Immunomodulatory and Anti-fibrotic Effects Following the Infusion of Umbilical Cord Mesenchymal Stromal Cells in a Critically Ill Patient With COVID-19 Presenting Lung Fibrosis: A Case Report.

Background: The patients with coronavirus disease 2019 (COVID-19) associated with severe acute respiratory distress syndrome (ARDS) may require prolonged mechanical ventilation which often results in lung fibrosis, thus worsening the prognosis and increasing fatality rates. A mesenchymal stromal cell (MSC) therapy may decrease lung inflammation and accelerate recovery in COVID-19. In this context, some studies have reported the effects of MSC therapy for patients not requiring invasive ventilation or during the first hours of tracheal intubation. However, this is the first case report presenting the reduction of not only lung inflammation but also lung fibrosis in a critically ill long-term mechanically ventilated patient with COVID-19. Case Presentation: This is a case report of a 30-year-old male patient with COVID-19 under invasive mechanical ventilation for 14 days in the intensive care unit (ICU), who presented progressive clinical deterioration associated with lung fibrosis. The symptoms onset was 35 days before MSC therapy. The patient was treated with allogenic human umbilical-cord derived MSCs [5 × 107 (2 doses 2 days interval)]. No serious adverse events were observed during and after MSC administration. After MSC therapy, PaO2/FiO2 ratio increased, the need for vasoactive drugs reduced, chest CT scan imaging, which initially showed signs of bilateral and peripheral ground-glass, as well as consolidation and fibrosis, improved, and the systemic mediators associated with inflammation decreased. Modulation of the different cell populations in peripheral blood was also observed, such as a reduction in inflammatory monocytes and an increase in the frequency of patrolling monocytes, CD4+ lymphocytes, and type 2 classical dendritic cells (cDC2). The patient was discharged 13 days after the cell therapy. Conclusions: Mesenchymal stromal cell therapy may be a promising option in critically ill patients with COVID-19 presenting both severe lung inflammation and fibrosis. Further clinical trials could better assess the efficacy of MSC therapy in critically ill patients with COVID-19 with lung fibrosis associated with long-term mechanical ventilation.

Characterization of Crystalline Phase of TiO2 Nanocrystals, Cytotoxicity and Cell Internalization Analysis on Human Adipose Tissue-Derived Mesenchymal Stem Cells.

Titanium dioxide (TiO2) is manufactured worldwide as crystalline and amorphous forms for multiple applications, including tissue engineering, but our study proposes analyzing the impact of crystalline phases of TiO2 on Mesenchymal Stem Cells (MSCs). Several studies have already described the regenerative potential of MSCs and TiO2 has been used for bone regeneration. In this study, polydispersity index and sizes of TiO2 nanocrystals (NCs) were determined. Adipose tissue-derived Mesenchymal Stem Cells (AT-MSCs) were isolated and characterized in order to evaluate cellular viability and the internalization of nanocrystals (NCs). All of the assays were performed using the TiO2 NCs with 100% anatase (A), 91.6% anatase/9.4% rutile (AR), 64.6% rutile/35.4% anatase (RA), and 84.0% rutile/16% brookite (RB), submitted to several concentrations in 24-h treatments. Cellular localization of TiO2 NCs in the AT-MSCs was resolved by europium-doped NCs. Viability was significantly improved under the predominance of the rutile phase in NCs with localization restricted at the cytoplasm, suggesting that AR and RA NCs are not genotoxic and can be associated with most cellular activities and metabolic pathways, including glycolysis and cell division.

Generation of human iPS cell line CBTCi001-A from dermal fibroblasts obtained from a healthy donor.

Human-induced pluripotent stem cell (hiPSC) CBTCi001-A line was generated from a healthy 30-year old male dermal fibroblasts using non-integrative reprogramming method using episomal-based plasmids expressing OCT4, SOX2, KLF4, and MYCL. Characterization of CBTCi001-A was confirmed by the expression of typical markers of pluripotency and differentiation potential in vitro.

Protective effects of mito-TEMPO against doxorubicin cardiotoxicity in mice.

