RESUMEN

The number of patients with functional loss of bone and cartilage tissue has shown an increasing trend. Insufficient or inappropriate conventional treatments applied for trauma, orthopedic diseases, or other bone and cartilage-related disorders can lead to bone and cartilage damage. This represents a worldwide public health issue and a significant economic burden. Advanced therapeutic medicinal products (ATMPs) proposed promising alternative therapeutic modalities by application of cell-based and tissue engineering approaches. Recently, several ATMPs have been developed to promote bone and cartilage tissue regeneration. Fifteen ATMPs, two related to bone and 13 related to cartilage, have received regulatory approval and marketing authorization. However, four ATMPs were withdrawn from the market for various reasons. However, ATMPs that are still on the market have demonstrated positive results, their broad application faced limitations. The development and standardization of methodologies will be a major challenge in the coming decades. Currently, the number of ATMPs in clinical trials using mesenchymal stromal cells or chondrocytes indicates a growing recognition that current ATMPs can be improved. Research on bone and cartilage tissue regeneration continues to expand. Cell-based therapies are likely to be clinically supported by the new ATMPs, innovative fabrication processes, and enhanced surgical approaches. In this study, we highlighted the available ATMPs that have been used in bone and cartilage defects and discussed their advantages and disadvantages in clinical applications.

Asunto(s)

Ingeniería de Tejidos , Humanos , Ingeniería de Tejidos/métodos , Animales , Enfermedades de los Cartílagos/terapia , Enfermedades Óseas/terapia , Cartílago/lesiones , Regeneración Ósea/efectos de los fármacos

RESUMEN

Gliomas are primary malignant brain tumors. These tumors seem to be more and more frequent, not only because of a true increase in their incidence, but also due to the increase in life expectancy of the general population. Among gliomas, malignant gliomas and more specifically glioblastomas (GBM) are a challenge in their diagnosis and treatment. There are few effective therapies for these tumors, and patients with GBM fare poorly, even after aggressive surgery, chemotherapy, and radiation. Over the last decade, it is now appreciated that these tumors are composed of numerous distinct tumoral and non-tumoral cell populations, which could each influence the overall tumor biology and response to therapies. Monocytes have been proved to actively participate in tumor growth, giving rise to the support of tumor-associated macrophages (TAMs). In GBM, TAMs represent up to one half of the tumor mass cells, including both infiltrating macrophages and resident brain microglia. Infiltrating macrophages/monocytes constituted ~ 85% of the total TAM population, they have immune functions, and they can release a wide array of growth factors and cytokines in response to those factors produced by tumor and non-tumor cells from the tumor microenvironment (TME). A brief review of the literature shows that this cell population has been increasingly studied in GBM TME to understand its role in tumor progression and therapeutic resistance. Through the knowledge of its biology and protumoral function, the development of therapeutic strategies that employ their recruitment as well as the modulation of their immunological phenotype, and even the eradication of the cell population, can be harnessed for therapeutic benefit. This revision aims to summarize GBM TME and localization in tumor niches with special focus on TAM population, its origin and functions in tumor progression and resistance to conventional and experimental GBM treatments. Moreover, recent advances on the development of TAM cell targeting and new cellular therapeutic strategies based on monocyte/macrophages recruitment to eradicate GBM are discussed as complementary therapeutics.

RESUMEN

Chronic kidney disease of unknown cause (CKDu), also known as Mesoamerican nephropathy, typically presents as an ischemic nephropathy with chronic tubulointerstitial fibrosis in normotensive patients, rapidly progressing to kidney failure. In this first-in-human, open-label, safety study, we followed 18 patients with CKDu (stages 3-5) for 36 months after receiving a single infusion of angiogenic/anti-fibrotic autologous adipose-derived stromal vascular fraction (SVF) cells into their kidneys bilaterally via renal artery catheterization. SVF therapy was safe and well tolerated. There were no SVF-related serious adverse events and no procedural complications. Color Doppler evaluation at 2 months demonstrated increased perfusion to the interlobar and/or arcuate artery levels in each kidney evaluated (36/36) with a reduction in resistance index at the hilar artery (35/36) kidneys. Beyond 12 months, patients with initial eGFR <30 mL/minute/1.73 m2 deteriorated, whereas those ≥30 mL/minute/1.73 m2 further sustained their renal function, suggesting a possible renal protective effect in that group.

