Jorge B. Aquino - Academia.edu (original) (raw)
Papers by Jorge B. Aquino
Purpose: Interleukin-12 (IL-12) is an immunostimulatory cytokine with potent antitumor effects in... more Purpose: Interleukin-12 (IL-12) is an immunostimulatory cytokine with potent antitumor effects in several animal models. However, serious toxicity has been associated with its systemic application in humans. Gene transfer has emerged as a tool to specifically express therapeutic genes into the tumor/peritumoral milieu, thus avoiding systemic toxicity. The aim of this study was to analyze whether subtherapeutic doses of an adenovirus encoding IL-12 (AdIL-12) might synergize with low immunopotentiating doses of cyclophosphamide in the treatment of colorectal carcinoma. Experimental Design: The antitumor effect of combining a single low dose of cyclophosphamide with an intratumoral injection of AdIL-12 was evaluated in an in vivo murine colorectal carcinoma model. The immune responses achieved with different treatments were monitored, comparing the effect of combining both therapies with individual treatments. Results:The combined therapy induced a complete tumor regression in >50%o...
The postnatal rodent spinal cord in-vitro is a useful model to investigate early pathophysiologic... more The postnatal rodent spinal cord in-vitro is a useful model to investigate early pathophysiological changes after injury. While low dose nicotine (1µM) induces neuroprotection, how higher doses affect spinal networks is unknown. Using spinal preparations of postnatal wild-type Wistar rat and Wnt1Cre2:Rosa26Tom double-transgenic mouse, we studied the effect of nicotine (0.5-10µM) on locomotor networks in-vitro. Nicotine 10µM induced motoneuron depolarization, suppressed monosynaptic reflexes, and decreased fictive locomotion in rat spinal cord. Delayed fall in neuronal numbers (including motoneurons) of central and ventral regions emerged without loss of dorsal neurons. Conversely, nicotine (0.5-1µM) preserved neurons throughout the spinal cord and strongly activated the Wnt1 signaling pathway. High-dose nicotine enhanced expression of S100 and GFAP in astrocytes suggesting their response to stress. Excitotoxicity induced by kainate was contrasted by nicotine (10µM) in the dorsal are...
Liver International
Liver fibrosis results from cycles of liver damage and scar formation. We herein aimed at analysi... more Liver fibrosis results from cycles of liver damage and scar formation. We herein aimed at analysing neural crest cells and/or bone marrow stromal cells contribution to the liver.
Journal of Hypertension
Objective: To describe immune basal profile and its predictive value on the incidence of cardiova... more Objective: To describe immune basal profile and its predictive value on the incidence of cardiovascular events and blood pressure evolution in hypertensive stage I subjects. Design and method: Patients with mild hypertension were recruited with at least 5 years from diagnosis. Exclusion criteria were: GFR> 60 ml/min/1.73 m2 (MDRD) microalbuminuria> 30 mg/24 hs, previous CV events, autoimmune disease, use of imunomodulatory agents or corticosteroids. At entry and follow up office and 24 hs ambulatory BP was measured; cell subpopulations were measured by flow cytometry in peripheral blood and direct cell count respectively, using T and dendritic cells monoclonal antibodies. End points were defined as the incidence of stroke, ischemic heart disease, new onset diabetes, cardiovascular and all-cause mortality, and number/doses of antihypertensive drugs and BP. Results: 72 subjects were classified in two groups: a) hipertensives, n:50 (24 women, 55.0 ± 9.0 years, 132 ± 6.4/80.3 ± 8.7 mmHg, number of antihypertensive drugs 2.0 ± 1.5.) and b) normotensive, n:22 (12 women, 53 ± 11 years). Median follow up: 5.4. ± 3.3 years. The distribution of immune markers in hypertensive was expressed as median x 106 cells / L (range): 650.40 CD4 + (272–980), CD8 + 110.37 (80–143), CD4 + / CD8 + 5.30 (2.50–9.90), CD25 + 86.90 (80.0–99.6), CD86 + (69.8–448.70), CD83 + (69.40–145). Compared to controls, HTs had a profile with higher CD3 + CD4 + CD83 + CD86 + (<0.001). At follow up, we found a direct association between the RR of events in the entire population (HT and NT) with higher baseline CD4 +, CD83 +, CD86 +, increased CD4 + / CD8 +, CD25 + lower ratio / CD4 + (<0.001). HTs had more events than NTs: 9.4 vs 0% stroke, ischemic heart disease 12.5 vs 7.1%, all-cause mortality 2 vs 0%. Among hypertensive greater CD4 + / CD8 + and / or lower ratio CD25 + / CD4 + were highly predictive of new cases of DBT. Conclusions: In hypertensive stage I we identified a specific immune cell activation pattern.
