Efficacy Of Regenerative Therapies Research Articles

Chimerism through the activation of invariant natural killer T cells prolongs graft survival after transplantation of induced pluripotent stem cell-derived allogeneic cardiomyocytes.

The loss of functional cells through immunological rejection after transplantation reduces the efficacy of regenerative therapies for cardiac failure that use allogeneic induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). Recently, mixed-chimera mice with donor-specific immunotolerance have been established using the RGI-2001 (liposomal formulation of α-galactosyl ceramide) ligand, which activates invariant natural killer T (iNKT) cells. The present study aimed to investigate whether mixed chimerism, established using RGI-2001, prolongs graft survival in allogeneic iPSC-CM transplantation. Mixed-chimera mice were established via combinatorial treatment with RGI-2001 and anti-CD154 antibodies in an irradiated murine bone marrow transplant model. Luciferase-expressing allogeneic iPSC-CMs were transplanted into mixed-chimera and untreated mice, followed by in vivo imaging. RGI-2001 enhanced iNKT cell activation in mice, and mixed chimerism was successfully established. In vivo imaging revealed that while the allografts were completely obliterated within 2 weeks when transplanted to untreated mice, their survivals were not affected in the mixed-chimera mice. Furthermore, numerous CD3+ cells infiltrated allografts in untreated mice, but fewer CD3+ cells were present in mixed-chimera mice. We conclude that mixed-chimera mice established using RGI-2001 showed prolonged graft survival after allogeneic iPSC-CM transplantation. This donor-specific immunotolerance might increase the efficacy of regenerative therapies for heart failure with allogeneic iPSC-CMs.

Generation of Acute Hind Limb Ischemia in NOD/SCID Mice and Treatment with Nanofiber-Expanded CD34+ Hematopoietic Stem Cells.

Critical limb ischemia (CLI) is primarily associated with a high risk of major amputation, cardiovascular events, and death. The current therapy involves direct endovascular intervention and is associated with long-term recurrence. However, patients with significant comorbidities are not eligible for this therapy. Hind limb ischemia model via femoral artery excision has commonly been used to determine therapeutic potential and for investigating cellular and molecular mechanisms. This protocol describes the ischemic model development in NOD/SCID mice and the use of human umbilical cord blood-derived and nanofiber scaffold-expanded CD34+ stem cells to investigate the efficacy of regenerative therapy.

IPSCs from people with MS can differentiate into oligodendrocytes in a homeostatic but not an inflammatory milieu.

Multiple sclerosis (MS) is an inflammatory and demyelinating disease of the central nervous system (CNS) that results in variable severities of neurodegeneration. The understanding of MS has been limited by the inaccessibility of the affected cells and the lengthy timeframe of disease development. However, recent advances in stem cell technology have facilitated the bypassing of some of these challenges. Towards gaining a greater understanding of the innate potential of stem cells from people with varying degrees of disability, we generated induced pluripotent stem cells (iPSCs) from peripheral blood mononuclear cells derived from stable and progressive MS patients, and then further differentiated them into oligodendrocyte (OL) lineage cells. We analyzed differentiation under both homeostatic and inflammatory conditions via sustained exposure to low-dose interferon gamma (IFNγ), a prominent cytokine in MS. We found that all iPSC lines differentiated into mature myelinating OLs, but chronic exposure to IFNγ dramatically inhibited differentiation in both MS groups, particularly if exposure was initiated during the pre-progenitor stage. Low-dose IFNγ was not toxic but led to an early upregulation of interferon response genes in OPCs followed by an apparent redirection in lineage commitment from OL to a neuron-like phenotype in a significant portion of the treated cells. Our results reveal that a chronic low-grade inflammatory environment may have profound effects on the efficacy of regenerative therapies.

Efficacy of regenerative therapy in aggressive periodontitis: a systematic review and meta-analysis of randomised controlled clinical trials.

To analyse evidence regarding the efficacy of periodontal regenerative procedures in intrabony defects in patients treated for aggressive periodontitis (AgP). A systematic search of the literature for randomised controlled clinical trials including patients treated for aggressive periodontitis that compared a group treated with regenerative therapy with another group treated with surgical debridement alone was conducted by two independent reviewers. Six studies were included in the meta-analysis of clinical and/or radiographic parameters at 6 and 12months. Probing pocket depth was smaller at 6months in patients treated with regenerative therapies compared with those treated with regular debridement (1.00mm, p < 0.001, 95% CI (0.67, 1.34)). At 12months this difference was more marked (0.41mm, p = 0.12, 95% CI (- 0.10, 0.91)). The distance between the cemento-enamel junction and the alveolar crest at both 6 (1.36mm, p < 0.001, 95% CI (1.03, 1.68)) and 12months (0.90mm, p = 0.01, 95% CI (0.24, 1.56)) was smaller in the group treated with regeneration. The use of biomaterials for regenerative therapy in AgP may be more effective than surgical debridement. Better outcomes were observed in terms of probing pocket depth and distance between the cemento-enamel junction and the alveolar crest at 6months. Regeneration should be considered as a therapy to prevent tooth loss, although more studies with larger sample size and longer follow-up are needed. Periodontal regeneration is effective in the treatment of intrabony defects in patients with AgP, as it leads to better outcomes in clinical and radiographic parameters.

Abstract 366: Cardiac Strain From Magnetic Resonance Imaging Offers Sensitive Detection of Therapeutic Efficacy Following Transplantation of Tissue Engineered Heart Muscles

Background: Myocardial infarction (MI) leads to gradually decreased cardiac contractility that can ultimately cause heart failure or sudden death. One potential therapy to recover this MI-impaired contractile function is the regenerative approach that integrates both tissue engineering and exogenously produced cardiomyocytes. Although this contractile recovery has been assessed by different imaging methods in previous studies, these assessments in global cardiac performance are plagued by their relatively low sensitivity. As this treatment is locally performed, the sensitivity of its therapeutic assessment can be improved by myocardial strain imaging that assesses regional contractility. Methods: We first made tissue engineered heart muscles (EHMs) by casting human embryonic stem cell-derived cardiomyocytes (ESC-CMs) with collagen in preformed molds. Then we transplanted these EHMs (n=12) into the post-MI rat hearts one month after this injure. We also performed sham surgeries on a control group (n=9) without EHM transplantation. Meanwhile, strain imaging from cardiac magnetic resonance imaging (MRI) and ultrasound were performed prior to and four weeks after EHM transplantations. In addition, global cardiac performance such as left ventricular ejection fraction (EF) was estimated from cardiac MRI. Results: Based on the measurements, regional myocardial strain measured from tagged MRI detected the preserved systolic function in the EHM-treated group compared to control group (P=0.04). In contrary, the global function EF was unable to detect this significant difference between both groups (P=0.38). Similarly, myocardial strain measured from cardiac ultrasound also failed to detect the significance between both treatment and control groups (P=0.24). Conclusions: This study for the first time confirmed that regional assessment of contractile function offered higher sensitivity compared to the conventional measure of global systolic performance. This finding highlights the feasibility and sensitivity of cardiac strain derived from tagged MRI as a sensitive method to assess the efficacy of regenerative therapies in both preclinical and clinical studies.