Asunto(s)

Enfermedades Renales Crónicas de Etiología Incierta , Insuficiencia Renal Crónica , Humanos , Tejido Adiposo , Tratamiento Basado en Trasplante de Células y Tejidos , Fibrosis , Riñón/patología , Insuficiencia Renal Crónica/terapia , Células del Estroma , Fracción Vascular Estromal

RESUMEN

BACKGROUND AIMS: Although bone marrow-derived mesenchymal stromal cells (MSCs) have demonstrated success in pre-clinical studies, they have shown only mild therapeutic effects in clinical trials. Hypoxia pre-conditioning may optimize the performance of bone marrow-derived MSCs because it better reflects the physiological conditions of their origin. It is not known whether changes in the protein profile caused by hypoxia in MSCs can be extended to the extracellular vesicles (EVs) released from them. The aim of this study was to evaluate the proteomics profile of MSCs and their EVs under normoxic and hypoxic conditions. METHODS: Bone marrow-derived MSCs were isolated from six healthy male Wistar rats. After achieving 80% confluence, MSCs were subjected to normoxia (MSC-Norm) (21% oxygen, 5% carbon dioxide, 74% nitrogen) or hypoxia (MSC-Hyp) (1% oxygen, 5% carbon dioxide, 94% nitrogen) for 48 h. Cell viability and oxygen consumption rate were assessed. EVs were extracted from MSCs for each condition (EV-Norm and EV-Hyp) by ultracentrifugation. Total proteins were isolated from MSCs and EVs and prepared for mass spectrometry. EVs were characterized by nanoparticle tracking analysis. Proteomics data were analyzed by PatternLab 4.0, Search Tool for the Retrieval of Interacting Genes/Proteins, Gene Ontology, MetaboAnalyst and Reactome software. RESULTS: Cell viability was higher in MSC-Hyp than MSC-Norm (P = 0.007). Basal respiration (P = 0.001), proton leak (P = 0.004) and maximal respiration (P = 0.014) were lower in MSC-Hyp than MSC-Norm, and no changes in adenosine triphosphate-linked and residual respiration were observed. The authors detected 2177 proteins in MSC-Hyp and MSC-Norm, of which 147 were identified in only MSC-Hyp and 512 were identified in only MSC-Norm. Furthermore, 718 proteins were identified in EV-Hyp and EV-Norm, of which 293 were detected in only EV-Hyp and 30 were detected in only EV-Norm. Both MSC-Hyp and EV-Hyp showed enrichment of pathways and biological processes related to glycolysis, the immune system and extracellular matrix organization. CONCLUSIONS: MSCs subjected to hypoxia showed changes in their survival and metabolic activity. In addition, MSCs under hypoxia released more EVs, and their content was related to expression of regulatory proteins of the immune system and extracellular matrix organization. Because of the upregulation of proteins involved in glycolysis, gluconeogenesis and glucose uptake during hypoxia, production of reactive oxygen species and expression of immunosuppressive properties may be affected.

Asunto(s)

Vesículas Extracelulares , Células Madre Mesenquimatosas , Animales , Ratas , Masculino , Proteómica , Dióxido de Carbono/metabolismo , Ratas Wistar , Células Madre Mesenquimatosas/metabolismo , Vesículas Extracelulares/metabolismo , Hipoxia/metabolismo , Oxígeno/metabolismo , Nitrógeno/metabolismo

RESUMEN

There is a steadily growing interest in the use of mitochondria as therapeutic agents. The use of mitochondria derived from mesenchymal stem/stromal cells (MSCs) for therapeutic purposes represents an innovative approach to treat many diseases (immune deregulation, inflammation-related disorders, wound healing, ischemic events, and aging) with an increasing amount of promising evidence, ranging from preclinical to clinical research. Furthermore, the eventual reversal, induced by the intercellular mitochondrial transfer, of the metabolic and pro-inflammatory profile, opens new avenues to the understanding of diseases' etiology, their relation to both systemic and local risk factors, and also leads to new therapeutic tools for the control of inflammatory and degenerative diseases. To this end, we illustrate in this review, the triggers and mechanisms behind the transfer of mitochondria employed by MSCs and the underlying benefits as well as the possible adverse effects of MSCs mitochondrial exchange. We relay the rationale and opportunities for the use of these organelles in the clinic as cell-based product.