Medicina, 2017
Mesenchymal stem cells (MSCs) are multipotent cells with self-renewal capacity which are present ... more Mesenchymal stem cells (MSCs) are multipotent cells with self-renewal capacity which are present in diverse tissues. Recently, significant progresses have been made in the field of MSCs because of its therapeutic potential in regenerative medicine. MSCs selectively migrate toward sites of damage and remodeling, and have the ability to evade the immune system and to promote tissue repair through the production of a number of growth factors and cytokines. Many pre-clinical and clinical studies have been carried out to study its therapeutic effect in liver cirrhosis with promising results. In addition, experimental studies showed that this therapeutic effect can be improved by engineering MSCs to produce therapeutic genes. In this work, the role of MSCs in regenerative medicine and its clinical and pre-clinical applications are reviewed, with an emphasis on its potential as vehicles for therapeutic genes.
Glia, Mar 10, 2017
Schwann cell precursors (SCPs) are frequently regarded as neural crest-derived cells (NCDCs) foun... more Schwann cell precursors (SCPs) are frequently regarded as neural crest-derived cells (NCDCs) found in contact with axons during nerve formation. Nevertheless, cells with SCPs properties can be found up to the adulthood. They are well characterized with regard to both gene expression profile and cellular behavior -for instance, proliferation, migratory capabilities and survival requirements-. They differ in origin regarding their anatomic location: even though most of them are derived from migratory NCCs, there is also contribution of the boundary cap neural crest cells (bNCCs) to the skin and other tissues. Many functions are known for SCPs in normal development, including nerve fasciculation and target innervation, arterial branching patterning and differentiation, and other morphogenetic processes. In addition, SCPs are now known to be a source of many neural (glia, endoneural fibroblasts, melanocytes, visceral neurons, and chromaffin cells) and non-neural-like (mesenchymal stroma...
Stem Cells and Development, 2017
Some late embryonic and adult postmigratory neural crest-derived cells (NCDCs) from diverse tissu... more Some late embryonic and adult postmigratory neural crest-derived cells (NCDCs) from diverse tissues were shown to grow as multipotent neurospheres. Neural crest stem cells (NCSCs) contained in these spheres were found to give rise not only to neuroectodermal derivatives but also to some of the progeny of the other embryonic germ layers. In this review, evidences regarding the in vivo properties of NCDCs contributing to NCSCs are discussed. Even though in many cases the final proof for the phenotype identity of in vivo cells generating NCSCs is lacking, some evidences suggest that such postmigratory NCDCs would differ from neural crest cells. The streamline of this review follows a historical perspective that helps understanding the advancements in knowledge of this field of research and highlighting its importance, in an appropriate context. Finally, the potential for regenerative medicine purpose of NCDCs and more specifically of tissues that can be a source of peripheral glia progenitors in the adult is underlined.
Stem Cell Research & Therapy, 2016
Background Cirrhosis is a major health problem worldwide and new therapies are needed. Hepatic ma... more Background Cirrhosis is a major health problem worldwide and new therapies are needed. Hepatic macrophages (hMø) have a pivotal role in liver fibrosis, being able to act in both its promotion and its resolution. It is well-known that mesenchymal stromal cells (MSCs) can modulate the immune/inflammatory cells. However, the effects of MSCs over hMø in the context of liver fibrosis remain unclear. We previously described evidence of the antifibrotic effects of in vivo applying MSCs, which were enhanced by forced overexpression of insulin-like growth factor 1 (AdIGF-I-MSCs). The aim of this work was to analyze the effect of MSCs on hMø behavior in the context of liver fibrosis resolution. Methods Fibrosis was induced in BALB/c mice by chronic administration of thioacetamide (8 weeks). In vivo gene expression analyses, in vitro experiments using hMø isolated from the nonparenchymal liver cells fraction, and in vivo experiments with depletion of Mø were performed. Results One day after tr...
Molecular therapy : the journal of the American Society of Gene Therapy, Jan 24, 2015
We have previously demonstrated that a low-dose of cyclophosphamide (Cy) combined with gene thera... more We have previously demonstrated that a low-dose of cyclophosphamide (Cy) combined with gene therapy of interleukin-12 (AdIL-12) has a synergistic, although limited, antitumoral effect in mice with colorectal carcinoma. The main mechanism involved in the efficacy of Cy+AdIL-12 was the induction of a specific immune response mediated by cytotoxic T lymphocytes. Our current aims were to evaluate the effects of 4-methylumbelliferone (4Mu), a selective inhibitor of hyaluronan (HA) synthesis, on tumor microenvironment and to investigate how 4Mu affects the therapeutic efficacy of Cy+AdIL-12. The results showed that 4Mu significantly reduced the amount of tumoral HA leading to a significant decrease in tumor interstitial pressure. As a consequence, tumor perfusion was improved allowing an increased adenoviral transgene expression. In addition, treatment with 4Mu boosted the number of cytotoxic T lymphocytes that reach the tumor after adoptive transfer resulting in a potent inhibition of tu...
