LUPUS

Preclinical Studies

TITLE: “Reversal of serologic, immunologic, and histologic dysfunction in mice with systemic lupus erythematosus by long-term serial adipose tissue-derived mesenchymal stem cell transplantation”

SOURCE: Choi EW, Shin IS, Park SY, Park JH, Kim JS, Yoon EJ, Kang SK, Ra JC, Hong SH. Reversal of serologic, immunologic, and histologic dysfunction in mice with systemic lupus erythematosus by long-term serial adipose tissue-derived mesenchymal stem cell transplantation. Arthritis Rheum. 2012 Jan;64(1):243-53.

SUMMARY: Long-term serial administration (total of 28 times) of human AD-MSCs ameliorated SLE without any adverse effects. Compared with the control group, the human AD-MSC-treated group had a significantly higher survival rate with improvement of histologic and serologic abnormalities and immunologic function, and also had a decreased incidence of proteinuria. Anti-double-stranded DNA antibodies and blood urea nitrogen levels decreased significantly with transplantation of human AD-MSCs, and serum levels of granulocyte-macrophage colony-stimulating factor, interleukin-4 (IL-4), and IL-10 increased significantly. A significant increase in the proportion of CD4+FoxP3+ cells and a marked restoration of capacity for cytokine production were observed in spleens from the human AD-MSC-treated group. In the second experiment, an early stage treatment group showed better results (higher survival rates and lower incidence of proteinuria) than an advanced stage treatment group.

PUBLIC DOWNLOAD OF FULL MANUSCRIPT: Not available for public download


TITLE: “Adipose tissue-derived mesenchymal stem cells induce expansion of interleukin-10-producing regulatory B cells and ameliorate autoimmunity in a murine model of systemic lupus erythematosus”

SOURCE: Park MJ, Kwok SK, Lee SH, Kim EK, Park SH, Cho ML. Adipose tissue-derived mesenchymal stem cells induce expansion of interleukin-10-producing regulatory B cells and ameliorate autoimmunity in a murine model of systemic lupus erythematosus. Cell Transplant. 2015;24(11):2367-77.

SUMMARY: Mesenchymal stem cells (MSCs) are multipotent cells characterized by immunomodulatory properties and are therefore considered a promising tool for the treatment of autoimmune diseases. One functional B-cell subset, regulatory B cells (Bregs), has recently been shown to restrain excessive inflammatory responses in autoimmune diseases. In the present study, we investigated the impact of human adipose-derived MSCs on Bregs and their therapeutic effect in an animal model of systemic lupus erythematosus (SLE). Coculture of human adipose-derived MSCs with splenocytes from C57BL/6 mice expanded the population of interleukin-10-producing B cells (B10 B cells). In vivo treatment with human adipose-derived MSCs reduced serum anti-double-stranded antibody levels and improved renal pathology of lupus mice (Roquin(san/san) mice). MSCs decreased ICOS(+)CD44(+) follicular helper T cells, Th1 cells and Th17 cells, in spleens of Roquin(san/san) mice. In contrast, MSCs increased Foxp3-expressing regulatory T cells. MSCs also decreased the size and number of germinal centers and effector B cells. As expected, in vivo treatment with MSCs expanded the population of Bregs in spleens of Roquin(san/san) mice. Our results indicate that human adipose-derived MSCs induce the expansion of Bregs and ameliorate autoimmunity in a murine model of SLE. These findings suggest that human adipose-derived MSCs may be a promising therapeutic strategy targeting B-cell-mediated autoimmune diseases such as SLE.

PUBLIC DOWNLOAD OF FULL MANUSCRIPT: Not available for public download

MULTIPLE SCLEROSIS

Multiple Sclerosis: Clinical Studies

TITLE: “Adipose-derived mesenchymal stem cells (AdMSC) for the treatment of secondary-progressive multiple sclerosis: A triple blinded, placebo controlled, randomized phase I/II safety and feasibility study”

SOURCE: Fernández O, Izquierdo G, Fernández V, Leyva L, Reyes V, Guerrero M, León A, Arnaiz C, Navarro G, Páramo MD, Cuesta A, Soria B, Hmadcha A, Pozo D, Fernandez-Montesinos R, Leal M, Ochotorena I, Gálvez P, Geniz MA, Barón FJ, Mata R, Medina C, Caparrós-Escudero C, Cardesa A, Cuende N; Research Group Study EudraCT 2008-004015-35. Adipose-derived mesenchymal stem cells (AdMSC) for the treatment of secondary-progressive multiple sclerosis: A triple blinded, placebo controlled, randomized phase I/II safety and feasibility study. PLoS One. 2018 May 16;13(5):e0195891.