Asunto(s)

Mitocondrias/metabolismo , Tratamiento Basado en Trasplante de Células y Tejidos , Humanos , Enfermedades Pulmonares/terapia , Macrófagos/citología , Macrófagos/inmunología , Macrófagos/metabolismo , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/metabolismo , Mitocondrias/trasplante , Dinámicas Mitocondriales , Comunicación Paracrina

RESUMEN

The route used in the transplantation of mesenchymal stem cells (MSCs) can directly affect the treatment success. The transplantation of MSCs via the intrathecal (IT) route can be an important therapeutic strategy for neurological disorders. The objective of this study was to evaluate the safety and feasibility of the IT transplantation of autologous (Auto-MSCs) and allogeneic (Allo-MSCs) bone marrow mesenchymal stem cells (BM-MSCs) in healthy dogs. Based on neurodisability score, cerebrospinal fluid (CSF) and magnetic resonance imaging (MRI), no significant differences from the control group were observed on day 1 or day 5 after IT Auto- or Allo-MSCs transplantation (P > 0.05). In addition, analysis of matrix metalloproteinase (MMP)-2 and MMP-9 expression in the CSF revealed no significant differences (P > 0.05) at 5 days after IT transplantation in the Auto- or Allo-MSCs group when compared to the control. Intrathecal transplantation of BM-MSCs in dogs provides a safe, easy and minimally invasive route for the use of cell-based therapeutics in central nervous system diseases.

Asunto(s)

Médula Ósea/metabolismo , Tratamiento Basado en Trasplante de Células y Tejidos/métodos , Inyecciones Espinales/métodos , Trasplante de Células Madre Mesenquimatosas/métodos , Células Madre Mesenquimatosas/metabolismo , Trasplante Autólogo/métodos , Trasplante Homólogo/métodos , Animales , Perros

RESUMEN

BACKGROUND: Nerve injuries are debilitating, leading to long-term motor deficits. Remyelination and axonal growth are supported and enhanced by growth factor and cytokines. Combination of nerve guidance conduits (NGCs) with adipose-tissue-derived multipotent mesenchymal stromal cells (AdMSCs) has been performing promising strategy for nerve regeneration. METHODS: 3D-printed polycaprolactone (PCL)-NGCs were fabricated. Wistar rats subjected to critical sciatic nerve damage (12-mm gap) were divided into sham, autograft, PCL (empty NGC), and PCL + MSCs (NGC multi-functionalized with 106 canine AdMSCs embedded in heterologous fibrin biopolymer) groups. In vitro, the cells were characterized and directly stimulated with interferon-gamma to evaluate their neuroregeneration potential. In vivo, the sciatic and tibial functional indices were evaluated for 12 weeks. Gait analysis and nerve conduction velocity were analyzed after 8 and 12 weeks. Morphometric analysis was performed after 8 and 12 weeks following lesion development. Real-time PCR was performed to evaluate the neurotrophic factors BDNF, GDNF, and HGF, and the cytokine and IL-10. Immunohistochemical analysis for the p75NTR neurotrophic receptor, S100, and neurofilament was performed with the sciatic nerve. RESULTS: The inflammatory environment in vitro have increased the expression of neurotrophins BDNF, GDNF, HGF, and IL-10 in canine AdMSCs. Nerve guidance conduits multi-functionalized with canine AdMSCs embedded in HFB improved functional motor and electrophysiological recovery compared with PCL group after 12 weeks. However, the results were not significantly different than those obtained using autografts. These findings were associated with a shift in the regeneration process towards the formation of myelinated fibers. Increased immunostaining of BDNF, GDNF, and growth factor receptor p75NTR was associated with the upregulation of BDNF, GDNF, and HGF in the spinal cord of the PCL + MSCs group. A trend demonstrating higher reactivity of Schwann cells and axonal branching in the sciatic nerve was observed, and canine AdMSCs were engrafted at 30 days following repair. CONCLUSIONS: 3D-printed NGCs multi-functionalized with canine AdMSCs embedded in heterologous fibrin biopolymer as cell scaffold exerted neuroregenerative effects. Our multimodal approach supports the trophic microenvironment, resulting in a pro-regenerative state after critical sciatic nerve injury in rats.