During the last two decades, a number of immunotherapy-based strategies for advanced gastrointest... more During the last two decades, a number of immunotherapy-based strategies for advanced gastrointestinal carcinomas (GICs) has given promising results, not only at preclinical stage but also in the clinic. 1 However, immunotherapeutic approaches have to face an important obstacle: the ability of tumor cells to evade immune attack. 2 Several immunosuppres-sive mechanisms elicited by cancer cells have been identified in animal models and in patients including: 1 loss of MHC Class I molecules from the surface of tumor cells, 2 increased oxidative stress and 3 recruit-ment of myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs). A correlation between increased levels of these immunosuppressive cell populations and poor prognosis has been observed in many types of cancer. 3 Increasing evidence suggests that immune responses are involved in the con-trol of cancer and that the immune system can be manipulated in different ways to recognize and fight cancer cells. The sys-te...
Stem cell reviews, Jan 29, 2015
Mesenchymal stem/stromal cells (MSCs) are progenitors which share plastic-adherence capacity and ... more Mesenchymal stem/stromal cells (MSCs) are progenitors which share plastic-adherence capacity and cell surface markers but have different properties according to their cell and tissue sources and to culture conditions applied. Many recent publications suggest that MSCs can differentiate into hepatic-like cells, which can be a consequence of either a positive selection of rare in vivo pluripotent cells or of the original plasticity of some cells contributing to MSC cultures. A possible role of MSCs in hereditary transmission of obesity and/or diabetes as well as properties of MSCs regarding immunomodulation, cell fusion and exosome release capacities are discussed according to recent literature. Limitations in methods used to track MSCs in vivo especially in the context of liver cirrhosis are addressed as well as strategies explored to enhance their migratory, survival and proliferation properties, which are known to be relevant for their future clinical use. Current knowledge regardi...
Current Gene Therapy, 2015
Surgical resection is the only curative option for patients with gastrointestinal carcinomas. Unf... more Surgical resection is the only curative option for patients with gastrointestinal carcinomas. Unfortunately, the majority of patients are diagnosed in advanced stages when surgery is not possible. Moreover, the incidence and mortality for certain type of tumors such as hepatocellular carcinoma or pancreatic cancer are steadily increasing worldwide. In spite of the advances in the development of molecular targeted therapies for cancer, the impact on patient survival has been rather limited. It is unlikely that individual agents would be ultimately successful as monotherapy. There is a growing area of research focused on the combination of classical chemotherapy (e.g. cyclophosphamide, gemcitabine, paclitaxel and doxorubicin) with radiotherapy and/or gene therapy strategies. Combined approaches seem to be required due to multiple resistance mechanisms that tumors utilize to limit the activity of chemotherapeutic agents (e.g. the occurrence of multidrug resistance or epigenetic alterations), evade immune responses (e.g. induction of regulatory T cells or myeloid-derived suppressor cells) and to generate resistance against anti-angiogenesis or to radiotherapy by, for example, the induction of hypoxia-inducible factor 1. In addition, new studies suggest that combination of low dose of conventional chemotherapy and gene therapy could allow the development of synergic mechanisms able to achieve significant therapeutic effects against diverse tumors. Although cancer gene therapy is not yet available in clinical practice, advances being recently made look promising, especially when it was applied in combination with standard chemo- or radiotherapy protocols.
Neurochemical research, 2002
In this work we analyzed variations in the expression of MBPs and P0 in ligated sciatic nerves of... more In this work we analyzed variations in the expression of MBPs and P0 in ligated sciatic nerves of young and adult rats at 3, 7, and 14 days postligation (PL), by immunohistochemistry and SDS-PAGE of isolated myelin. A protein redistribution was seen in the distal stump of ligated nerves with the appearance of immunoreactive clusters. Using the KS400 image analyzer, immunostained area values were obtained from the different nerves dissected. In adult rats, there was an increase of the immunostained area for MBP from 3 to 7 days PL, coincident with a reorganization of the marker in clusters, followed by a marked decrease at 14 days. P0 immunolabeling gave similar results without, however, a decrease of the immunostained area at the longer survival time tested. Young animals showed an acceleration in the process of protein redistribution and digestion within ligated nerves, which followed a similar pattern as that of adult animals. Analysis by electrophoresis showed a marked decrease i...