SUMMARY: In this triple-blind, placebo-controlled study, cell samples were obtained from consenting patients by lipectomy and subsequently expanded. Patients were randomized to a single infusion of placebo, low-dose(1x106cells/kg) or high-dose(4x106cells/kg) autologous AdMSC product and followed for 12 months. Safety was monitored recording adverse events, laboratory parameters, vital signs and spirometry. Expanded disability status score (EDSS), magnetic-resonance-imaging, and other measures of possible treatment effects were also recorded. Thirty-four patients underwent lipectomy for AdMSCs collection, were randomized and thirty were infused (11 placebo, 10 low-dose and 9 high-dose); 4 randomized patients were not infused because of karyotype abnormalities in the cell product. Only one serious adverse event was observed in the treatment arms (urinary infection, considered not related to study treatment). No other safety parameters showed changes. Measures of treatment effect showed an inconclusive trend of efficacy. Infusion of autologous AdMSCs is safe and feasible in patients with SPMS. Larger studies and probably treatment at earlier phases would be needed to investigate the potential therapeutic benefit of this technique.

PUBLIC DOWNLOAD OF FULL MANUSCRIPT: Fernandez 2018 PDF

Multiple Sclerosis: Preclinical Studies

TITLE: “Therapeutic effects of human adipose tissue-derived stem cell (hADSC) transplantation on experimental autoimmune encephalomyelitis (EAE) mice”

SOURCE: Li J, Chen Y, Chen Z, Huang Y, Yang D, Su Z, Weng Y, Li X, Zhang X. Therapeutic effects of human adipose tissue-derived stem cell (hADSC) transplantation on experimental autoimmune encephalomyelitis (EAE) mice. Sci Rep. 2017 Feb 15;7:42695.

SUMMARY: This study is to investigate the therapeutic effects of human adipose tissue-derived stem cell (hADSC) transplantation on experimental autoimmune encephalomyelitis (EAE) in mice. EAE mouse model was established by MOG35-55 immunization. Body weight and neurological function were assessed. H&E and LFB staining was performed to evaluate histopathological changes. Flow cytometry was used to detect Th17 and Treg cells. ELISA and real-time PCR were performed to determine transcription factor and pro-inflammatory cytokine levels. Transplantation of hADSCs significantly alleviated the body weight loss and neurological function impairment of EAE mice. Inflammatory cell infiltration and demyelination were significantly increased, which were relieved by hADSC transplantation. Moreover, the Th17 cells and the ROR-γt mRNA level were significantly elevated, while the Treg cells and the Foxp3 mRNA level were significantly declined, resulting in significantly increased Th17/Treg ratio. This was reversed by the transplantation of hADSCs. Furthermore, serum levels of IL-17A, IL-6, IL-23, and TGF-β, were significantly increased, which could be influenced by the hADSC transplantation. Transplantation of hADSCs alleviates the neurological function impairment and histological changes, and reduces the inflammatory cell infiltration and demyelination in EAE mice, which might be associated with the regulation of Th17/Treg balance.

PUBLIC DOWNLOAD OF FULL MANUSCRIPT: Chen 2017 PDF


TITLE: “Transplantation of human adipose-derived stem cells enhances remyelination in lysolecithin-induced focal demyelination of rat spinal cord”

SOURCE: Ghasemi N, Razavi S, Mardani M, Esfandiari E, Salehi H, Zarkesh Esfahani SH. Transplantation of human adipose-derived stem cells enhances remyelination in lysolecithin-induced focal demyelination of rat spinal cord. Mol Biotechnol. 2014 May;56(5):470-8.