Asunto(s)

Células Madre Mesenquimatosas , Animales , Perros , Regeneración Nerviosa , Impresión Tridimensional , Ratas , Ratas Wistar , Células de Schwann , Nervio Ciático

RESUMEN

PURPOSE: In deep burns, wound contraction and hypertrophic scar formation can generate functional derangement and debilitation of the affected part. In order to improve the quality of healing in deep second-degree burns, we developed a new treatment in a preclinical model using nanostructured membranes seeded with mesenchymal stem cells (MSCs). METHODS: Membranes were obtained by reconstitution of bacterial cellulose (reconstituted membrane [RM]) and produced by a dry-cast process, then RM was incorporated with 10% tamarind xyloglucan plus gellan gum 1:1 and 10% lysozyme (RMGT-LZ) and with 10% gellan gum and 10% lysozyme (RMG-LZ). Membrane hydrophobic/hydrophilic characteristics were investigated by static/dynamic contact-angle measurements. They were cultivated with MSCs, and cell adhesion, proliferation, and migration capacity was analyzed with MTT assays. Morphological and topographic characteristics were analyzed by scanning electron microscopy. MSC patterns in flow cytometry and differentiation into adipocytes and osteocytes were checked. In vivo assays used RMG-LZ and RMGT-LZ (with and without MSCs) in Rattus norvegicus rats submitted to burn protocol, and histological sections and collagen deposits were analyzed and immunocytochemistry assay performed. RESULTS: In vitro results demonstrated carboxyl and amine groups made the membranes moderately hydrophobic and xyloglucan inclusion decreased wettability, favoring MSC adhesion, proliferation, and differentiation. In vivo, we obtained 40% and 60% reduction in acute/chronic inflammatory infiltrates, 96% decrease in injury area, increased vascular proliferation and collagen deposition, and complete epithelialization after 30 days. MSCs were detected in burned tissue, confirming they had homed and proliferated in vivo. CONCLUSION: Nanostructured cellulose-gellan-xyloglucan-lysozyme dressings, especially when seeded with MSCs, improved deep second-degree burn regeneration.

Asunto(s)

Vendajes , Quemaduras/terapia , Celulosa/química , Glucanos/química , Células Madre Mesenquimatosas/citología , Muramidasa/química , Nanoestructuras/química , Polisacáridos Bacterianos/química , Xilanos/química , Animales , Vasos Sanguíneos/patología , Quemaduras/patología , Adhesión Celular , Diferenciación Celular , Proliferación Celular , Celulosa/ultraestructura , Colágeno/metabolismo , Inflamación/patología , Masculino , Trasplante de Células Madre Mesenquimatosas/métodos , Células Madre Mesenquimatosas/ultraestructura , Nanoestructuras/ultraestructura , Ratas Wistar , Cicatrización de Heridas

RESUMEN

Parkinson's disease (PD) is a disabling and highly costly neurodegenerative condition with worldwide prevalence. Despite advances in treatments that slow progression and minimize locomotor impairments, its clinical management is still a challenge. Previous preclinical studies, using mesenchymal stem cell (MSC) transplantation and isolated physical exercise (EX), reported beneficial results for treatment of PD. Therefore, this experimental randomized study aimed to elucidate the therapeutic potential of combined therapy using adipose-derived human MSCs (ADSCs) grafted into the striatum in conjunction with aerobic treadmill training, specifically in terms of locomotor performance in a unilateral PD rat model induced by 6-hydroxydopamine (6-OHDA). Forty-one male Wistar rats were categorized into five groups in accordance with the type of treatment to which they were subjected (Sham, 6-OHDA - injury, 6-OHDA + exercise, 6-OHDA + cells, and 6-OHDA + combined). Subsequently, dopaminergic depletion was assessed by the methylphenidate challenge and the specified therapeutic intervention was conducted in each group. The foot fault task was performed at the end of the experiment to serve as an assessment of motor skills. The results showed that despite disturbances in motor balance and coordination, locomotor dysfunction was ameliorated in all treatment categories in comparison to the injury group (sign test, p < 0.001, effect size: 0.71). The exercise alone and combined groups were the categories that exhibited the best recovery in terms of movement performance (p < 0.001). Overall, this study confirms that exercise is a powerful option to improve motor function and a promising adjuvant intervention for stem cell transplantation in the treatment of PD motor symptoms. OPEN PRACTICES: This article has been awarded Open Data. All materials and data are publicly accessible at https://figshare.com/s/18a543c101a17a1d5560. Learn more about the Open Practices badges from the Center for Open Science: https://osf.io/tvyxz/wiki.

