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1.
MOHSEN EMADEDIN NARGES LABIBZADEH MAEDE GHORBANI LIASTANI ALIASGHAR KARIMI NEDA JAROUGHI TINA BOLURIEH SEYYEDEH-ESMAT HOSSEINI HOSSEIN BAHARVAND NASSER AGHDAMI 《Cytotherapy》2018,20(10):1238-1246
Background
The intra-articular implantation of mesenchymal stromal cells (MSCs) as a treatment for knee osteoarthritis (OA) is an emerging new therapy. In this study, patients with knee OA received intra-articular implantations of autologous bone marrow–derived MSCs. We sought to assess the safety and efficacy of this implantation.Materials and Methods
This was a phase 1/2 single-center, triple-blind, randomized controlled trial (RCT) with a placebo control. The subjects consisted of patients with knee OA randomly assigned to either an intra-articular implantation of MSCs (40?×?106 cells) or 5 mL normal saline (placebo). Patients were followed up for 6 months after the implantations. The pain level and function improvements for patient-reported outcomes were assessed based on a visual analog scale (VAS), Western Ontario and McMaster Universities Arthritis Index (WOMAC) and its subscales, walking distance, painless walking distance, standing time and knee flexion compared with the placebo group at 3 and 6 months following the implantations.Results
Overall, 43 patients (Kellgren-Lawrence grades 2, 3 and 4) were assigned to either the MSCs (n?=?19) or placebo (n?=?24) group. Patients who received MSCs experienced significantly greater improvements in WOMAC total score, WOMAC pain and physical function subscales and painless walking distance compared with patients who received placebo. There were no major adverse events attributed to the MSC therapy.Conclusion
This randomized, triple-blind, placebo-controlled RCT demonstrated the safety and efficacy of a single intra-articular implantation of 40?×?106 autologous MSCs in patients with knee OA. Intra-articular implantation of MSCs provided significant and clinically relevant pain relief over 6 months versus placebo and could be considered a promising novel treatment for knee OA. We propose that further investigations should be conducted over an extended assessment period and with a larger cohort. 相似文献2.
MATTHEW LI LING-YEE CHIN SYUKRI SHUKOR ALFRED TAMAYO MARCELA V. MAUS BIJU PAREKKADAN 《Cytotherapy》2019,21(1):76-82
Background aim
Translation of therapeutic cell therapies to clinical-scale products is critical to realizing widespread success. Currently, however, there are limited tools that are accessible at the research level and readily scalable to clinical-scale needs.Methods
We herein developed and assessed a closed loop bioreactor system in which (i) a highly gas-permeable silicone material was used to fabricate cell culture bags and (ii) dynamic flow was introduced to allow for dissociation of activated T-cell aggregates.Results
Using this system, we find superior T-cell proliferation compared with conventional bag materials and flasks, especially at later time points. Furthermore, intermittent dynamic flow could easily break apart T-cell clusters.Conclusions
Our novel closed loop bioreactor system is amenable to enhanced T-cell proliferation and has broader implications for being easily scaled for use in larger need settings. 相似文献3.
ROMAIN Guiho KEVIN BITEAU GIULIA GRISENDI MATHIAS CHATELAIS REGIS BRION JULIEN TAURELLE SARAH RENAULT DOMINIQUE HEYMANN MASSIMO DOMINICI FRANÇOISE REDINI 《Cytotherapy》2018,20(8):1037-1045
Background
Osteosarcoma (OS) is the most frequent pediatric malignant bone tumor. OS patients have not seen any major therapeutic progress in the last 30 years, in particular in the case of metastatic disease, which requires new therapeutic strategies. The pro-apoptotic cytokine Tumor necrosis factor (TNF)–Related Apoptosis Inducing Ligand (TRAIL) can selectively kill tumor cells while sparing normal cells, making it a promising therapeutic tool in several types of cancer. However, many OS cell lines appear resistant to recombinant human (rh)TRAIL-induced apoptosis. We, therefore, hypothesized that TRAIL presentation at the membrane level of carrier cells might overcome this resistance and trigger apoptosis.Methods
To address this, human adipose mesenchymal stromal cells (MSCs) transfected in a stable manner to express membrane-bound full-length human TRAIL (mbTRAIL) were co-cultured with several human OS cell lines.Results
This induced apoptosis by cell-to-cell contact even in cell lines initially resistant to rhTRAIL. In contrast, mbTRAIL delivered by MSCs was not able to counteract tumor progression in this OS orthotopic model.Discussion
This was partly due to the fact that MSCs showed a potential to support tumor development. Moreover, the expression of mbTRAIL did not show caspase activation in adjacent tumor cells. 相似文献4.
