Successful Treatment of Plaque Psoriasis with Allogeneic Gingival Mesenchymal Stem Cells: A Case Study

Plaque psoriasis is the most common type of psoriasis that manifests as red scaly patches with white scales affecting body areas including scalp, elbows, knees, trunk, and buttocks. Although many treatment options are available including novel biologics, no cure is available. Mesenchymal stem cells (MSCs) have been safely used to treat a variety of human diseases. Allogeneic MSCs possess unique characteristics including hypoimmunogenicity, immunomodulatory, and anti-inflammatory properties, and they are currently being explored for potential therapeutic use for many systemic inflammatory diseases. The human gingival tissue is an easily accessible and obtainable source for the isolation of MSCs. MSCs from adult human gingiva are of fetal-like phenotype, multipotent, and easy to isolate and expand in vitro. Herein, we report a case of a 19-year-old man with a 5-year history of severe plaque psoriasis refractory to multiple topical and systemic therapies who was treated with allogeneic human gingival MSCs. Complete regression was achieved after 5 infusions with no adverse reaction occurred. The patient has been followed for three years and has remained disease free.

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Mesenchymal stem cells are injured by complement after their contact with serum

Blood ◽

10.1182/blood-2012-03-420612 ◽

2012 ◽

Vol 120 (17) ◽

pp. 3436-3443 ◽

Cited By ~ 94

Author(s):

Yan Li ◽

Feng Lin

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Cell Surface ◽

Complement Activation ◽

Human Mscs ◽

Cellular Injury ◽

Allogeneic Mscs ◽

Complement Regulators

Abstract Despite the potent immunosuppressive activity that mesenchymal stem cells (MSCs) display in vitro, recent clinical trial results are disappointing, suggesting that MSC viability and/or function are greatly reduced after infusion. In this report, we demonstrated that human MSCs activated complement of the innate immunity after their contact with serum. Although all 3 known intrinsic cell-surface complement regulators were present on MSCs, activated complement overwhelmed the protection of these regulators and resulted in MSCs cytotoxicity and dysfunction. In addition, autologous MSCs suffered less cellular injury than allogeneic MSCs after contacting serum. All 3 complement activation pathways were involved in generating the membrane attack complex to directly injure MSCs. Supplementing an exogenous complement inhibitor, or up-regulating MSC expression levels of CD55, one of the cell-surface complement regulators, helped to reduce the serum-induced MSC cytotoxicity. Finally, adoptively transferred MSCs in complement deficient mice or complement-depleted mice showed reduced cellular injury in vivo compared with those in wild type mice. These results indicate that complement is integrally involved in recognizing and injuring MSCs after their infusion, suggesting that autologous MSCs may have ad-vantages over allogeneic MSCs, and that inhibiting complement activation could be a novel strategy to improve existing MSC-based therapies.

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Mesenchymal stem cells derived from normal gingival tissue inhibit the proliferation of oral cancer cells in vitro and in vivo

International Journal of Oncology ◽

10.3892/ijo.2016.3715 ◽

2016 ◽

Vol 49 (5) ◽

pp. 2011-2022 ◽

Cited By ~ 10

Author(s):

Xiaoli Ji ◽

Zhihui Zhang ◽

Ying Han ◽

Jiangyuan Song ◽

Xiangliang Xu ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Oral Cancer ◽

Cancer Cells ◽

Gingival Tissue ◽

Oral Cancer Cells

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185 Overexpression or CRISPr/Cas9-mediated inhibition of prostaglandin E2 receptors EP2 and EP4 in equine adipose mesenchymal stem cells: implications for cell migration and cellular therapies

Reproduction Fertility and Development ◽

10.1071/rdv31n1ab185 ◽

2019 ◽

Vol 31 (1) ◽

pp. 217

Author(s):