Asunto(s)

Trasplante de Células Madre Mesenquimatosas , Enfermedad de Parkinson Secundaria/terapia , Condicionamiento Físico Animal , Animales , Neuronas Dopaminérgicas/metabolismo , Humanos , Masculino , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/metabolismo , Metilfenidato , Actividad Motora/efectos de los fármacos , Oxidopamina , Enfermedad de Parkinson Secundaria/inducido químicamente , Ratas , Ratas Wistar , Sustancia Negra/metabolismo , Tirosina 3-Monooxigenasa/metabolismo , Área Tegmental Ventral/metabolismo

RESUMEN

BACKGROUND: Based on several attributes involved in bone formation, bone marrow-resident mesenchymal stem cells (MSCs) have been employed in the treatment of patients suffering from femoral head osteonecrosis. Due to the low content of MSCs in the bone marrow, ex vivo expansion procedures are utilized to increase the cell number. Customarily, before administration of the resulting expanded cell product MSCs to the patient, its cellular identity is usually evaluated according to a set of "minimal phenotypic" markers, which are not modified by ex vivo processing. However, MSC functional ("reparative") markers, which are severely impaired along the ex vivo expansion routine, are usually not assessed. PATIENTS AND METHODS: In this proof-of-concept study, a cohort of five avascular osteonecrosis patients received an instillation of ex vivo-expanded autologous MSCs, manufactured under controlled conditions, with an aim to protect their functional ("reparative") capacity. RESULTS AND CONCLUSION: Outcomes of this study confirmed the safety and effectiveness of the MSC-based therapy used. After a follow-up period (19-54 months), in all patients, the hip function was significantly improved and pain intensity markedly reduced. As a corollary, no patient required hip arthroplasty.

RESUMEN

BACKGROUND: Preconditioning of cell recipients may exert a significant role in attenuating the hostility of the infarction milieu, thereby enhancing the efficacy of cell therapy. This study was conducted to examine whether exercise training potentiates the cardioprotective effects of adipose-derived stem cell (ADSC) transplantation following myocardial infarction (MI) in rats. METHODS: Four groups of female Fisher-344 rats were studied: Sham; non-trained rats with MI (sMI); non-trained rats with MI submitted to ADSCs transplantation (sADSC); trained rats with MI submitted to ADSCs (tADSC). Rats were trained 9 weeks prior to MI and ADSCs transplantation. Echocardiography was applied to assess cardiac function. Myocardial performance was evaluated in vitro. Protein expression analyses were carried out by immunoblotting. Periodic acid-Schiff staining was used to analyse capillary density and apoptosis was evaluated with terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) assay. RESULTS: Echocardiography performed 4 weeks after the infarction revealed attenuated scar size in the both sADSC and tADSC groups compared to the sMI group. However, fractional shortening was improved only in the tADSC group. In vitro myocardial performance was similar between the tADSC and Sham groups. The expression of phosphoSer473Akt1 and VEGF were found to be higher in the hearts of the tADSC group compared to both the sADSC and sMI groups. Histologic analysis demonstrated that tADSC rats had higher capillary density in the remote and border zones of the infarcted sites compared to the sMI rats. CONCLUSIONS: Preconditioning with exercise induces a pro-angiogenic milieu that may potentiate the therapeutic effects of ADSCs on cardiac remodelling following MI.

Asunto(s)

Infarto del Miocardio , Condicionamiento Físico Animal , Trasplante de Células Madre , Remodelación Ventricular , Animales , Femenino , Modelos Animales de Enfermedad , Infarto del Miocardio/diagnóstico , Infarto del Miocardio/fisiopatología , Infarto del Miocardio/terapia , Condicionamiento Físico Animal/métodos , Distribución Aleatoria , Ratas Endogámicas F344 , Trasplante de Células Madre/métodos , Remodelación Ventricular/fisiología , Ratas