Background
Multiple myeloma (MM) is a hematologic cancer caused by the abnormal expansion of plasma cells, but the exact mechanism underlying MM development is not completely known. Recently, multiple long noncoding RNAs (lncRNAs) were implicated in the regulation of MM development.Methods
Samples from patients with MM were collected and detected for LINC00461 expression using real-time polymerase chain reaction (PCR). LINC00461 was knocked down in MM cell lines by short hairpin RNAs (shRNAs) to measure its effect on MM cell proliferation and apoptosis. The function of mesenchymal stromal cell (MSC)–derived exosomes was analyzed using chamber assays.Results
LINC00461 was highly expressed in MM. Knockdown of LINC00461 dramatically reduced MM cell proliferation and induced cell apoptosis. Further study showed that LINC00461 relieved the inhibitory effect of microRNA (miR)-15a/miR-16 on BCL-2. In addition, we observed that MSC-derived exosomes promoted MM cell proliferation through LINC00461.Conclusion
Our findings demonstrate that LINC00461, a sponge for miR-15a/16, is highly expressed in MSC-derived exosomes, and enhances MM cell proliferation, which may become an excellent candidate for therapeutic applications. 相似文献5.
Alann Thaffarell Portilho Souza Gileade Pereira Freitas Helena Bacha Lopes Emanuela Prado Ferraz Fabiola Singaretti Oliveira Marcio Mateus Beloti Adalberto Luiz Rosa 《Cytotherapy》2018,20(10):1267-1277
Background aims
Regenerative medicine strategies based on cell therapy are considered a promising approach to repair bone defects. The aims of this study were to evaluate the effect of subculturing on the osteogenic potential of osteoblasts derived from newborn rat calvaria and the effect of these osteoblasts on bone repair of rat calvaria defects.Methods
Cells were obtained from 50 newborn rat calvaria, and primary osteoblasts (OB) were compared with first passage (OB-P1) in terms of osteogenic potential by assaying cell proliferation, alkaline phosphatase (ALP) activity, extracellular matrix mineralization and gene expression of the osteoblastic markers RUNX2, ALP, osteocalcin and bone sialoprotein. Then, 5-mm calvaria defects were created in 24 Wistar rats, and after 2 weeks, they were locally injected with 50 µL of phosphate-buffered saline containing either 5?×?106 osteoblasts (OB-P1, n?=?12) or no cells (control, n?=?12). Four weeks post-injection, the bone formation was evaluated by micro-computed tomography and histological analyses. Data were compared by analysis of variance, followed by the Student-Newman-Keuls's test or Student's t-test (P ≤ 0.05).Results
OB-P1 showed high proliferation and ALP activity, and despite the reduced gene expression of osteoblastic markers and extracellular matrix mineralization compared with OB, they displayed osteogenic potential, being a good choice for injection into calvaria defects. The micro-tomographic and histological data showed that defects treated with OB-P1 presented higher bone formation compared with control defects.Discussion
Our results indicate that cells derived from newborn rat calvaria retain osteoblastic characteristics after subculturing and that these osteoblasts stimulate bone repair in a rat calvaria defect model. 相似文献6.