A. C. F. Mançanares ◽

J. O. Manríquez ◽

J. Cabezas ◽

F. Telleria ◽

L. Rodriguez ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Prostaglandin E2 ◽

Lentiviral Vector ◽

Inflammatory Diseases ◽

Calf Serum ◽

Negative Control ◽

Cell Surface Receptor ◽

Surface Receptor

Prostaglandin E2 (PGE2) acts through 4 cellular receptors: EP1, EP2, EP3, and EP4; only EP2 and EP4 are relevant for immunomodulation and migration in immune cells. Besides those, several cells express these receptors on their surface, including mesenchymal stem cells. Pharmacological inhibition of the EP2 receptor prevents migration of immune system cells to inflamed sites, where the concentration of PGE2 is high. Based on this, we hypothesised that overexpression of EP2 or EP4 receptors in equine mesenchymal stem cells (eMSC) will improve their migration to inflammatory sites and subsequent homing capability. Conversely, their suppression will lead to low or no migration, favouring the paracrine properties of MSC in the processes of tissue regeneration and reduction of inflammation. To test this, we manipulated the PGE2-EP2-EP4 axis and evaluated the effect of such modifications on transgenic cells in vitro. Equine MSC from adipose tissue were obtained from 5 animals. The coding sequences of both receptors were synthesised (GenScript, Hong Kong) based on the published horse genome (National Center for Biotechnology Information; https://www.ncbi.nlm.nih.gov/) and cloned into pcDNA3.1 overexpression vectors (Addgene). The resulting constructs were lipofected into naïve adipose eMSC. For knockouts, we PCR-amplified and sequenced horse EP2 and EP4 receptors, and gRNAs were created based on the obtained sequences and ligated into LentiCRISPRV2 plasmid (Addgene, Cambridge, MA, USA). The lentiviral vector plus helping packaging plasmids were co-transfected into HEK293FT cells and the produced viral particles were harvested and transduced into adipose eMSC. After 48h of transfection (for overexpression) or transduction (for knockout, KO), cells were probed for the presence/absence of EP2 and EP4 receptors by immunohistochemistry and/or quantitative (q)PCR. Mitomycin-C-treated cells of both phenotypes and naïve, were subjected to migration in scratch assay, towards 3mM PGE2. Fetal calf serum (10 or 0%) was used as positive or negative control, respectively, in migration experiments. Receptors EP2 and EP4 were clearly overexpressed after transfection as determined by immunocytochemistry or qPCR assays (phenotype MSC-EP2+/EP4+), whereas in the cells that underwent KO, little or no expression of EP2 and EP4 was detected (phenotype MSC-EP2ko/EP4ko) compared with unmanipulated cells (naïve MSC-Ctr). In the migration experiments towards 3mM of PGE2, MSC-EP2+/EP4+ cells at 24h filled the scratch faster (P<0.05) than MSC-EP2ko/EP4ko or MSC-Ctr. These results showed that manipulation of PGE2-EP2/EP4 axis receptors led to changes in cell surface receptor availability and increased the migration pattern in overexpressed cells compared with KO and unmanipulated cells. These factors may affect the design of cellular therapeutic tools for inflammatory diseases in the equine species. This research was supported by FONDECYT 3170390 to ACFM, Ministry of Education, Chile.

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TNF-α Priming Elicits Robust Immunomodulatory Potential of Human Tonsil-Derived Mesenchymal Stem Cells to Alleviate Murine Colitis

Biomedicines ◽

10.3390/biomedicines8120561 ◽

2020 ◽

Vol 8 (12) ◽

pp. 561

Author(s):

Tae-Hoon Shin ◽

Ji-Su Ahn ◽

Su-Jeong Oh ◽

Ye Young Shin ◽

Ji Won Yang ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Inflammatory Diseases ◽

Human Tonsil ◽

Cell Therapies ◽

Promising Tool ◽

Tnf Α ◽

Pre Treatment ◽

Specific Tissue

Mesenchymal stem cells (MSCs) have been spotlighted in the field of cell therapies as a promising tool for the treatment of intractable inflammatory diseases. However, their therapeutic potency still shows a gap between preclinical and clinical settings, and distinctive characteristics of specific tissue-derived MSCs and definitive ways to maximize their beneficial functions have not been fully elucidated yet. We previously identified the unique MSCs population from human palatine tonsil (TMSCs) and revealed their superior properties in proliferation and ROS regulation. Based on these findings, we explored further characteristics of TMSCs particularly focused on immunomodulatory function. We found the merit of TMSCs as a therapeutic agent that retains favorable MSCs properties until relatively late passages and revealed that pre-treatment of TNF-α can enhance the immunomodulatory abilities of TMSCs through the upregulation of the PTGS2/PGE2 axis. TMSCs primed with TNF-α effectively restrained the proliferation and differentiation of T lymphocytes and macrophages in vitro, and more interestingly, these TNF-α-licensed TMSCs exhibited significant prophylactic and therapeutic efficacy in a murine model of autoimmune-mediated acute colitis via clinical and histopathological assessment compared to unprimed naïve TMSCs. These findings provide novel insight into the optimization and standardization of MSCs-based anti-inflammatory therapies, especially targeting inflammatory bowel disease (IBD).

