, including mRNAs, microRNAs (miRNAs), and soluble proteins, interact with target cells and influence their fate in tissue regeneration and remolding [ 52 , 53 ].…”

Short-Term Autophagy Preconditioning Upregulates the Expression of COX2 and PGE2 and Alters the Immune Phenotype of Human Adipose-Derived Stem Cells In Vitro

“…Preconditioning strategies to improve immunomodulatory potency of MSCs for various anti-inflammatory and regenerative medicine applications is an active focus of the stem cell research field. Rapamycin has emerged as a promising candidate compound, and Rapa-treated MSCs from adipose [29,40], bone marrow [41], and umbilical cord [42] have been examined in preclinical models. In a 2016 report by Kim and colleagues, hASCs were treated with Rapa for 48 h prior to administration in a GvHD mouse model.…”

“…For example, short-term (2 h) treatment of rat BMSCs improved survival and repair of damaged myocardium following transplant into an ischemia/reperfusion model [41]. However, in an animal model of multiple sclerosis, short-term (4 h) preconditioning of human ASCs did not yield any therapeutic benefit and was in fact correlated with worsened disease measures [40]. Thus, to improve translational potential, it is critically important to define the dynamic immunomodulatory response of MSCs and fine-tune these strategies to each pathological situation.…”

Secretome as a Tool to Treat Neurological Conditions: Are We Ready?

“…Additionally, reduced neuropathological signs, either by decreasing the secretion of proinflammatory factors (IL-1α [151,153], IL-1β, IL-6, and TNF-α [150,151,153,155]), microglial activation [150,151,155], and improved cellular morphology [148], were also mentioned in these studies. Increased secretion of anti-inflammatory cytokines [150,154], growth factors [148,153], and angiogenesis [139,148,149], expression of proteins such as SDF-1 and CXCR4 [149], and improved homing efficiency [139,149] and cell survival following transplantation [147,149,152] were also shown.…”

“…Preconditioning with pharmacological or chemical compounds is one of the methods being investigated to improve the efficacy of treatment with MSCs, the secretome, or its components. The compounds tested include valproate, lithium chloride [139,147], hydrogen sulfate [148], tetramethylpyrazine [149], calpain inhibitors [150], thrombin [151,152], fasudil [153], rapamycin [154], roxadustat [155], cobalt chloride [138], and salidroside [156]. Despite their differences, all have been proposed to trigger anti-inflammatory [150,156], neuroprotective [138,148,[150][151][152]156], and other regulatory effects, which influence both the activation of important signaling pathways, cell migratory mechanisms and differentiation, ultimately leading to the regeneration of injured tissue [139,[147][148][149][153][154][155].…”