ILARIA ZOLLINO DIANA CAMPIONI MARIA GRAZIA SIBILLA MIRKO TESSARI ANNA MARIA MALAGONI PAOLO ZAMBONI 《Cytotherapy》2019,21(2):200-211
Background aims
Preclinical and observational reports indicate that adipose tissue (AT) is a safe and promising tool to treat non-healing venous leg ulcers (VLUs).Methods
From an initial cohort of 38 patients, 16 patients affected by non-healing VLUs were randomly allocated to the experimental arm (5 men and 3 women) and control arm (5 men and 3 women). In the experimental arm, wounds were treated by debridement, centrifuged adipose tissue (CAT), advanced dressings and compression. No experimental treatment (CAT) was administered to the control arm. We investigated the functional and the immunophenotypical features of the harvested CAT-derived stem cells. The primary outcome measures were healing time and safety of the cell treatment. Secondary outcomes were pain evaluated by numeric rating scale (NRS), complete wound healing at 24 weeks by Margolis Index and wound-healing process expressed in square centimeters per week. The various immunophenotypic and functional characteristics of CAT-derived stem cells were then correlated with the clinical outcomes.Results
No major adverse events were recorded. The healing time was significantly faster by applying CAT, 17.5 ± 7.0 weeks versus 24.5 ± 4.9 weeks recorded in the control arm (P < 0.036). NRS dropped after the first week to 2.7 ± 2.0 in the experimental arm versus 6.6 ± 3.0 in the control group (P < 0.01). The rate of healing at the 24th week was not significantly different between arms. Interestingly, we found a strong reverse correlation between the percent of CD34+/CD45– non-hematopoietic cells, respectively, with the healing time (r?=?–0.894, P < 0.041) and NRS (r?=?–0.934, P < 0.020).Conclusions
CAT is safe and may accelerate healing time in VLUs as well as reduce wound pain. The percentage of CD34+/CD45– cells in stromal vascular fraction (SVF) seems to be a predictive biomarker of successful CAT treatment in these patients. 相似文献7.
FABIANY DA COSTA GONÇALVES MICHELE ARAMBURU SERAFINI HELENA FLORES MELLO BIANCA PFAFFENSELLER ANELISE BERGMANN ARAÚJO FERNANDA VISIOLI ANA HELENA PAZ 《Cytotherapy》2018,20(12):1459-1471
Background aims
Although mesenchymal stromal cells (MSCs) have shown therapeutic potential in intestinal tissue repair, controversy concerning their short survival and poor biodistribution in recipient tissues still remains. Therefore, we investigated the paracrine role of MSC in three-dimensional culture of colon with experimental colitis.Methods
Colitis was induced in mice by oral administration of dextran sulfate sodium (DSS) for 7 days. Inflammatory responses were assessed on the basis of clinical signs, morphological, and histopathological parameters. On days 2 and 5, colonic explants were removed, and a three-dimensional culture was performed. The structural integrity of the intestinal mucosa was tested by treating the cultures with MSC or conditioned medium (CM) for 24 h, and then the colons were analyzed for histology/immunohistochemistry and interleukin (IL)-6 production.Results
Histological analysis demonstrated that both MSC and CM treatment reduced colon damage in organ culture. An increase in cell proliferation (Ki-67 staining) was observed after CM treatment. Additionally, MSC treatment was able to reduce CD3+ cells. The therapeutic effect of MSC and CM was mediated by the downregulation of IL-6.Discussion
The intestinal in vitro model has shown to be potentially useful for studying cellular interactions in a three-dimensional cell arrangement. Moreover, our results provide strong evidence that both MSC and CM treatments can alleviate colonic damage in organ culture. Importantly, these results suggest that MSC-secreted factors are able to protect the colon from inflammation caused by DSS-induced colitis independent of cell transplantation. 相似文献8.