SUMMARY: Adipose-derived stem cells (ADSCs) are a desirable stem cell source in neurodegenerative diseases treatment due to their ability to differentiate into different cell lineages. In this study, we transplanted human ADSCs (hADSCs) into a lysophosphatidylcholine (lysolecithin) model of multiple sclerosis (MS) and determined the efficiency of these cells in remyelination process. Forty adult rats were randomly divided into control, lysolecithin, vehicle, and transplantation groups, and focal demyelination was induced by lysolecithin injection into spinal cord. To assess motor performance, all rats were examined weekly with a standard EAE scoring scale. Four weeks after cell transplantation, to assess the extent of demyelination and remyelination, Luxol Fast Blue staining was used. In addition, immunohistochemistry technique was used for assessment of the presence of oligodendrocyte phenotype cells in damaged spinal cord. Our results indicated that hADSCs had ability to differentiate into oligodendrocyte phenotype cells and improved remyelination process. Moreover, the evaluation of rat motor functions showed that animals which were treated with hADSC compared to other groups had significant improvement (P < 0.001). Our finding showed that hADSCs transplantation for cell-based therapies may play a proper cell source in the treatment of neurodegenerative diseases such as MS.

PUBLIC DOWNLOAD OF FULL MANUSCRIPT: Not available for public download

PSORIATIC ARTHRITIS

Psoriatic Arthritis: Clinical Studies

TITLE: “Autologous Adipose-Derived Mesenchymal Stromal Cells for the Treatment of Psoriasis Vulgaris and Psoriatic Arthritis: A Case Report”

SOURCE: De Jesus MM, Santiago JS, Trinidad CV, See ME, Semon KR, Fernandez MO Jr, Chung FS. Autologous Adipose-Derived Mesenchymal Stromal Cells for the Treatment of Psoriasis Vulgaris and Psoriatic Arthritis: A Case Report. Cell Transplant. 2016 Nov;25(11):2063-2069.

SUMMARY: Psoriasis is a dermatologic disease of immune origins with no definitive cure. We report the Makati Medical Center experience of utilizing autologous mesenchymal stromal cells (MSCs) for one patient with psoriasis vulgaris (PV) and another with psoriatic arthritis (PA). Patients were educated and gave informed consent, according to the principles of the Declaration of Helsinki. The protocol was approved by the Cellular Transplantation Ethics Committee of the Makati Medical Center. Autologous MSCs were cultured from lipoaspirate and expanded in a clean room class 100 facility (Cellular Therapeutics Center, Makati Medical Center). MSCs were infused intravenously at a dose of 0.5-3.1 million cells/kg after complying with quality control parameters. Psoriasis area and severity index (PASI) evaluations were conducted by third-party dermatologists. The PA patient, who was previously unresponsive to standard treatment modalities, demonstrated a decrease in PASI (from 21.6 to 9.0, mild state after two infusions). No improvements were noted in joint pain until further treatment with etanercept and infliximab. The PV patient, who was previously dependent on methotrexate, showed a decrease in PASI from 24.0 to 8.3 after three infusions; this clinical improvement was sustained for 292 days (9.7 months) without methotrexate. The PV patient illustrated a marginal reduction in serum tumor necrosis factor-α (TNF-α), while significant (3.5- to 5-fold) decreases in reactive oxygen species (ROS) activity were noted. The ROS levels correlated with the clinical improvement of the PV patient. No serious adverse events were noted for either patient as a result of MSC infusions. This report demonstrates safe and tolerable transplantation of autologous MSCs for the treatment of psoriasis and warrants large clinical studies to investigate the long-term safety and efficacy of this approach.

PUBLIC DOWNLOAD OF FULL MANUSCRIPT: Not available for public download

RHEUMATOID ARTHRITIS

Rheumatoid Arthritis: Clinical Studies

TITLE: “Intravenous administration of expanded allogeneic adipose-derived mesenchymal stem cells in refractory rheumatoid arthritis (Cx611): results of a multicentre, dose escalation, randomised, single-blind, placebo-controlled phase Ib/IIa clinical trial”

SOURCE: Álvaro-Gracia JM, Jover JA, García-Vicuña R, Carreño L, Alonso A, Marsal S, Blanco F, Martínez-Taboada VM, Taylor P, Martín-Martín C, DelaRosa O, Tagarro I, Díaz-González F. Intravenous administration of expanded allogeneic adipose-derived mesenchymal stem cells in refractory rheumatoid arthritis (Cx611): results of a multicentre, dose escalation, randomised, single-blind, placebo-controlled phase Ib/IIa clinical trial. Ann Rheum Dis. 2017 Jan;76(1):196-202.