Stem Cells and Development, 2014
Liver cirrhosis involves chronic wound healing and fibrotic processes. Mesenchymal stromal cells ... more Liver cirrhosis involves chronic wound healing and fibrotic processes. Mesenchymal stromal cells (MSCs) are multipotent adult progenitor cells that are used as vehicles of therapeutic genes. Insulin growth factor like-I (IGF-I) was shown to counteract liver fibrosis. We aimed at analyzing the effect of applying IGF-I overexpressing mouse bone marrow-derived MSCs on hepatic fibrosis. Fibrosis was induced by chronic thioacetamide application or bile duct ligation. MSCs engineered to produce green fluorescent protein (GFP) (AdGFP-MSCs) or IGF-I (AdIGF-I-MSCs) were applied systemically, and changes in collagen deposition and in the expression of key pro-fibrogenic and pro-regenerative genes/proteins were assessed. In addition, immunogenicity of transduced cells was analyzed. Liver fibrosis was further ameliorated after a single-dose application of AdIGF-I-MSCs when compared with AdGFP-MSCs and/or recombinant IGF-I treatments. Interestingly, an early and transitory upregulation in IGF-I and hepatocyte growth factor (HGF) mRNA expression was found in the liver of MSC-treated animals, which was more pronounced in AdIGF-I-MSCs condition. A reduction in hepatic stellate cell activation status was found after incubation with MSCs conditioned media. In addition, the AdIGF-I-MSCs cell-free supernatant induced the expression of IGF-I and HGF in primary cultured hepatocytes. From day 1 after transplantation, the proliferation marker proliferating cell nuclear antigen was upregulated in the liver of AdIGF-I-MSCs group, mainly in hepatocytes. MSCs were in vivo traced till day 14 after injection. In addition, multiple doses of Ad-IGF-I-MSCs likely suppressed antiviral immune response and it further reduced collagen deposition. Our results uncover early events that are likely involved in the anti-fibrogenic effect of genetically modified MSCs and overall would support the use of AdIGF-I-MSCs in treatment of liver fibrosis.
PLoS ONE, 2013
Introduction: Secreted Protein, Acidic and Rich in Cysteine (SPARC) is a matricellular protein in... more Introduction: Secreted Protein, Acidic and Rich in Cysteine (SPARC) is a matricellular protein involved in many biological processes and found over-expressed in cirrhotic livers. By mean of a genetic approach we herein provide evidence from different in vivo liver disease models suggesting a profibrogenic role for SPARC. Methods: Two in vivo models of liver fibrosis, based on TAA administration and bile duct ligation, were developed on SPARC wild-type (SPARC +/+) and knockout (SPARC 2/2) mice. Hepatic SPARC expression was analyzed by qPCR. Fibrosis was assessed by Sirius Red staining, and the maturation state of collagen fibers was analyzed using polarized light. Necroinflammatory activity was evaluated by applying the Knodell score and liver inflammatory infiltration was characterized by immunohistochemistry. Hepatic stellate cell activation was assessed by a-SMA immunohistochemistry. In addition, pro-fibrogenic genes and inflammatory cytokines were measured by qPCR and/or ELISA. Liver gene expression profile was analyzed in SPARC 2/2 and SPARC +/+ mice using Affymetrix Mouse Gene ST 1.0 array. Results: SPARC expression was found induced in fibrotic livers of mouse and human. SPARC 2/2 mice showed a reduction in the degree of inflammation, mainly CD4+ cells, and fibrosis. Consistently, collagen deposits and mRNA expression levels were decreased in SPARC 2/2 mice when compared to SPARC +/+ mice; in addition, MMP-2 expression was increased in SPARC 2/2 mice. A reduction in the number of activated myofibroblasts was observed. Moreover, TGF-b1 expression levels were down-regulated in the liver as well as in the serum of TAA-treated knockout animals. Ingenuity Pathway Analysis (IPA) analysis suggested several gene networks which might involve protective mechanisms of SPARC deficiency against liver fibrogenesis and a better established machinery to repair DNA and detoxify from external chemical stimuli. Conclusions: Overall our data suggest that SPARC plays a significant role in liver fibrogenesis. Interventions to inhibit SPARC expression are suggested as promising approaches for liver fibrosis treatment.
…, 2012
Abstract: The use of conventional cytotoxic agents at metronomic schedules, alone or in combinati... more Abstract: The use of conventional cytotoxic agents at metronomic schedules, alone or in combination with targeted agents or immunotherapy, is being explored as a promising anticancer strategy. We previously reported a potent antitumor effect of a single low-dose ...
The EMBO Journal, 2012
The formation of functional connectivity in the nervous system is governed by axon guidance that ... more The formation of functional connectivity in the nervous system is governed by axon guidance that instructs nerve growth and branching during development, implying a similarity between neuronal subtypes in terms of nerve extension. We demonstrate the molecular mechanism of another layer of complexity in vertebrates by defining a transcriptional program underlying growth differences between positionally different neurons. The rate of axon extension of the early subset of embryonic dorsal root ganglion sensory neurons is encoded in neurons at different axial levels. This code is determined by a segmental pattern of axial levels of Runx family transcription factor Runx3. Runx3 in turn determines transcription levels of genes encoding cytoskeletal proteins involved in axon extension, including Rock1 and Rock2 which have ongoing activities determining axon growth in early sensory neurons and blocking Rock activity reverses axon extension deficits of Runx3 À / À neurons. Thus, Runx3 acts to regulate positional differences in axon extension properties apparently without affecting nerve guidance and branching, a principle that could be relevant to other parts of the nervous system.