ABEL TRUJILLO-OCAMPO HYUN-WOO CHO AMANDA C. HERRMANN WILFREDO RUIZ-VAZQUEZ ANDREW B. THORNTON HONG HE DAN LI MARIAM A. QAZILBASH QING MA STEVEN A. PORCELLI ELIZABETH J. SHPALL JEFFREY MOLLDREM JIN S. IM 《Cytotherapy》2018,20(8):1089-1101
Background aims
CD1d-restricted invariant natural killer (iNK) T cells are rare regulatory T cells that may contribute to the immune-regulation in allogeneic stem cell transplantation (ASCT). Here, we sought to develop an effective strategy to expand human iNK T cells for use in cell therapy to prevent graft-versus-host disease (GVHD) in ASCT.Methods
Human iNK T cells were first enriched from peripheral blood mononuclear cells (PBMCs) using magnetic-activated cell sorting separation, then co-cultured with dendritic cells in the presence of agonist glycolipids, alpha-galactosylceramide, for 2 weeks.Results
The single antigenic stimulation reliably expanded iNK T cells to an average of 2.8?×?107 per 5?×?108 PBMCs in an average purity of 98.8% in 2 weeks (N?=?24). The expanded iNK T cells contained a significantly higher level of CD4+ and central memory phenotype (CD45RA?CD62L+) compared with freshly isolated iNK T cells, and maintained their ability to produce both Th-1 (interferon [IFN]γ and tumor necrosis factor [TNF]α) and Th-2 type cytokines (interleukin [IL]-4, IL-5 and IL-13) upon antigenic stimulation or stimulation with Phorbol 12-myristate 13-acetate/ionomycin. Interestingly, expanded iNK T cells were highly autoreactive and produced a Th-2 polarized cytokine production profile after being co-cultured with dendritic cells alone without exogenous agonist glycolipid antigen. Lastly, expanded iNK T cells suppressed conventional T-cell proliferation and ameliorated xenograft GVHD (hazard ratio, 0.1266; P < 0.0001).Conclusion
We have demonstrated a feasible approach for obtaining ex vivo expanded, highly enriched human iNK T cells for use in adoptive cell therapy to prevent GVHD in ASCT. 相似文献9.
HANNE Salmenkari ANITA LAITINEN RICHARD A. FORSGÅRD MERVI HOLAPPA JERE LINDÉN LAURI PASANEN MATTI KORHONEN RIITTA KORPELA JOHANNA NYSTEDT 《Cytotherapy》2019,21(2):175-188
Background
Mesenchymal stromal cells (MSCs) are a promising candidate for treatment of inflammatory disorders, but their efficacy in human inflammatory bowel diseases (IBDs) has been inconsistent. Comparing the results from various pre-clinical and clinical IBD studies is also challenging due to a large variation in study designs.Methods
In this comparative pre-clinical study, we compared two administration routes and investigated the safety and feasibility of both fresh and cryopreserved platelet-lysate–expanded human bone marrow–derived MSCs without additional licensing in a dextran sodium sulfate (DSS) colitis mouse model both in the acute and regenerative phases of colitis. Body weight, macroscopic score for inflammation and colonic interleukin (IL)-1β and tumor necrosis factor (TNF)α concentrations were determined in both phases of colitis. Additionally, histopathology was assessed and Il-1β and Agtr1a messenger RNA (mRNA) levels and angiotensin-converting enzyme (ACE) protein levels were measured in the colon in the regenerative phase of colitis.Results
Intravenously administered MSCs exhibited modest anti-inflammatory capacity in the acute phase of colitis by reducing IL-1β protein levels in the inflamed colon. There were no clear improvements in mice treated with fresh or cryopreserved unlicensed MSCs according to weight monitoring results, histopathology and macroscopic score results. Pro-inflammatory ACE protein expression and shedding were reduced by cryopreserved MSCs in the colon.Conclusions
In conclusion, we observed a good safety profile for bone marrow–derived platelet lysate–expanded MSCs in a mouse pre-clinical colitis model, but the therapeutic effect of MSCs prepared without additional licensing (i.e. such as MSCs are administered in graft-versus-host disease) was modest in the chosen in vivo model system and limited to biochemical improvements in cytokines without a clear benefit in histopathology or body weight development. 相似文献10.