RESUMEN

Crush injuries in peripheral nerves are frequent and induce long-term disability with motor and sensory deficits. Due to axonal and myelin sheath disruptions, strategies for optimized axonal regeneration are needed. Multipotent mesenchymal stromal cells (MSC) are promising because of their anti-inflammatory properties and secretion of neurotrophins. The present study investigated the effect of canine adipose tissue MSC (Ad-MSC) transplantation in an experimental sciatic nerve crush injury. Wistar rats were divided into three groups: sham ( n = 8); Crush+PBS ( n = 8); Crush+MSC ( n = 8). Measurements of sciatic nerve functional index (SFI), muscle mass, and electromyography (EMG) were performed. Canine Ad-MSC showed mesodermal characteristics (CD34-, CD45-, CD44+, CD90+ and CD105+) and multipotentiality due to chondrogenic, adipogenic, and osteogenic differentiation. SFI during weeks 3 and 4 was significantly higher in the Crush+MSC group ( p < 0.001). During week 4, the EMG latency in the Crush+MSC groups had better near normality ( p < 0.05). The EMG amplitude showed results close to normality during week 4 in the Crush+MSC group ( p < 0.04). There were no statistical differences in muscle weight between the groups ( p > 0.05), but there was a tendency toward weight gain in the Crush+MSC groups. Better motor functional recovery after crush and perineural canine Ad-MSC transplantation was observed during week 2. This was maintained till week 4. In conclusion, the canine Ad-MSC transplantation showed early pro-regenerative effects between 2-4 weeks in the rat model of sciatic nerve crush injury.

Asunto(s)

Tejido Adiposo/citología , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/fisiología , Regeneración Nerviosa/fisiología , Traumatismos de los Nervios Periféricos/fisiopatología , Traumatismos de los Nervios Periféricos/terapia , Neuropatía Ciática/fisiopatología , Neuropatía Ciática/terapia , Tejido Adiposo/metabolismo , Animales , Tratamiento Basado en Trasplante de Células y Tejidos/métodos , Perros , Electromiografía , Vaina de Mielina/fisiología , Ratas

RESUMEN

This systematic review evaluated the transplantation of cells derived from adipose tissue for applications in dentistry. SCOPUS, PUBMED and LILACS databases were searched for in vitro studies and pre-clinical animal model studies using the keywords "ADIPOSE", "CELLS", and "PERIODONTAL", with the Boolean operator "AND". A total of 160 titles and abstracts were identified, and 29 publications met the inclusion criteria, 14 in vitro and 15 in vivo studies. In vitro studies demonstrated that adipose- derived cells stimulate neovascularization, have osteogenic and odontogenic potential; besides adhesion, proliferation and differentiation on probable cell carriers. Preclinical studies described improvement of bone and periodontal healing with the association of adipose-derived cells and the carrier materials tested: Platelet Rich Plasma, Fibrin, Collagen and Synthetic polymer. There is evidence from the current in vitro and in vivo data indicating that adipose-derived cells may contribute to bone and periodontal regeneration. The small quantity of studies and the large variation on study designs, from animal models, cell sources and defect morphology, did not favor a meta-analysis. Additional studies need to be conducted to investigate the regeneration variability and the mechanisms of cell participation in the processes. An overview of animal models, cell sources, and scaffolds, as well as new perspectives are provided for future bone and periodontal regeneration study designs.

Asunto(s)

Adipocitos , Regeneración Ósea , Periodoncio/fisiología , Medicina Regenerativa/métodos , Trasplante de Células Madre/métodos , Animales , Humanos , Modelos Animales , Osteogénesis , Regeneración , Ingeniería de Tejidos/métodos

RESUMEN

BACKGROUND: Osteonecrosis of the femoral head (ONFH) is associated with regional loss of cells within bone, often resulting in pain and mechanical collapse. Our purpose was to analyze the cell-therapies used in clinical trials for the treatment of ONFH with regard to (1) cell-sources, (2) collection techniques, (3) cell-processing, (4) qualitative and quantitative characterizations, and (5) delivery methods. METHODS: A systematic review of the current literature on the use of cell therapies for the treatment of ONFH was performed. Studies with a level-of-evidence III or higher were evaluated. A total of 1483 articles were screened. Eleven studies met the criteria to be included in this review. RESULTS: Ten studies used bone-marrow, and 1 study used blood as the cell-source. Nine studies used freshly isolated tissue-derived nucleated cells from bone-marrow, mixed bone marrow-derived nucleated cells, 1 study used mixed blood-derived nucleated cells, and 1 study used culture-expanded cells derived from bone marrow aspirate. Cell dose varied from 2-million to 3-billion cells. Qualitative cell characterization of injected cells using surface markers was done by 5 studies using CD34. Two studies assayed the cell-population using a colony-forming-unit assay. CONCLUSION: There is a lack of standardization with respect to the quantitative and qualitative characterization of methods for cell-harvest, cell-processing, and cell-transplantation/delivery. Cell-therapy holds promise as a means of restoring local cell populations that are made deficient because of injury or disease. However, the orthopedic community and patients will benefit greatly by a greater investment in blinded, randomized, controlled trials and clinical effectiveness trials that embrace rigorous standards.