SUMMARY: It is a multicentre, dose escalation, randomised, single-blind (double-blind for efficacy), placebo-controlled, phase Ib/IIa clinical trial. Patients with active refractory RA (failure to at least two biologicals) were randomised to receive three intravenous infusions of Cx611: 1 million/kg (cohort A), 2 million/kg (cohort B), 4 million/kg (cohort C) or placebo, on days 1, 8 and 15, and they were followed for therapy assessment for 24 weeks. Fifty-three patients were treated (20 in cohort A, 20 in cohort B, 6 in cohort C and 7 in placebo group). A total of 141 adverse events (AEs) were reported. Seventeen patients from the group A (85%), 15 from the group B (75%), 6 from the group C (100%) and 4 from the placebo group (57%) experienced at least one AE.Eight AEs from 6 patients were grade 3 in intensity (severe), 5 in cohort A (lacunar infarction, diarrhoea, tendon rupture, rheumatoid nodule and arthritis), 2 in cohort B (sciatica and RA) and 1 in the placebo group (asthenia). Only one of the grade 3 AEs was serious (the lacunar infarction). American College of Rheumatology 20 responses for cohorts A, B, C and placebo were 45%, 20%, 33% and 29%, respectively, at month 1, and 25%, 15%, 17% and 0%, respectively, at month 3.

The intravenous infusion of Cx611 was in general well tolerated, without evidence of dose-related toxicity at the dose range and time period studied. In addition, a trend for clinical efficacy was observed. These data, in our opinion, justify further investigation of this innovative therapy in patients with RA.

PUBLIC DOWNLOAD OF FULL MANUSCRIPT: Not available for public download

Rheumatoid Arthritis: Preclinical Studies

TITLE: “Human adipose tissue-derived mesenchymal stem cells in rheumatoid arthritis: Regulatory effects on peripheral blood mononuclear cells activation”

SOURCE: Baharlou R, Ahmadi-Vasmehjani A, Faraji F, Atashzar MR, Khoubyari M, Ahi S, Erfanian S, Navabi SS. Human adipose tissue-derived mesenchymal stem cells in rheumatoid arthritis: Regulatory effects on peripheral blood mononuclear cells activation. Int Immunopharmacol. 2017 Jun;47:59-69.

SUMMARY: PBMCs from RA patients and healthy donors were co-cultured with Ad-MSCs and HeLa with or without Phytohemagglutinin (PHA). Finally, IL-6, IL-17, IL-21, IL-23 and TGF-β levels were determined by ELISA and quantitative real-time RT-PCR on co-culture supernatants and PBMCs, respectively. In co-culture interaction, Ad-MSCs inhibited IL-17 secretion by PBMCs compared to unstimulated PBMCs cultured alone. In addition, IL-21 expressions in PBMCs of the patient group, and IL-17 and IL-21 in healthy group were inhibited by Ad-MSCs compared to PBMCs cultured alone. TGF-β expression in healthy individuals remarkably increased in both MSC-treated groups with and without PHA in comparison to PHA-stimulated and -unstimulated PBMCs. This study demonstrates that human Ad-MSCs act as key regulators of immune tolerance by inhibiting the inflammation. Therefore, they can be attractive candidates for immunomodulatory cell-based therapy in RA.

PUBLIC DOWNLOAD OF FULL MANUSCRIPT: Not available for public download


TITLE: “Human adipose-derived mesenchymal stem cells reduce inflammatory and T cell responses and induce regulatory T cells in vitro in rheumatoid arthritis”

SOURCE: Gonzalez-Rey E, Gonzalez MA, Varela N, O'Valle F, Hernandez-Cortes P, Rico L, Büscher D, Delgado M. Human adipose-derived mesenchymal stem cells reduce inflammatory and T cell responses and induce regulatory T cells in vitro in rheumatoid arthritis. Ann Rheum Dis. 2010 Jan;69(1):241-8.