Purpose: Interleukin-12 (IL-12) is an immunostimulatory cytokine with potent antitumor effects in... more Purpose: Interleukin-12 (IL-12) is an immunostimulatory cytokine with potent antitumor effects in several animal models. However, serious toxicity has been associated with its systemic application in humans. Gene transfer has emerged as a tool to specifically express therapeutic genes into the tumor/peritumoral milieu, thus avoiding systemic toxicity. The aim of this study was to analyze whether subtherapeutic doses of an adenovirus encoding IL-12 (AdIL-12) might synergize with low immunopotentiating doses of cyclophosphamide in the treatment of colorectal carcinoma. Experimental Design: The antitumor effect of combining a single low dose of cyclophosphamide with an intratumoral injection of AdIL-12 was evaluated in an in vivo murine colorectal carcinoma model. The immune responses achieved with different treatments were monitored, comparing the effect of combining both therapies with individual treatments. Results:The combined therapy induced a complete tumor regression in >50%o...
The postnatal rodent spinal cord in-vitro is a useful model to investigate early pathophysiologic... more The postnatal rodent spinal cord in-vitro is a useful model to investigate early pathophysiological changes after injury. While low dose nicotine (1µM) induces neuroprotection, how higher doses affect spinal networks is unknown. Using spinal preparations of postnatal wild-type Wistar rat and Wnt1Cre2:Rosa26Tom double-transgenic mouse, we studied the effect of nicotine (0.5-10µM) on locomotor networks in-vitro. Nicotine 10µM induced motoneuron depolarization, suppressed monosynaptic reflexes, and decreased fictive locomotion in rat spinal cord. Delayed fall in neuronal numbers (including motoneurons) of central and ventral regions emerged without loss of dorsal neurons. Conversely, nicotine (0.5-1µM) preserved neurons throughout the spinal cord and strongly activated the Wnt1 signaling pathway. High-dose nicotine enhanced expression of S100 and GFAP in astrocytes suggesting their response to stress. Excitotoxicity induced by kainate was contrasted by nicotine (10µM) in the dorsal are...
Liver International
Liver fibrosis results from cycles of liver damage and scar formation. We herein aimed at analysi... more Liver fibrosis results from cycles of liver damage and scar formation. We herein aimed at analysing neural crest cells and/or bone marrow stromal cells contribution to the liver.
Journal of Hypertension
Objective: To describe immune basal profile and its predictive value on the incidence of cardiova... more Objective: To describe immune basal profile and its predictive value on the incidence of cardiovascular events and blood pressure evolution in hypertensive stage I subjects. Design and method: Patients with mild hypertension were recruited with at least 5 years from diagnosis. Exclusion criteria were: GFR> 60 ml/min/1.73 m2 (MDRD) microalbuminuria> 30 mg/24 hs, previous CV events, autoimmune disease, use of imunomodulatory agents or corticosteroids. At entry and follow up office and 24 hs ambulatory BP was measured; cell subpopulations were measured by flow cytometry in peripheral blood and direct cell count respectively, using T and dendritic cells monoclonal antibodies. End points were defined as the incidence of stroke, ischemic heart disease, new onset diabetes, cardiovascular and all-cause mortality, and number/doses of antihypertensive drugs and BP. Results: 72 subjects were classified in two groups: a) hipertensives, n:50 (24 women, 55.0 ± 9.0 years, 132 ± 6.4/80.3 ± 8.7 mmHg, number of antihypertensive drugs 2.0 ± 1.5.) and b) normotensive, n:22 (12 women, 53 ± 11 years). Median follow up: 5.4. ± 3.3 years. The distribution of immune markers in hypertensive was expressed as median x 106 cells / L (range): 650.40 CD4 + (272–980), CD8 + 110.37 (80–143), CD4 + / CD8 + 5.30 (2.50–9.90), CD25 + 86.90 (80.0–99.6), CD86 + (69.8–448.70), CD83 + (69.40–145). Compared to controls, HTs had a profile with higher CD3 + CD4 + CD83 + CD86 + (<0.001). At follow up, we found a direct association between the RR of events in the entire population (HT and NT) with higher baseline CD4 +, CD83 +, CD86 +, increased CD4 + / CD8 +, CD25 + lower ratio / CD4 + (<0.001). HTs had more events than NTs: 9.4 vs 0% stroke, ischemic heart disease 12.5 vs 7.1%, all-cause mortality 2 vs 0%. Among hypertensive greater CD4 + / CD8 + and / or lower ratio CD25 + / CD4 + were highly predictive of new cases of DBT. Conclusions: In hypertensive stage I we identified a specific immune cell activation pattern.