Chloe L. Rackham Stefan Amisten Shanta J. Persaud Aileen J.F. King Peter M. Jones 《Cytotherapy》2018,20(12):1427-1436
Background aims
Mesenchymal stromal cells (MSCs) enhance islet function both in vitro and in vivo, at least in part by secreting ligands that activate islet G-protein coupled receptors (GPCRs). We assessed whether pre-treatment with a defined “cocktail” of MSC-secreted GPCR ligands enhances islet functional survival in vitro and improves the outcomes of islet transplantation in an experimental model of diabetes.Methods
Isolated islets were cultured for 48 h with ANXA1, SDF-1 or C3a, alone or in combination. Glucose-stimulated insulin secretion (GSIS) and cytokine-induced apoptosis were measured immediately after the 48 h culture period and at 24 h or 72 h following removal of the ligands from the culture media. Islets were syngeneically transplanted underneath the kidney capsule of streptozotocin-induced diabetic C57BL/6 mice and blood glucose levels monitored for 28 days.Results
Pre-culturing islets with a cocktail of ANXA1/SDF-1/C3a potentiated GSIS and protected islet cells from cytokine-induced apoptosis in vitro. These effects were maintained for up to 72 h after the removal of the factors from the culture medium, suggesting a sustained protection of islet graft functional survival during the immediate post-transplantation period. Islets pre-treated with the cocktail of MSC secretory factors were more effective in reducing blood glucose in diabetic mice, consistent with their improved functional survival in vivo.Discussion
Pre-culturing islets with a cocktail of MSC secretory products offers a well-defined, cell-free approach to improve clinical islet transplantation outcomes while avoiding many of the safety, regulatory and logistical hurdles of incorporating MSCs into transplantation protocols. 相似文献11.
ZHILONG MA GUODONG SONG DONGBO ZHAO DALU LIU XIAOLEI LIU YUXIANG DAI ZHIGANG HE DAOHAI QIAN JIAN GONG HONGBO MENG BO ZHOU TINGSONG YANG ZHENSHUN SONG 《Cytotherapy》2019,21(2):162-174
Background and aims
It has been previously verified that mesenchymal stromal cells (MSCs) have a good therapeutic effect on severe acute pancreatitis (SAP) and the potential for regeneration of damaged pancreatic tissue, but the exact molecular mechanism remains unclear. In this study, we demonstrated the therapeutic effect of bone morrow MSCs (BMSCs) on SAP, probably by targeting heme oxygenase-1 (HO-1).Methods
Six hours after SAP induction, either phosphate-buffered saline (PBS) or BMSCs were transfused into the caudal vein of rats, zinc protoporphyrin (ZnPP) was administered intraperitoneally. Pancreatic pathological scoring, serum levels of amylase and inflammatory factors, as well as levels of reactive oxygen species (ROS), malondialdehyde (MDA) and myeloperoxidase (MPO), superoxide dismutase (SOD) and catalase (CAT) activity in the pancreas were evaluated.Results
Our data showed that BMSCs significantly reduce inflammation and oxidative stress, reduce apoptosis and promote angiogenesis of damaged pancreas. Moreover, BMSCs increased the level of HO-1 in the serum and pancreatic tissue in rats with SAP. In addition, the protective effect of BMSCs was partially neutralized by the HO-1 activity inhibitor ZnPP, suggesting a key role of HO-1 in the therapeutic effect of BMSCs on SAP.Conclusions
BMSCs ameliorated SAP, probably by inducing expression of HO-1, which can exert anti-inflammatory and anti-oxidant effects, reduce apoptosis and promote angiogenesis. 相似文献12.