SUMMARY: The effects of hASCs on collagen-reactive RA human T cell proliferation and cytokine production were investigated, as well as effects on the production of inflammatory mediators by monocytes and fibroblast-like synoviocytes from patients with RA. hASCs suppressed the antigen-specific response of T cells from patients with RA. hASCs inhibited the proliferative response and the production of inflammatory cytokines by collagen-activated CD4 and CD8 T cells. In contrast, the numbers of IL10-producing T cells and monocytes were significantly augmented upon hASC treatment. The suppressive activity of hASCs was cell-to-cell contact dependent and independent. hASCs also stimulated the generation of FoxP3 protein-expressing CD4(+)CD25(+) regulatory T cells, with the capacity to suppress collagen-specific T cell responses. Finally, hASCs downregulated the inflammatory response and the production of matrix-degrading enzymes by synovial cells isolated from patients with RA. The present work identifies hASCs as key regulators of immune tolerance, with the capacity to suppress T cell and inflammatory responses and to induce the generation/activation of antigen-specific regulatory T cells.

PUBLIC DOWNLOAD OF FULL MANUSCRIPT: Not available for public download


TITLE: “Human mesenchymal stem cells as a tool for joint repair in rheumatoid arthritis”

SOURCE: Tanaka Y. Human mesenchymal stem cells as a tool for joint repair in rheumatoid arthritis. Clin Exp Rheumatol. 2015 Jul-Aug;33(4 Suppl 92):S58-62.

SUMMARY: Rheumatoid arthritis (RA) is characterised with chronic inflammatory synovitis and progressive joint. Because damaged and/or deformed joints cannot be repaired, a novel treatment strategy aimed at both anti-inflammation and bone regeneration is a prerequisite. Mesenchymal stem cells (MSCs) can be easily isolated from various organs and possess multipotent capacity and exhibit immunoregulatory properties. Using human MSC derived from bone marrow and adipose tissue, we have clarified the following novel findings in vitro. 1) MSCs differentiated into osteoblasts or osteocytes under osteoblast-conditioned medium including the inflammatory stimuli such as IL-1. 2) The combination of IL-6 and soluble IL-6 receptor induced differentiation of MSCs to chondrocyte. 3) MSCs produced osteoprotegerin and inhibited osteoclastogenesis. Furthermore, we developed a local delivery system of MSCs by using nano-fibre scaffold. MSCs seeded on nano-fibre scaffold suppressed arthritis and joint destruction by inhibiting systemic inflammatory reaction and immune response through the induction of regulatory T cells and subsequent reduction in the production of anti-type II collagen antibody in vivo. Thus, our data may serve as a new strategy for MSC-based therapy in inflammatory diseases and an alternative delivery method for the treatment of damaged joints in RA.

PUBLIC DOWNLOAD OF FULL MANUSCRIPT: Not available for public download

SCLERODERMA

Scleroderma: Clinical Studies

TITLE: “Safety, tolerability and potential efficacy of injection of autologous adipose-derived stromal vascular fraction in the fingers of patients with systemic sclerosis: an open-label phase I trial”

SOURCE: Granel B, Daumas A, Jouve E, Harlé JR, Nguyen PS, Chabannon C, Colavolpe N, Reynier JC, Truillet R, Mallet S, Baiada A, Casanova D, Giraudo L, Arnaud L, Veran J, Sabatier F, Magalon G. Safety, tolerability and potential efficacy of injection of autologous adipose-derived stromal vascular fraction in the fingers of patients with systemic sclerosis: an open-label phase I trial. Ann Rheum Dis. 2015 Dec;74(12):2175-82. doi: 10.1136/annrheumdis-2014-205681.