Asunto(s)

Tratamiento Basado en Trasplante de Células y Tejidos/métodos , Necrosis de la Cabeza Femoral/terapia , Ensayos Clínicos como Asunto , Cabeza Femoral , Humanos , Trasplante Autólogo

RESUMEN

BACKGROUND AND OBJECTIVES: Maintaining a permissive microenvironment is essential for adequate nerve regeneration. Cell-based therapy has the potential based cell replacement and promotion of axonal growth. The adipose tissue derived mesenchymal stromal cells (Ad-MSC) attract interest because neuroregenerative and anti-inflammatory properties. The aim of this study was to evaluate the effects of canine and murine Ad-MSC transplantation on the sciatic nerve regeneration. METHODS: Forty Wistar rats were divided randomly into: control group - CG (n=8); denervated group - DG (n=8); decellularized vein group - VG (n=8); decellularized vein＋canine MSC-cMSC (n=8); descellularized vein＋murine MSC-mMSC (n=8). After 10-mm nerve gap, the tubulation technique was performed with decellularized vein filled with 106 MSC labeled with quantum dots (Qtracker 665®). The sciatic nerve functional index (SFI) and electroneuromyography (ENMG) measurements were carried and morphometric and immunohistochemistry analysis of the tissue. RESULTS: The SFI values were higher in the cMSC and mMSC groups at day 27 (p<0.020) and day 35 (p<0.011). The ENMG analysis also revealed better results in the mMSC group. Density, number, and total area of the fibers were increased in the mMSC and cMSC groups. Brain-derived neurotrophic factor BDNF and S-100 protein positive immunoreactivity showed a higher expression for both in the nerve of the mMSC and cMSC groups. The MSC labeled with quantum dots were detected at day 35, indicating neuronal survival long after the nerve damage. CONCLUSIONS: Murine and canine Ad-MSC associated with decellularized vein scaffold had positive effects on sciatic nerve regeneration in rats.

RESUMEN

BACKGROUND: Cell-therapy has been promoted among the therapeutic arsenal that can aid in bone formation and remodeling, in early stages of osteonecrosis of the femoral head (ONFH). The purpose of this systematic review was to assess the evidence supporting the (1) clinical efficacy; (2) structural modifying effect, as evaluated radiographically; (3) revision rates; and (4) safety of cell-therapy for the treatment of ONFH. METHODS: A systematic review was performed including studies with a level-of-evidence of III or higher. A total of 1483 articles were screened. Eleven studies met the criteria for inclusion in this review (level-of-evidence: 6 level-I, 1 level-II, and 4 level-III), including 683 cases of ONFH. RESULTS: All 10 studies that reported patient-reported outcomes showed improved outcomes in the cell-therapy groups compared with the control group. Overall, 24.5% (93/380 hips) that received cell-therapy showed radiographic progression compared with 40% (98/245 hips) in the control group. Nine of 10 studies that reported failure rates showed a lower total hip arthroplasty conversion rate in the cell-therapy group 16% (62/380 hips) compared with the control group 21% (52/252 hips). There was a low complication rate (<3%) with no major adverse effects. CONCLUSION: Cell-therapies for the treatment of ONFH have been reported to be safe and suggest improved clinical outcomes with lower disease progression rate. However, there was substantial heterogeneity in the included studies, and in the cell-based therapies used. Specific clinical indications and cell-therapy standardization are required because studies varied widely with respect to cell sourcing, cell characterization, adjuvant therapies, and assessment of outcomes.