GYUNGAH KIM YOON MI JIN YEONSIL YU HA YEONG KIM SANGMEE AHN JO YOON JEONG PARK YOON SHIN PARK INHO JO 《Cytotherapy》2018,20(8):1013-1027
Background and aims
Osteoporosis, which is a disease characterized by weakening of the bone, affects a large portion of the senior population. The current therapeutic options for osteoporosis have side effects, and there is no effective treatment for severe osteoporosis. Thus, we urgently need new treatment strategies, such as topical therapies and/or safe and effective stem cell therapies.Methods
We investigated the therapeutic potential of directly injecting human tonsil-derived mesenchymal stem cells (TMSC) into the right proximal tibias of ovariectomized postmenopausal osteoporosis model mice. Injections were given once (1×) or twice (2×) during the 3-month experimental period. At the end of the experiment, micro-computed tomographic images revealed some improvement in the proximal tibias and more significant improvement in the femoral heads of treated mice.Results
Osteogenic effect was qualitatively and quantitatively more pronounced in TMSC/2×-treated mice. Furthermore, TMSC/2×?mice exhibited significant recovery of the serum osteocalcin level, which is pathologically elevated in osteoporosis, and increased serum alkaline phosphatase, which indicates bone formation. TMSC therapy was generally well tolerated and caused no apparent toxicity in the experimental mice. Moreover, TMSC therapy reduced visceral fat.Conclusion
Our results demonstrate that double injection of TMSC directly into the proximal tibia triggers recovery of osteoporosis, and thus could be a potential therapeutic approach for severe bone loss. 相似文献13.
ROSS A. MARKLEIN MATTHEW W. KLINKER KATHERINE A. DRAKE HANNAH G. POLIKOWSKY ELIZABETH C. LESSEY-MORILLON STEVEN R. BAUER 《Cytotherapy》2019,21(1):17-31
Background
Although a preponderance of pre-clinical data demonstrates the immunosuppressive potential of mesenchymal stromal cells (MSCs), significant heterogeneity and lack of critical quality attributes (CQAs) based on immunosuppressive capacity likely have contributed to inconsistent clinical outcomes. This heterogeneity exists not only between MSC lots derived from different donors, tissues and manufacturing conditions, but also within a given MSC lot in the form of functional subpopulations. We therefore explored the potential of functionally relevant morphological profiling (FRMP) to identify morphological subpopulations predictive of the immunosuppressive capacity of MSCs derived from multiple donors, manufacturers and passages.Methods
We profiled the single-cell morphological response of MSCs from different donors and passages to the functionally relevant inflammatory cytokine interferon (IFN)-γ. We used the machine learning approach visual stochastic neighbor embedding (viSNE) to identify distinct morphological subpopulations that could predict suppression of activated CD4+ and CD8+ T cells in a multiplexed quantitative assay.Results
Multiple IFN-γ–stimulated subpopulations significantly correlated with the ability of MSCs to inhibit CD4+ and CD8+ T-cell activation and served as effective CQAs to predict the immunosuppressive capacity of additional manufactured MSC lots. We further characterized the emergence of morphological heterogeneity following IFN-γ stimulation, which provides a strategy for identifying functional subpopulations for future single-cell characterization and enrichment techniques.Discussion
This work provides a generalizable analytical platform for assessing functional heterogeneity based on single-cell morphological responses that could be used to identify novel CQAs and inform cell manufacturing decisions. 相似文献14.