Medicina, 2017
Mesenchymal stem cells (MSCs) are multipotent cells with self-renewal capacity which are present ... more Mesenchymal stem cells (MSCs) are multipotent cells with self-renewal capacity which are present in diverse tissues. Recently, significant progresses have been made in the field of MSCs because of its therapeutic potential in regenerative medicine. MSCs selectively migrate toward sites of damage and remodeling, and have the ability to evade the immune system and to promote tissue repair through the production of a number of growth factors and cytokines. Many pre-clinical and clinical studies have been carried out to study its therapeutic effect in liver cirrhosis with promising results. In addition, experimental studies showed that this therapeutic effect can be improved by engineering MSCs to produce therapeutic genes. In this work, the role of MSCs in regenerative medicine and its clinical and pre-clinical applications are reviewed, with an emphasis on its potential as vehicles for therapeutic genes.
Glia, Mar 10, 2017
Schwann cell precursors (SCPs) are frequently regarded as neural crest-derived cells (NCDCs) foun... more Schwann cell precursors (SCPs) are frequently regarded as neural crest-derived cells (NCDCs) found in contact with axons during nerve formation. Nevertheless, cells with SCPs properties can be found up to the adulthood. They are well characterized with regard to both gene expression profile and cellular behavior -for instance, proliferation, migratory capabilities and survival requirements-. They differ in origin regarding their anatomic location: even though most of them are derived from migratory NCCs, there is also contribution of the boundary cap neural crest cells (bNCCs) to the skin and other tissues. Many functions are known for SCPs in normal development, including nerve fasciculation and target innervation, arterial branching patterning and differentiation, and other morphogenetic processes. In addition, SCPs are now known to be a source of many neural (glia, endoneural fibroblasts, melanocytes, visceral neurons, and chromaffin cells) and non-neural-like (mesenchymal stroma...
Stem Cells and Development, 2017
Some late embryonic and adult postmigratory neural crest-derived cells (NCDCs) from diverse tissu... more Some late embryonic and adult postmigratory neural crest-derived cells (NCDCs) from diverse tissues were shown to grow as multipotent neurospheres. Neural crest stem cells (NCSCs) contained in these spheres were found to give rise not only to neuroectodermal derivatives but also to some of the progeny of the other embryonic germ layers. In this review, evidences regarding the in vivo properties of NCDCs contributing to NCSCs are discussed. Even though in many cases the final proof for the phenotype identity of in vivo cells generating NCSCs is lacking, some evidences suggest that such postmigratory NCDCs would differ from neural crest cells. The streamline of this review follows a historical perspective that helps understanding the advancements in knowledge of this field of research and highlighting its importance, in an appropriate context. Finally, the potential for regenerative medicine purpose of NCDCs and more specifically of tissues that can be a source of peripheral glia progenitors in the adult is underlined.
Stem Cell Research & Therapy, 2016
Background Cirrhosis is a major health problem worldwide and new therapies are needed. Hepatic ma... more Background Cirrhosis is a major health problem worldwide and new therapies are needed. Hepatic macrophages (hMø) have a pivotal role in liver fibrosis, being able to act in both its promotion and its resolution. It is well-known that mesenchymal stromal cells (MSCs) can modulate the immune/inflammatory cells. However, the effects of MSCs over hMø in the context of liver fibrosis remain unclear. We previously described evidence of the antifibrotic effects of in vivo applying MSCs, which were enhanced by forced overexpression of insulin-like growth factor 1 (AdIGF-I-MSCs). The aim of this work was to analyze the effect of MSCs on hMø behavior in the context of liver fibrosis resolution. Methods Fibrosis was induced in BALB/c mice by chronic administration of thioacetamide (8 weeks). In vivo gene expression analyses, in vitro experiments using hMø isolated from the nonparenchymal liver cells fraction, and in vivo experiments with depletion of Mø were performed. Results One day after tr...
Molecular therapy : the journal of the American Society of Gene Therapy, Jan 24, 2015
We have previously demonstrated that a low-dose of cyclophosphamide (Cy) combined with gene thera... more We have previously demonstrated that a low-dose of cyclophosphamide (Cy) combined with gene therapy of interleukin-12 (AdIL-12) has a synergistic, although limited, antitumoral effect in mice with colorectal carcinoma. The main mechanism involved in the efficacy of Cy+AdIL-12 was the induction of a specific immune response mediated by cytotoxic T lymphocytes. Our current aims were to evaluate the effects of 4-methylumbelliferone (4Mu), a selective inhibitor of hyaluronan (HA) synthesis, on tumor microenvironment and to investigate how 4Mu affects the therapeutic efficacy of Cy+AdIL-12. The results showed that 4Mu significantly reduced the amount of tumoral HA leading to a significant decrease in tumor interstitial pressure. As a consequence, tumor perfusion was improved allowing an increased adenoviral transgene expression. In addition, treatment with 4Mu boosted the number of cytotoxic T lymphocytes that reach the tumor after adoptive transfer resulting in a potent inhibition of tu...
