Bone marrow derived mesenchymal stem cells ameliorate inflammatory response in an in vitro model of familial hemophagocytic lymphohistiocytosis 2

Abstract

BackgroundFamilial hemophagocytic lymphohistiocytosis 2 (FHL2) is the most common familial type of hemophagocytic lymphohistiocytosis with immune dysregulation. FHL2 patients have mutations in the perforin gene which cause overactivation and proliferation of cytotoxic T lymphocytes and natural killer cells. Perforin is the key component of the cytolytic granule response function of cytotoxic T lymphocytes and natural killer cells. Perforin dysfunction causes a cytotoxic immune deficiency with a clinical outcome of uncontrolled and continuous immune stimulation response. This excessive stimulation leads to continuous systemic inflammation and, ultimately, multiorgan failure. Radical therapy is hematopoietic stem cell transplantation which is limited by the availability of a donor. Exacerbations of inflammatory attacks require a palliative immunosuppressive regimen. There is a need for an alternative or adjuvant therapy to maintain these patients when immunosuppression is ineffective or a donor is not available. Beneficial actions of mesenchymal stem cells (MSCs) have been shown in autoimmune diseases in clinical trials and are attributed to their immune-modulatory properties. This study aimed to assess the immune-modulatory effect of MSCs in an in-vitro model of FHL2.MethodsWe generated a targeted mutation in the perforin gene of NK92 cells to create an in-vitro FLH2 model using Crispr/Cas technology. A coculture setup was employed to assess the immunomodulatory efficacy of MSCs.ResultsEngineered NK92 clones did not show PRF1 mRNA expression and failed to secrete perforin upon phorbol myristate acetate–ionomycin stimulation, providing evidence for a valid FHL2 model. Coculture media of the engineered cells were investigated for the abundance of several cytokines. Coculture with MSCs revealed a reduction in major proinflammatory cytokines and an induction in anti-inflammatory and immunomodulatory cytokines compared to the parental NK92 cells.ConclusionsThis study shows the ameliorating effect of MSCs as an adjuvant immune modulator toward the therapy of FHL2 patients. MSCs are supportive therapy candidates for FHL2 patients under circumstances where prolonged immunosuppression is required to gain time before allogeneic hematopoietic stem cell transplantation.Electronic supplementary materialThe online version of this article (10.1186/s13287-018-0941-y) contains supplementary material, which is available to authorized users.

Mesenchymal Stem Cells Extract (MSCsE)-Based Therapy Alleviates Xerostomia and Keratoconjunctivitis Sicca in Sjogren’s Syndrome-Like Disease

“…MSCs have demonstrated promising therapeutic potentials when used in different diseases and in tissue regeneration. They were successfully deployed in the management of neural injuries, GVHD (graft versus host disease), cardiac regeneration, and most importantly autoimmune diseases [39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58]. MSCs display a unique combination of immunoregulatory/immunosuppression, tissue regeneration/repair, and anti-fibrotic properties [59,60] which make them a suitable therapeutic modality for autoimmune diseases.…”

How mesenchymal stem cell conditioned media affect the HeLa cells on Wnt/beta-catenin signaling, Notch-1 signaling, and apoptosis?

“…MSCs-CM shows promising opportunities for the therapy of various diseases including cancer, inflammation-induced tissue damage, and neurodegenerative diseases [25,26]. It has been shown that factors secreted by MSCs-CM influence cell proliferation, differentiation, immunoregulation, as well as regeneration [22,23,[25][26][27].…”

“…Human bone marrow-derived MSCs were obtained and characterized as described our previous report in accordance with the Hacettepe University Local Ethical Committee (LUT12/134-16) [22]. Conditioned media of P2 and P3 MSCs were freshly collected and filtered (0.22 μm filters) before use.…”

“…MSCs are the sources of several secretory mediators that account for their anti-inflammatory properties as well as contribu-ting to accelerated tissue regeneration [18,19]. Studies including us have reported secretion of soluble factors as well as several cytokines and chemokines including Vascular endothelial growth factor (VEGF), Insulin-like growth factor 1 (IGF1), C-X-C Motif Chemokine Ligand 12 (CXCL12), Interleukin 4 (IL4), IL10 that contribute to the therapeutic potential of MSCs [20][21][22]. It has been elucidated that the MSCs may impact the microenvironment through these secreted factors at the site of tumor growth as well as injury and repair.…”

Application and perspective of CRISPR/Cas9 genome editing technology in human diseases modeling and gene therapy

“…There are also many studies on the application of CRISPR/Cas9 to construct in vitro cell models of autoimmune diseases. Sevim et al constructed a model for familial hemophagocytic lymphohistiocytosis 2 (FHL2) in order to assess the effectiveness of coculturing with mesenchymal stromal cells as an alternative therapy when bone marrow transplantation is unavailable ( Sevim et al, 2018 ). The autoimmune regulatory gene (AIRE) has also been investigated using CRISPR technology, revealing that disruption of adhesion between the thymic medullary epithelial cells and thymus cells is one mechanism through which AIRE interference leads to autoimmunity ( Speck-Hernandez et al, 2018 ).…”