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In Vivo Immunogenic Response to Allogeneic Mesenchymal Stem Cells and the Role of Preactivated Mesenchymal Stem Cells Cotransplanted with Allogeneic Islets

Stem Cells International ◽

10.1155/2017/9824698 ◽

2017 ◽

Vol 2017 ◽

pp. 1-12 ◽

Cited By ~ 11

Author(s):

Régis Linhares Oliveira ◽

Pedro Cesar Chagastelles ◽

Patrícia Sesterheim ◽

Patricia Pranke

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Inflammatory Cells ◽

Therapeutic Effects ◽

Allogeneic Mscs ◽

Inflammatory Conditions ◽

Immunogenic Response

Mesenchymal stem cells (MSCs) are multipotent cells capable of differentiating into cells from the mesenchymal lineage. The hypoimmunogenic characteristic of MSCs has encouraged studies using allogeneic MSCs for the treatment of autoimmune diseases and inflammatory conditions. Promising preclinical results and the safety of allogeneic MSC transplantation have created the possibility of “off-the-shelf” clinical application of allogeneic cells. This study has aimed to evaluate the survival of untreated and IFN-γ- and TNF-α-treated (preactivated) allogeneic MSCs transplanted under the kidney capsule of immunocompetent mice together with the role of preactivated MSCs after cotransplantation with allogeneic islets. The preactivation of MSCs upregulated the gene expression of anti-inflammatory molecules and also enhanced their immunomodulatory capacity in vitro. In vivo, allogeneic MSCs provoked an immunogenic response, with the infiltration of inflammatory cells at the transplant site and full graft rejection in both the untreated and preactivated groups. Allogeneic islets cotransplanted with preactivated MSCs prolonged graft survival for about 6 days, compared with islet alone. The present results corroborate the hypothesis that allogeneic MSCs are not immune-privileged and that after playing their therapeutic role they are rejected. Strategies that reduce allogeneic MSC immunogenicity can potentially prolong their in vivo persistence and improve the therapeutic effects.

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The Modulatory Effects of Mesenchymal Stem Cells on Osteoclastogenesis

Stem Cells International ◽

10.1155/2016/1908365 ◽

2016 ◽

Vol 2016 ◽

pp. 1-13 ◽

Cited By ~ 15

Author(s):

Wessam E. Sharaf-Eldin ◽

Nourhan Abu-Shahba ◽

Marwa Mahmoud ◽

Nagwa El-Badri

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Therapeutic Potential ◽

Inflammatory Diseases ◽

Suppressive Effect ◽

Osteoclast Formation ◽

Inducing Factors ◽

High Concentrations

The effect of mesenchymal stem cells (MSCs) on bone formation has been extensively demonstrated through severalin vitroandin vivostudies. However, few studies addressed the effect of MSCs on osteoclastogenesis and bone resorption. Under physiological conditions, MSCs support osteoclastogenesis through producing the main osteoclastogenic cytokines, RANKL and M-CSF. However, during inflammation, MSCs suppress osteoclast formation and activity, partly via secretion of the key anti-osteoclastogenic factor, osteoprotegerin (OPG).In vitro, co-culture of MSCs with osteoclasts in the presence of high concentrations of osteoclast-inducing factors might reflect thein vivoinflammatory pathology and prompt MSCs to exert an osteoclastogenic suppressive effect. MSCs thus seem to have a dual effect, by stimulating or inhibiting osteoclastogenesis, depending on the inflammatory milieu. This effect of MSCs on osteoclast formation seems to mirror the effect of MSCs on other immune cells, and may be exploited for the therapeutic potential of MSCs in bone loss associated inflammatory diseases.

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Study On Mechanism of Bone Marrow Mesenchymal Stem Cell in Treating Patients with Rheumatoid Arthritis.

Blood ◽

10.1182/blood.v114.22.4486.4486 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4486-4486

Author(s):

Zhenhua Qiao ◽

Lihui Ma

Keyword(s):