During the last two decades, a number of immunotherapy-based strategies for advanced gastrointest... more During the last two decades, a number of immunotherapy-based strategies for advanced gastrointestinal carcinomas (GICs) has given promising results, not only at preclinical stage but also in the clinic. 1 However, immunotherapeutic approaches have to face an important obstacle: the ability of tumor cells to evade immune attack. 2 Several immunosuppres-sive mechanisms elicited by cancer cells have been identified in animal models and in patients including: 1 loss of MHC Class I molecules from the surface of tumor cells, 2 increased oxidative stress and 3 recruit-ment of myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs). A correlation between increased levels of these immunosuppressive cell populations and poor prognosis has been observed in many types of cancer. 3 Increasing evidence suggests that immune responses are involved in the con-trol of cancer and that the immune system can be manipulated in different ways to recognize and fight cancer cells. The sys-te...
Stem cell reviews, Jan 29, 2015
Mesenchymal stem/stromal cells (MSCs) are progenitors which share plastic-adherence capacity and ... more Mesenchymal stem/stromal cells (MSCs) are progenitors which share plastic-adherence capacity and cell surface markers but have different properties according to their cell and tissue sources and to culture conditions applied. Many recent publications suggest that MSCs can differentiate into hepatic-like cells, which can be a consequence of either a positive selection of rare in vivo pluripotent cells or of the original plasticity of some cells contributing to MSC cultures. A possible role of MSCs in hereditary transmission of obesity and/or diabetes as well as properties of MSCs regarding immunomodulation, cell fusion and exosome release capacities are discussed according to recent literature. Limitations in methods used to track MSCs in vivo especially in the context of liver cirrhosis are addressed as well as strategies explored to enhance their migratory, survival and proliferation properties, which are known to be relevant for their future clinical use. Current knowledge regardi...
Current Gene Therapy, 2015
Surgical resection is the only curative option for patients with gastrointestinal carcinomas. Unf... more Surgical resection is the only curative option for patients with gastrointestinal carcinomas. Unfortunately, the majority of patients are diagnosed in advanced stages when surgery is not possible. Moreover, the incidence and mortality for certain type of tumors such as hepatocellular carcinoma or pancreatic cancer are steadily increasing worldwide. In spite of the advances in the development of molecular targeted therapies for cancer, the impact on patient survival has been rather limited. It is unlikely that individual agents would be ultimately successful as monotherapy. There is a growing area of research focused on the combination of classical chemotherapy (e.g. cyclophosphamide, gemcitabine, paclitaxel and doxorubicin) with radiotherapy and/or gene therapy strategies. Combined approaches seem to be required due to multiple resistance mechanisms that tumors utilize to limit the activity of chemotherapeutic agents (e.g. the occurrence of multidrug resistance or epigenetic alterations), evade immune responses (e.g. induction of regulatory T cells or myeloid-derived suppressor cells) and to generate resistance against anti-angiogenesis or to radiotherapy by, for example, the induction of hypoxia-inducible factor 1. In addition, new studies suggest that combination of low dose of conventional chemotherapy and gene therapy could allow the development of synergic mechanisms able to achieve significant therapeutic effects against diverse tumors. Although cancer gene therapy is not yet available in clinical practice, advances being recently made look promising, especially when it was applied in combination with standard chemo- or radiotherapy protocols.
Neurochemical research, 2002
In this work we analyzed variations in the expression of MBPs and P0 in ligated sciatic nerves of... more In this work we analyzed variations in the expression of MBPs and P0 in ligated sciatic nerves of young and adult rats at 3, 7, and 14 days postligation (PL), by immunohistochemistry and SDS-PAGE of isolated myelin. A protein redistribution was seen in the distal stump of ligated nerves with the appearance of immunoreactive clusters. Using the KS400 image analyzer, immunostained area values were obtained from the different nerves dissected. In adult rats, there was an increase of the immunostained area for MBP from 3 to 7 days PL, coincident with a reorganization of the marker in clusters, followed by a marked decrease at 14 days. P0 immunolabeling gave similar results without, however, a decrease of the immunostained area at the longer survival time tested. Young animals showed an acceleration in the process of protein redistribution and digestion within ligated nerves, which followed a similar pattern as that of adult animals. Analysis by electrophoresis showed a marked decrease i...