GAMZE DERELI CAN ÖZGE EKIN AKDERE MEHMET EROL CAN MENEMŞE GÜMÜŞDERELIOĞLU 《Cytotherapy》2019,21(1):83-95
Background
Several methods to cultivate limbal epithelial stem cells (LESCs) in vitro with the support of feeder layers and different growth medium formulations have been established for several years. The initial green medium consists of various ingredients that exhibit a non-optimal level of biosafety, therefore, different modifications have been made to suit it to safe clinical applications. However, the question of which formulation is the most appropriate remains to be answered.Aims
This study evaluated the outgrowth kinetics and stemness of cells cultured from human limbal explants with the aim of preserving LESC characteristics in the human-derived platelet-rich fibrin (HPRF)–conditioned medium with no feeder cell layer or carrier for the first time. The final composition of the cell culture system included only human-derived products without any xenobiotic or chemical substances to minimize the potential risk for human health, which will be useful for clinical purposes.Methods
To test our hypothesis, limbal explants were incubated with either Dulbecco's Modified Eagle's Medium (DMEM)/F12-10% human serum (HS), human-derived amniotic membrane (HAM)-conditioned DMEM/F12-10% HS or HPRF-conditioned DMEM/F12-10% HS to determine whether outgrowth kinetics and stemness of cells show any differences among groups.Results
The results showed that the HPRF-conditioned medium showed higher concentration levels of growth factors, which may be involved in the promotion of LESC expansion while preserving the stem cell characteristics. HPRF-conditioned medium had significantly superior capacity to enhance the cell growth rate, the stem/progenitor cell phenotype and the expressions of putative stem cell markers.Conclusion
This novel xeno-feeder-chemical-free, completely human-derived and biologically safe culture system including HPRF and HS would be of interest to replace conventional cell culture strategies to meet safety requirements mandatory for clinical use in humans. 相似文献15.
María Álvarez-Fuente Luis Arruza Paloma Lopez-Ortego Laura Moreno Manuel Ramírez-Orellana Carlos Labrandero África González Gustavo Melen Maria Jesús Del Cerro 《Cytotherapy》2018,20(11):1337-1344
Background
Bronchopulmonary dysplasia (BPD) is the most prevalent sequelae of premature birth, for which therapeutic options are currently limited. Mesenchymal stromal cells (MSCs) are a potential therapy for prevention or reversal of BPD.Series of cases
We report on two infants with severe BPD in whom off-label treatment with repeated intravenous doses of allogeneic bone marrow–derived MSCs were administered. We analyzed the temporal profile of serum and tracheal cytokines and growth factors as well as safety, tolerability and clinical response. The administration of repeated intravenous doses of MSCs in two human babies with severe and advanced BPD was feasible and safe and was associated with a decrease of pro-inflammatory molecules and lung injury biomarkers. Both patients were at very advanced stages of BPD with very severe lung fibrosis and did not survive the disease.Conclusions
MSCs are a promising therapy for BPD, but they should be administered in early stages of the disease. 相似文献16.
TZUHUA LIN JUKKA PAJARINEN YUSUKE KOHNO MASAHIRO MARUYAMA MONICA ROMERO-LOPEZ JHIH-FONG HUANG KARTHIK NATHAN TAHSIN N. KHAN ZHENYU YAO STUART B. GOODMAN 《Cytotherapy》2018,20(8):1028-1036
Background
Mesenchymal stromal cell (MSC)–based therapy has great potential to modulate chronic inflammation and enhance tissue regeneration. Crosstalk between MSC-lineage cells and polarized macrophages is critical for bone formation and remodeling in inflammatory bone diseases. However, the translational application of this interaction is limited by the short-term viability of MSCs after cell transplantation.Methods
Three types of genetically modified (GM) MSCs were created: (1) luciferase-expressing reporter MSCs; (2) MSCs that secrete interleukin (IL)-4 either constitutively; and (3) MSCs that secrete IL-4 as a response to nuclear factor kappa-light-chain-enhancer of activated B cell (NFκB) activation. Cells were injected into the murine distal femoral bone marrow cavity. MSC viability and bone formation were examined in vivo. Cytokine secretion was determined in a femoral explant organ culture model.Results
The reporter MSCs survived up to 4 weeks post-implantation. No difference in the number of viable cells was found between high (2.5?×?106) and low (0.5?×?106) cell-injected groups. Injection of 2.5?×?106 reporter MSCs increased local bone mineral density at 4 weeks post-implantation. Injection of 0.5?×?106 constitutive IL-4 or NFκB-sensing IL-4–secreting MSCs increased bone mineral density at 2 weeks post-implantation. In the femoral explant organ culture model, LPS treatment induced IL-4 secretion in the NFκB-sensing IL-4–secreting MSC group and IL-10 secretion in all the femur samples. No significant differences in tumor necrosis factor (TNF)α and IL-1β secretion were observed between the MSC-transplanted and control groups in the explant culture.Discussion
Transplanted GM MSCs demonstrated prolonged cell viability when transplanted to a compatible niche within the bone marrow cavity. GM IL-4–secreting MSCs may have great potential to enhance bone regeneration in disorders associated with chronic inflammation. 相似文献17.