Rheumatoid Arthritis ◽

Stem Cells ◽

Bone Marrow ◽

Mesenchymal Stem Cells ◽

Tissue Damage ◽

Conflicts Of Interest ◽

Allogeneic Mscs ◽

Colony Forming Unit ◽

Marrow Mesenchymal Stem Cells

Abstract Abstract 4486 Objective To explore mechanism of Mesenchymal stem cells in treating Rheumatoid arthritis. Methods (1) MSCs were isolated from Bone marrow samples of Rheumatoid arthritis(RA)patients and purified by density gradient centrifagation and cultured in vitro. Morphology, immunophenotype, and proliferative property of bMSC and colony forming unit-fibroblast (CFU-F) were measured and analyzed. (2) In an in vitro co-culture system, MSCs were observed to modulate proliferation,activation, and maturation of T and B lymphocytes of Rheumatoid arthritis(RA)patients. The expression of IL-1?ATNF-a?ATGF-β were obviously changed.(3) Bone marrow- derived BMSCs of wistar rats were isolated and cultured in vitro routinely and the fourth passage as taken for identification of specific surface antigens by flowcytometry, then were labled with 5- BrdU in vitro. The model of collagen-induced arthritis (CIA) rats were established. 5- BrdU labled BMSCs were implanted through tail vein to model rats. At 4 weeks after BMSCs transplantation, immunohistochemical examinations were used to investigate BMSCs aggregate around the knee joints.and identify the contribution of bone marrow– derived cells to joints damage repair. Results (1) The culture expanded cells from RA patients presented a typical fibroblast-like morphology. Cells were positive for SH2(CD105),CD71,and CD44, but negative for CD45.Their proliferative capacity and CFU-F number were similar to those of bMSCs from healthy donors. (2) MSCs significantly inhibited T,B cell proliferation. MSCs also could down-regulating the levels of IL-1, TNF and up-regulating TGF-β. (3) Flow cytometry showed that BMSCs expressed CD44, CD71and CD105, but no CD45,CD34. At 4 weeks after the cells transplantation, the implanted cells were detected in the damaged joints of the model rats, which is not founded in normal knee joints of the rats'.and at same time there are more OPG(osteoprotegerin) positive. Conclusion (1) In the aspect of morphology, immuno -phenotypen, proliferative property and colony forming unit-fibroblast (CFU-F),MSCs from bone marrow of RA patients are not different from those of MSCs isolated from bone marrow of normal donors,MSCs from the bone marrow of RA patients have the potentiality in clinical application.(2) Human bone marrow MSCs inhibited Tcell and Bcell activation and proliferation in patients with RA in vitro. And these immuno –modulatory effects were not MHC-restricted. (3) bone marrow mesenchymal stem cells prevents tissue damage in arthritis. Allogeneic MSCs can engraft at sites of tissue damage,and prepair damage. That provided positive results for developing effective therapy for Rheumatoid arthritis. Disclosures: No relevant conflicts of interest to declare.

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Immunophenotyping of bone marrow-derived mesenchymal stem cells after transplantation in a heterologous in-vitro model using Laser Scanning Cytometry

The Thoracic and Cardiovascular Surgeon ◽

10.1055/s-2004-816714 ◽

2004 ◽

Vol 52 (S 1) ◽

Author(s):

J Garbade ◽

D Lenz ◽

A Rastan ◽

MJ Barten ◽

A Tarnok ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Mesenchymal Stem Cells ◽

Laser Scanning ◽

In Vitro Model ◽

Laser Scanning Cytometry ◽

Vitro Model

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Autologous transplantation of mesenchymal stem cells into the portal vein of the miniature pig; a preliminary experiment for NOTES approach

Perspectives in Surgery ◽

10.33699/pis.2019.98.9.350-355 ◽

2019 ◽

Vol 98 (9) ◽

pp. 350-355

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Cell Therapy ◽

Portal Vein ◽

Liver Parenchyma ◽

Miniature Pig ◽

Hepatic Diseases ◽

Study Results

Introduction: There is evidence that mesenchymal stem cells (MSCs) could trans-differentiate into the liver cells in vitro and in vivo and thus may be used as an unfailing source for stem cell therapy of liver disease. Combination of MSCs (with or without their differentiation in vitro) and minimally invasive procedures as laparoscopy or Natural Orifice Transluminal Endoscopic Surgery (NOTES) represents a chance for many patients waiting for liver transplantation in vain. Methods: Over 30 millions of autologous MSCs at passage 3 were transplanted via the portal vein in an eight months old miniature pig. The deposition of transplanted cells in liver parenchyma was evaluated histologically and the trans-differential potential of CM-DiI labeled cells was assessed by expression of pig albumin using immunofluorescence. Results: Three weeks after transplantation we detected the labeled cells (solitary, small clusters) in all 10 samples (2 samples from each lobe) but no diffuse distribution in the samples. The localization of CM-DiI+ cells was predominantly observed around the portal triads. We also detected the localization of albumin signal in CM-DiI labeled cells. Conclusion: The study results showed that the autologous MSCs (without additional hepatic differentiation in vitro) transplantation through the portal vein led to successful infiltration of intact miniature pig liver parenchyma with detectable in vivo trans-differentiation. NOTES as well as other newly developed surgical approaches in combination with cell therapy seem to be very promising for the treatment of hepatic diseases in near future.

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