Asunto(s)

Artroplastia de Reemplazo de Cadera , Tratamiento Basado en Trasplante de Células y Tejidos/métodos , Necrosis de la Cabeza Femoral/cirugía , Cabeza Femoral/cirugía , Cadera/cirugía , Adulto , Terapia Combinada , Progresión de la Enfermedad , Femenino , Cabeza Femoral/patología , Humanos , Masculino , Persona de Mediana Edad , Radiografía , Resultado del Tratamiento

RESUMEN

Tolerogenic dendritic cells (TolDCs) are promising tools for therapy of autoimmune diseases, such as rheumatoid arthritis (RA). Here, we characterize monocyte-derived TolDCs from RA patients modulated with dexamethasone and activated with monophosphoryl lipid A (MPLA), referred to as MPLA-tDCs, in terms of gene expression, phenotype, cytokine profile, migratory properties, and T cell-stimulatory capacity in order to explore their suitability for cellular therapy. MPLA-tDCs derived from RA patients displayed an anti-inflammatory profile with reduced expression of co-stimulatory molecules and high IL-10/IL-12 ratio, but were capable of migrating toward the lymphoid chemokines CXCL12 and CCL19. These MPLA-tDCs induced hyporesponsiveness of autologous CD4+ T cells specific for synovial antigens in vitro. Global transcriptome analysis confirmed a unique transcriptional profile of MPLA-tDCs and revealed that RA-associated genes, which were upregulated in untreated DCs from RA patients, returned to expression levels of healthy donor-derived DCs after treatment with dexamethasone and MPLA. Thus, monocyte-derived DCs from RA patients have the capacity to develop tolerogenic features at transcriptional as well as at translational level, when modulated with dexamethasone and MPLA, overcoming disease-related effects. Furthermore, the ability of MPLA-tDCs to impair T cell responses to synovial antigens validates their potential as cellular treatment for RA.

RESUMEN

Major advances are currently being made in regenerative medicine for cornea. Stem cell-based therapies represent a novel strategy that may substitute conventional corneal transplantation, albeit there are many challenges ahead given the singularities of each cellular layer of the cornea. This review recapitulates the current data on corneal epithelial stem cells, corneal stromal stem cells and corneal endothelial cell progenitors. Corneal limbal autografts containing epithelial stem cells have been transplanted in humans for more than 20 years with great successful rates, and researchers now focus on ex vivo cultures and other cell lineages to transplant to the ocular surface. A small population of cells in the corneal endothelium was recently reported to have self-renewal capacity, although they do not proliferate in vivo. Two main obstacles have hindered endothelial cell transplantation to date: culture protocols and cell delivery methods to the posterior cornea in vivo. Human corneal stromal stem cells have been identified shortly after the recognition of precursors of endothelial cells. Stromal stem cells may have the potential to provide a direct cell-based therapeutic approach when injected to corneal scars. Furthermore, they exhibit the ability to deposit organized connective tissue in vitro and may be useful in corneal stroma engineering in the future. Recent advances and future perspectives in the field are discussed.

RESUMEN

Tissue engineering is an emerging field of science that focuses on creating suitable conditions for the regeneration of tissues. The basic components for tissue engineering involve an interactive triad of scaffolds, signaling molecules, and cells. In this context, stem cells (SCs) present the characteristics of self-renewal and differentiation capacity, which make them promising candidates for tissue engineering. Although they present some common markers, such as cluster of differentiation (CD)105, CD146 and STRO-1, SCs derived from various tissues have different patterns in relation to proliferation, clonogenicity, and differentiation abilities in vitro and in vivo. Tooth-derived tissues have been proposed as an accessible source to obtain SCs with limited morbidity, and various tooth-derived SCs (TDSCs) have been isolated and characterized, such as dental pulp SCs, SCs from human exfoliated deciduous teeth, periodontal ligament SCs, dental follicle progenitor cells, SCs from apical papilla, and periodontal ligament of deciduous teeth SCs. However, heterogeneity among these populations has been observed, and the best method to select the most appropriate TDSCs for regeneration approaches has not yet been established. The objective of this review is to outline the current knowledge concerning the various types of TDSCs, and discuss the perspectives for their use in regenerative approaches.

RESUMEN

Cerebrovascular diseases are a major cause of death and long-term disability in developed countries. Tissue plasmin activator (tPA) is the only approved therapy for ischemic stroke, strongly limited by the short therapeutic window and hemorrhagic complications, therefore excluding most patients from its benefits. The rescue of the penumbra area of the ischemic infarct is decisive for functional recovery after stroke. Inflammation is a key feature in the penumbra area and it plays a dual role, improving injury in early phases but impairing neural survival at later stages. Stem cells can be opportunely used to modulate inflammation, abrogate cell death and, therefore, preserve neural function. We here discuss the possible role of stem cells derived from menstrual blood as restorative treatment for stroke. We highlight the availability, proliferative capacity, pluripotentiality and angiogenic features of these cells and explore their present and future experimental and clinical applications.