18.
GABRIELA OTERO CAROLINE AGORIO ALEXANDRA SUJANOV LOURDES ECHARTE ANA TCHEKMEDYIAN MONICA MONTELONGO ALBA MENYOU ANDRES RODRIGUEZ LILIAN DIAZ ISMAEL RODRIGUEZ CRISTINA TOURIÑO 《Cytotherapy》2019,21(2):189-199
Background
Chronic venous leg ulcers (VLUs) are a common problem in clinical practice and available treatments are not satisfactory. The use of adjuvant therapies in combination with lower limb compression may lead to improved healing rates. Chronic wounds are candidates for new strategies in the emergent field of regenerative medicine. Bone marrow–derived cells (BMDCs) contain cells and secrete cytokines known to participate in wound healing. Thus, BMDC therapy seems a logical strategy for the treatment of chronic wounds. Our objective was to evaluate feasibility, safety and initial clinical outcome of autologous BMDC therapy associated with standard treatment in patients with VLUs.Methods
We conducted an open-label, single-arm, prospective pilot clinical trial in four patients with six chronic VLUs. The study protocol was approved by the institutional and national review boards and ethics committees. Bone marrow was harvest, processed and then administered by multiple injections into the ulcers. All patients received standard treatment and non-healing characteristics of the VLUs were confirmed at study entry.Results
Ulcer size and wound pain evaluated 12 months after BMDC treatment were significantly reduced (P < 0.05). BMDC treatment was safe and well tolerated in long-term follow-up.Discussion
Despite the low number of patients studied, our results showed that autologous BMDC treatment could be a useful, feasible and safe procedure to enhance ulcer healing. However, randomized controlled trials with more patients are needed to address this question and translate this approach into clinical practice. 相似文献19.
REBECCA M. Harman MEGAN K. HE SHENG ZHANG GERLINDE R. VAN DE WALLE 《Cytotherapy》2018,20(8):1061-1076
Background
Impaired cutaneous wound healing is common in humans, and treatments are often ineffective. Based on the significant emotional and economic burden of impaired wound healing, innovative therapies are needed. The potential of mesenchymal stromal cell (MSC)–secreted factors to treat cutaneous wounds is an active area of research that is in need of refinement before effective clinical trials can be initiated. The aims of the present study were to (i) study which MSC-secreted factors stimulate dermal fibroblast (DF) migration in vitro and (ii) evaluate the potential of these factors to promote wound healing in vivo.Methods
To this end, MSCs were isolated from the peripheral blood of healthy horses, a physiologically relevant large animal model appropriate for translational wound-healing studies. Conditioned medium (CM) from cultured equine MSCs was analyzed using liquid chromatography-mass spectrophotometry (LC-MS/MS) to identify secreted proteins of interest. Double-stranded RNA-mediated interference (RNAi) was used to silence the genes encoding selected proteins, and the effects of CM from these transfected MSCs on migration of cultured equine DF cells in vitro and full-thickness wounds in mice were evaluated.Results
We found that MSC-derived plasminogen activator inhibitor-1 (PAI-1) and tenascin-C significantly increased DF migration in vitro and improved wound healing in vivo by decreasing time to wound closure.Discussion
These results suggest that in a complex wound environment, MSC-secreted factors PAI-1 and tenascin-C contribute to the positive effect of therapeutically applied MSC CM on wound healing. 相似文献20.
Mona Navaei-Nigjeh Milad Moloudizargari Maryam Baeeri Mahdi Gholami Nasrin Lotfibakhshaiesh Masoud Soleimani Ebrahim Vasheghani-farahani Jafar AI Mohammad Abdollahi 《Cytotherapy》2018,20(9):1124-1142