SUMMARY: We did an open-label, single arm, at one study site with 6-month follow-up among 12 female SSc patients with Cochin Hand Function Scale score >20/90. Autologous SVF was obtained from lipoaspirates, using an automated processing system, and subsequently injected into the subcutaneous tissue of each finger in contact with neurovascular pedicles. Primary outcome was the number and the severity of adverse events related to SVF-based therapy. Secondary endpoints were changes in hand disability and fibrosis, vascular manifestations, pain and quality of life from baseline to 2 and 6 months after cell therapy. All enrolled patients had surgery, and there were no dropouts or patients lost to follow-up. No severe adverse events occurred during the procedure and follow-up. Four minor adverse events were reported and resolved spontaneously. A significant improvement in hand disability and pain, Raynaud's phenomenon, finger oedema and quality of life was observed. This study outlines the safety of the autologous SVF cells injection in the hands of patients with SSc. Preliminary assessments at 6 months suggest potential efficacy needing confirmation in a randomised placebo-controlled trial on a larger population.

PUBLIC DOWNLOAD OF FULL MANUSCRIPT: Granel 2015 PDF


TITLE: “Autologous adipose-derived stromal vascular fraction in patients with systemic sclerosis: 12-month follow-up”

SOURCE: Guillaume-Jugnot P, Daumas A, Magalon J, Jouve E, Nguyen PS, Truillet R, Mallet S, Casanova D, Giraudo L, Veran J, Dignat-George F, Sabatier F, Magalon G, Granel B. Autologous adipose-derived stromal vascular fraction in patients with systemic sclerosis: 12-month follow-up. Rheumatology (Oxford). 2016 Feb;55(2):301-6.

SUMMARY: Twelve females, mean age 54.5 years (s.d. 10.3), were assessed 1 year after ADSVF injection. Patients were eligible if they had a Cochin Hand Function Scale score >20/90. ADSVF was obtained from lipoaspirate using an automated processing system and subsequently injected into the s.c. tissue of each finger in contact with neurovascular pedicles in a one-time procedure. Endpoints were changes in hand disability and skin fibrosis, vascular manifestations, pain and quality of life at the 12 month follow-up. During the visit, patients estimated the benefit of the procedure with a specific self-completed questionnaire. A significant decrease from baseline of 51.3% (P < 0.001) for Cochin Hand Function Scale score, 63.2% (P < 0.001) for RP severity and 46.8% (P = 0.001) for quality of life (Scleroderma Health Assessment Questionnaire) was observed. A significant improvement of finger oedema, skin sclerosis, motion and strength of the hands and of the vascular suppression score was also noted. The reduction in hand pain approached statistical significance (P = 0.052). The questionnaire revealed a benefit in daily activities, housework and social activities. ADSVF injection is a promising therapy and appears to have benefits that extend for at least 1 year.

PUBLIC DOWNLOAD OF FULL MANUSCRIPT: Not available for public download


TITLE: “Human Adipose-Derived Stromal Cells for Cell-Based Therapies in the Treatment of Systemic Sclerosis”

SOURCE: Scuderi N, Ceccarelli S, Onesti MG, Fioramonti P, Guidi C, Romano F, Frati L, Angeloni A, Marchese C. Human Adipose-Derived Stromal Cells for Cell-Based Therapies in the Treatment of Systemic Sclerosis. Cell Transplant. 2013;22(5):779-95.

SUMMARY: The present study was designed to evaluate the clinical outcome of cell-based therapy with cultured adipose derived stromal cells (ASCs) for the treatment of cutaneous manifestations in patients affected by systemic sclerosis (SSc). ASCs have an extraordinary developmental plasticity, including the ability to undergo multilineage differentiation and self-renewal. Moreover, ASCs can be easily harvested from small volumes of liposuction aspirate, showing great in vitro viability and proliferation rate. Here we isolated, characterized, and expanded ASCs, assessing both their mesenchymal origin and their capability to differentiate towards the adipogenic, osteogenic, and chondrogenic lineage. We developed an effective method for ASCs transplantation into sclerodermic patients by means of a hyaluronic acid (HA) solution, which allowed us to achieve precise structural modifications. ASCs were isolated from subcutaneous adipose tissue of six sclerodermic patients and cultured in a chemical-defined medium before autologous transplantation to restore skin sequelae. The results indicated that transplantation of a combination of ASCs in HA solution determined a significant improvement in tightening of the skin without complications such as anechoic areas, fat necrosis, or infections, thus suggesting that ASCs are a potentially valuable source of cells for skin therapy in rare diseases such as SSc and generally in skin disorders.

PUBLIC DOWNLOAD OF FULL MANUSCRIPT: Not available for public download