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1.
Cell Transplant ; 30: 963689721993774, 2021.
Article in English | MEDLINE | ID: mdl-33975446

ABSTRACT

In normal physiological conditions, restoration of a functional epidermal barrier is highly efficient; nevertheless, when it fails, one of the main consequences is a chronic ulcerative skin defect, one of the most frequently recognized complications of diabetes. Most of these chronic venous ulcers do not heal with conventional treatment, leading to the appearance of infections and complications in the patient. Treatments based on the use of autologous mesenchymal stem cells (MSC) have been successful; however, its implementation entails complications. The umbilical cord offers an unlimited source of adult MSC (ucMSC) from the Wharton's jelly tissue with the same relevant features for clinical applicability and avoiding difficulties. It has recently been characterized by one specific subpopulation derived from ucMSC, the differentiated mesenchymal cells (DMCs). This subpopulation expresses the human leukocyte antigen-G (HLA-G) molecule, a strong immunosuppressive checkpoint, and vascular endothelial growth factor (VEGF), the most potent angiogenic factor. Considering the importance of developing a more effective therapy for wound treatment, especially ulcerative skin lesions, we analyzed DMC safety, efficacy, and therapeutic potential. By immunohistochemistry, umbilical cords HLA-G and VEGF positive were selected. Flow cytometry revealed that 90% of the DMC subpopulation are HLA-G+, CD44+, CD73+, CD29+, CD105+, CD90+, and HLA-DR-. Reverse transcription-polymerase chain reaction revealed the expression of HLA-G in all of DMC subpopulations. Upon co-culture with the DMC, peripheral blood mononuclear cell proliferation was inhibited by 50%. In a xenograft transplantation assay, DMC improved wound healing with no signs of rejection of the transplanted cells in immunocompetent mice. This study confirms that HLA-G allows allogeneic cell transplantation, and VEGF is fundamental for the restoration of the failure in blood supply. DMC population has positive effects on wound healing by promoting local angiogenesis in skin lesions. DMC could play a very important role in regenerative medicine and could be a novel allogeneic cell-therapeutic tool for wound healing.


Subject(s)
Mesenchymal Stem Cells/metabolism , Transplantation, Homologous/methods , Umbilical Cord/metabolism , Wound Healing/physiology , Animals , Disease Models, Animal , Female , Humans , Mice
2.
BMC Cancer ; 20(1): 624, 2020 Jul 03.
Article in English | MEDLINE | ID: mdl-32620162

ABSTRACT

BACKGROUND: Clear cell renal cell carcinoma (ccRCC), the most aggressive renal cancer, is characterized by early lymph node metastases and bad prognosis. Most therapies targeting advanced or metastatic ccRCC are based, as first-line treatment, on the administration of the vascular endothelial growth factor (VEGF) neutralizing antibody termed Bevacizumab. Despite proven benefits, the expected results were not obtained for the majority of patients. The possibility that an intricate interplay between angiogenesis and immune-checkpoints might exist lead us to evaluate tumor angiogenesis, by means of VEGF expression together with the immune checkpoint HLA-G/ILT4. METHODS: Tumor specimens were obtained from patients from two separate cohorts: One from "Evita Pueblo" Hospital from Berazategui, (Buenos Aires, Argentina) and the second includes patients surgically operated at the Urology Department of Saint-Louis Hospital (Paris, France) with a confirmed ccRCC diagnosis. Immunohistochemistry was performed with specific antibodies directed against HLA-G, VEGF-A, VEGF-C, D240, CD34, ILT4 and Ca-IX. In addition, gene expression levels were measured in a cell line derived from a ccRCC patient by semi-quantitative RT-PCR. RESULTS: Our results show that the highly vascularized tumors of ccRCC patients express high levels of VEGF and the immune-checkpoint HLA-G. In addition, ILT4, one of the HLA-G receptors, was detected on macrophages surrounding tumor cells, suggesting the generation of an immune-tolerant microenvironment that might favor tumorigenesis. Notably, RT-qPCR analysis provided the first evidence on the transcriptional relationship between HLA-G/ILT4 and the VEGF family. Namely, in the presence of HLA-G or ILT4, the levels of VEGF-A are diminished whereas those of VEGF-C are increased. CONCLUSIONS: In an effort to find new therapeutic molecules and fight against metastasis dissemination associated with the poor survival rates of ccRCC patients, these findings provide the rationale for co-targeting angiogenesis and the immune checkpoint HLA-G.


Subject(s)
Carcinoma, Renal Cell/genetics , HLA-G Antigens/metabolism , Kidney Neoplasms/genetics , Membrane Glycoproteins/metabolism , Neovascularization, Pathologic/genetics , Receptors, Immunologic/metabolism , Vascular Endothelial Growth Factor A/genetics , Adult , Aged , Angiogenesis Inhibitors/pharmacology , Angiogenesis Inhibitors/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Renal Cell/immunology , Carcinoma, Renal Cell/mortality , Carcinoma, Renal Cell/therapy , Cell Line, Tumor , Female , Gene Expression Regulation, Neoplastic/drug effects , Gene Expression Regulation, Neoplastic/immunology , Humans , Immune Checkpoint Inhibitors/pharmacology , Immune Checkpoint Inhibitors/therapeutic use , Kidney/blood supply , Kidney/pathology , Kidney/surgery , Kidney Neoplasms/immunology , Kidney Neoplasms/mortality , Kidney Neoplasms/therapy , Male , Membrane Glycoproteins/antagonists & inhibitors , Middle Aged , Neovascularization, Pathologic/drug therapy , Neovascularization, Pathologic/pathology , Nephrectomy , Receptors, Immunologic/antagonists & inhibitors , Retrospective Studies , Survival Rate , Vascular Endothelial Growth Factor A/antagonists & inhibitors
3.
Biocell ; 21(1): 13-18, Apr. 1997.
Article in English | LILACS | ID: lil-335979