PURPOSE: Doxorubicin (DOX) is a chemotherapeutic that is widely used for the treatment of many human tumors. However, the development of cardiotoxicity has limited its use. The aim of the present study was to evaluate the possible efficacy of mito-TEMPO (mito-T) as a protective agent against DOX-induced cardiotoxicity in mice. METHODS: C57BL/6 mice were treated twice with mito-T at low (5 mg/kg body weight) or high (20 mg/kg body weight) dose and once with DOX (24 mg/kg body weight) or saline (0.1 mL/20 g body weight) by means of intraperitoneal injections. The levels of malondialdehyde (MLDA), a marker of lipid peroxidation, and serum levels of creatine kinase were evaluated 48 h after the injection of DOX. RESULTS: DOX induced lipid peroxidation in heart mitochondria (p < 0.001), and DOX-treated mice receiving mito-T at low dose had levels of MLDA significantly lower than the mice that received only DOX (p < 0.01). Furthermore, administration of mito-T alone did not cause any significant changes from control values. Additionally, DOX-treated mice treated with mito-T at high dose showed decrease in serum levels of total CK compared to mice treated with DOX alone (p < 0.05). CONCLUSION: Our results indicate that mito-T protects mice against DOX-induced cardiotoxicity.

Redução da inflamação das vias aéreas e da produção de anticorpos IgEatravés do uso de células dendríticas tolerogênicas pulsadas com extrato solúvel de Blomia tropicalis / Reduction in airway inflammation and the production of IgE antibodies through the use of tolerogenic dendritic cells pulsed with soluble extracts of Blomia tropicalis

As alergias afetam cerca de 20 a 30% da população mundial e sua prevalência, bem como a gravidade dos sintomas, tem aumentado nas últimas décadas. As terapias existentes para as desordens do trato respiratório ocorrem por períodos prolongados, apresentam efeitos colaterais, muitas vezes não são efetivas para pacientes graves e dependem do afastamento do alérgeno. Uma alternativa para esses pacientes seria a indução de tolerância imunológica, através da terapia celular com células dendríticas pulsadas com o alérgeno. O presente trabalho objetivou avaliar o efeito de células dendríticas mielóides sensibilizadas in vitro com extrato de B. tropicalis em modelo murino de alergia respiratória. Em modelos experimentais de alergia respiratória, células T auxiliares (Th2)...

Allergies affect about 20-30% of world population and its prevalence and severity of symptoms has increased in recent decades. Existing therapies to respiratory tract disorders are extense, with side effects, not effective for severe patients and depending on the allergen removal. An alternative for these patients is the induction of immune tolerance by cell therapy with dendritic cells pulsed with the allergen. This study aimed to evaluate the effect of myeloid dendritic cells sensitized in vitro with B. tropicalis extract in a murine model of respiratory allergy. In experimental models of respiratory allergy, T helper cells (Th2)...

Redução da inflamação das vias aéreas e da produção de anticorpos IgE através do uso de células dendríticas tolerogênicas pulsadas com extrato solúvel de Blomia tropicalis

As alergias afetam cerca de 20 a 30% da população mundial e sua prevalência, bem como a gravidade dos sintomas, tem aumentado nas últimas décadas. As terapias existentes para as desordens do trato respiratório ocorrem por períodos prolongados, apresentam efeitos colaterais, muitas vezes não são efetivas para pacientes graves e dependem do afastamento do alérgeno. Uma alternativa para esses pacientes seria a indução de tolerância imunológica, através da terapia celular com células dendríticas pulsadas com o alérgeno. O presente trabalho objetivou avaliar o efeito de células dendríticas mielóides sensibilizadas in vitro com extrato de B. tropicalis em modelo murino de alergia respiratória. Em modelos experimentais de alergia respiratória, células T auxiliares (Th2) alérgeno-específica produzem citocinas que regulam a síntese de anticorpos IgE alérgeno-específicos e controlam a inflamação eosinofílica e a remodelação do tecido das vias aéreas, e esses parâmetros foram analisados neste trabalho. Células dendríticas tolerogênicas de camundongos A/J foram obtidas na presença de GM-CSF e dexametasona e caracterizadas por apresentarem baixa expressão de MHC-II e moléculas coestimulatórias, redução acentuada de PD-L2 e um perfil antiinflamatório de produção de citocina.A inoculação prévia de células dendríticas sensibilizadascom Blomia reduziu especificamente e significativamente o número total de leucócitos e o número de eosinófilos no fluido de lavagem broncoalveolar e reduziu a produção de IgE, em comparação à inoculação de células sensibilizadas com ovalbumina, e estes efeitos foram mais intensos com uma segunda inoculação de células tolerogênicas. Além disso, redução do infiltrado inflamatório pulmonar foi observada em animais que tinham sido tratados com células dendríticas, independente do antígeno utilizado na sensibilização das mesmas. Estes resultados indicam que células dendríticas geradas como descrito neste trabalho podem inibir uma resposta alérgica Th2. A especificidade do tratamento, entretanto, deve ser melhor investigada.