Stem Cells and Development, 2014
Liver cirrhosis involves chronic wound healing and fibrotic processes. Mesenchymal stromal cells ... more Liver cirrhosis involves chronic wound healing and fibrotic processes. Mesenchymal stromal cells (MSCs) are multipotent adult progenitor cells that are used as vehicles of therapeutic genes. Insulin growth factor like-I (IGF-I) was shown to counteract liver fibrosis. We aimed at analyzing the effect of applying IGF-I overexpressing mouse bone marrow-derived MSCs on hepatic fibrosis. Fibrosis was induced by chronic thioacetamide application or bile duct ligation. MSCs engineered to produce green fluorescent protein (GFP) (AdGFP-MSCs) or IGF-I (AdIGF-I-MSCs) were applied systemically, and changes in collagen deposition and in the expression of key pro-fibrogenic and pro-regenerative genes/proteins were assessed. In addition, immunogenicity of transduced cells was analyzed. Liver fibrosis was further ameliorated after a single-dose application of AdIGF-I-MSCs when compared with AdGFP-MSCs and/or recombinant IGF-I treatments. Interestingly, an early and transitory upregulation in IGF-I and hepatocyte growth factor (HGF) mRNA expression was found in the liver of MSC-treated animals, which was more pronounced in AdIGF-I-MSCs condition. A reduction in hepatic stellate cell activation status was found after incubation with MSCs conditioned media. In addition, the AdIGF-I-MSCs cell-free supernatant induced the expression of IGF-I and HGF in primary cultured hepatocytes. From day 1 after transplantation, the proliferation marker proliferating cell nuclear antigen was upregulated in the liver of AdIGF-I-MSCs group, mainly in hepatocytes. MSCs were in vivo traced till day 14 after injection. In addition, multiple doses of Ad-IGF-I-MSCs likely suppressed antiviral immune response and it further reduced collagen deposition. Our results uncover early events that are likely involved in the anti-fibrogenic effect of genetically modified MSCs and overall would support the use of AdIGF-I-MSCs in treatment of liver fibrosis.
PLoS ONE, 2013
Introduction: Secreted Protein, Acidic and Rich in Cysteine (SPARC) is a matricellular protein in... more Introduction: Secreted Protein, Acidic and Rich in Cysteine (SPARC) is a matricellular protein involved in many biological processes and found over-expressed in cirrhotic livers. By mean of a genetic approach we herein provide evidence from different in vivo liver disease models suggesting a profibrogenic role for SPARC. Methods: Two in vivo models of liver fibrosis, based on TAA administration and bile duct ligation, were developed on SPARC wild-type (SPARC +/+) and knockout (SPARC 2/2) mice. Hepatic SPARC expression was analyzed by qPCR. Fibrosis was assessed by Sirius Red staining, and the maturation state of collagen fibers was analyzed using polarized light. Necroinflammatory activity was evaluated by applying the Knodell score and liver inflammatory infiltration was characterized by immunohistochemistry. Hepatic stellate cell activation was assessed by a-SMA immunohistochemistry. In addition, pro-fibrogenic genes and inflammatory cytokines were measured by qPCR and/or ELISA. Liver gene expression profile was analyzed in SPARC 2/2 and SPARC +/+ mice using Affymetrix Mouse Gene ST 1.0 array. Results: SPARC expression was found induced in fibrotic livers of mouse and human. SPARC 2/2 mice showed a reduction in the degree of inflammation, mainly CD4+ cells, and fibrosis. Consistently, collagen deposits and mRNA expression levels were decreased in SPARC 2/2 mice when compared to SPARC +/+ mice; in addition, MMP-2 expression was increased in SPARC 2/2 mice. A reduction in the number of activated myofibroblasts was observed. Moreover, TGF-b1 expression levels were down-regulated in the liver as well as in the serum of TAA-treated knockout animals. Ingenuity Pathway Analysis (IPA) analysis suggested several gene networks which might involve protective mechanisms of SPARC deficiency against liver fibrogenesis and a better established machinery to repair DNA and detoxify from external chemical stimuli. Conclusions: Overall our data suggest that SPARC plays a significant role in liver fibrogenesis. Interventions to inhibit SPARC expression are suggested as promising approaches for liver fibrosis treatment.
…, 2012
Abstract: The use of conventional cytotoxic agents at metronomic schedules, alone or in combinati... more Abstract: The use of conventional cytotoxic agents at metronomic schedules, alone or in combination with targeted agents or immunotherapy, is being explored as a promising anticancer strategy. We previously reported a potent antitumor effect of a single low-dose ...
The EMBO Journal, 2012
The formation of functional connectivity in the nervous system is governed by axon guidance that ... more The formation of functional connectivity in the nervous system is governed by axon guidance that instructs nerve growth and branching during development, implying a similarity between neuronal subtypes in terms of nerve extension. We demonstrate the molecular mechanism of another layer of complexity in vertebrates by defining a transcriptional program underlying growth differences between positionally different neurons. The rate of axon extension of the early subset of embryonic dorsal root ganglion sensory neurons is encoded in neurons at different axial levels. This code is determined by a segmental pattern of axial levels of Runx family transcription factor Runx3. Runx3 in turn determines transcription levels of genes encoding cytoskeletal proteins involved in axon extension, including Rock1 and Rock2 which have ongoing activities determining axon growth in early sensory neurons and blocking Rock activity reverses axon extension deficits of Runx3 À / À neurons. Thus, Runx3 acts to regulate positional differences in axon extension properties apparently without affecting nerve guidance and branching, a principle that could be relevant to other parts of the nervous system.