ABSTRACT

Liver extract, plasma from intact mice, ES2 tumour extract and plasma from tumour bearing mice has an inhibiting effect on the mitotic activity of hepatocytes and duodenal enterocytes. In the present experiments, the effect of these treatments on the mitotic activity of renal tubular cells was studied. C3HS 28 day-old male mice, standardized for periodicity analysis were used. The determination of normal mitotic circadian curve of the renocytes was done. A second batch of mice were injected with 0.01 ml/gr of either liver extract, plasma from intact mice, ES2 tumour extract or plasma from tumour bearing mice, at 16:00 hours and controlled at 08:00, 12:00 and 16:00 hs during 2 consecutive days post treatment. Colchicine (2 micrograms/gr) was injected 4 hours before killing. Kidneys were processed for histology and mitotic index determinations. Results were expressed as colchicine metaphases per 1000 nuclei, and showed that mitotic activity values of treated animals were significantly lower than those of controls. In conclusion, mitotic activity inhibition of renocytes may be due to some non specific plasmatic and/or tissue factors.


Subject(s)
Animals , Male , Mice , Plasma , Tissue Extracts , Kidney Tubules/cytology , Cell Division/drug effects , Liver Extracts/pharmacology , Hepatocyte Growth Factor/pharmacology , Mitosis , Neoplasms, Experimental , Tissue Extracts , Kidney Tubules/drug effects
4.
Biocell ; 21(1): 13-18, Apr. 1997.
Article in English | BINACIS | ID: bin-6368

ABSTRACT

Liver extract, plasma from intact mice, ES2 tumour extract and plasma from tumour bearing mice has an inhibiting effect on the mitotic activity of hepatocytes and duodenal enterocytes. In the present experiments, the effect of these treatments on the mitotic activity of renal tubular cells was studied. C3HS 28 day-old male mice, standardized for periodicity analysis were used. The determination of normal mitotic circadian curve of the renocytes was done. A second batch of mice were injected with 0.01 ml/gr of either liver extract, plasma from intact mice, ES2 tumour extract or plasma from tumour bearing mice, at 16:00 hours and controlled at 08:00, 12:00 and 16:00 hs during 2 consecutive days post treatment. Colchicine (2 micrograms/gr) was injected 4 hours before killing. Kidneys were processed for histology and mitotic index determinations. Results were expressed as colchicine metaphases per 1000 nuclei, and showed that mitotic activity values of treated animals were significantly lower than those of controls. In conclusion, mitotic activity inhibition of renocytes may be due to some non specific plasmatic and/or tissue factors.(AU)


Subject(s)
Animals , Male , Mice , Kidney Tubules/cytology , Plasma , Tissue Extracts/pharmacology , Cell Division/drug effects , Hepatocyte Growth Factor/pharmacology , Kidney Tubules/drug effects , Liver Extracts/pharmacology , Mice, Inbred C3H , Mitosis/physiology , Neoplasms, Experimental/blood , Tissue Extracts/chemistry
5.
Microsc. electron. biol. celular ; 15(1): 85-91, Jun. 1991. tab
Article in English | LILACS | ID: lil-121636

ABSTRACT

Se utilizaron ratones C3HS, endocriados, standardizados para análisis de periodicidad. Ciento setenta ratones de 25 ñ 2 días de edad fueron unyectados a las 16:00 horas con solución fisiológica, plasma o extracto de hígado de 27 machos de 90 días de edad. Los controles fueron realizados a las 08/16, 12/20, 16/24, 08/40, 12/44, 16/28, 08/64, 12/68 y 16/72 (hora día/hora post-inyección) y fue determinada la actividad mitótica de los hepatocitos y células litorales. La inyección de pequeñas dosis de extracto y plasma inhibe la actividad mitótica de los hepatocitos durante los dos primeros días de control. En el tercer día aparece una onda compensatoria. El extracto inhibe la actividad mitótica de las células litorales solo el primer día de control, mientras que el plasma inhibe esta variable el segundo y tercer día


Subject(s)
Animals , Male , Mice , Blood/physiology , Liver/physiology , Mitogens/pharmacology , Tissue Extracts/pharmacology , Cell Division , Liver/growth & development , Liver , Mitogens/isolation & purification , Mitosis/drug effects
6.
Microsc. electron. biol. celular ; 15(1): 85-91, Jun. 1991. tab
Article in English | BINACIS | ID: bin-25749

ABSTRACT

Se utilizaron ratones C3HS, endocriados, standardizados para análisis de periodicidad. Ciento setenta ratones de 25 ñ 2 días de edad fueron unyectados a las 16:00 horas con solución fisiológica, plasma o extracto de hígado de 27 machos de 90 días de edad. Los controles fueron realizados a las 08/16, 12/20, 16/24, 08/40, 12/44, 16/28, 08/64, 12/68 y 16/72 (hora día/hora post-inyección) y fue determinada la actividad mitótica de los hepatocitos y células litorales. La inyección de pequeñas dosis de extracto y plasma inhibe la actividad mitótica de los hepatocitos durante los dos primeros días de control. En el tercer día aparece una onda compensatoria. El extracto inhibe la actividad mitótica de las células litorales solo el primer día de control, mientras que el plasma inhibe esta variable el segundo y tercer día (AU)


Subject(s)
Animals , Male , Mice , Blood/physiology , Liver/physiology , Mitogens/pharmacology , Tissue Extracts/pharmacology , Cell Division/drug effects , Liver/growth & development , Liver/drug effects , Mice, Inbred C3H , Mitogens/isolation & purification , Mitosis/drug effects
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