New severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant, Omicron, contains 32 mu... more New severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant, Omicron, contains 32 mutations that have caused a high incidence of breakthrough infections or re-infections. These mutations have reduced vaccine protection against Omicron and other new emerging variants. This highlights the need to find effective treatment, which is suggested to be stem cell-based therapy. Stem cells could support respiratory epithelial cells and they could restore alveolar bioenergetics. In addition, they can increase the secretion of immunomodulatory cytokines. However, after transplantation, cell survival and growth rate are low because of an inappropriate microenvironment, and stem cells face ischemia, inflammation, and oxidative stress in the transplantation niche which reduces the cells’ survival and growth. Exercise-training can upregulate antioxidant, anti-inflammatory, and anti-apoptotic defense mechanisms and increase growth signaling, thereby improving transplanted cells’ surviva...
Cell therapy and tissue engineering (TE) are considered alternative therapeutic approaches to org... more Cell therapy and tissue engineering (TE) are considered alternative therapeutic approaches to organ transplantation. Since cell therapy approaches achieved little success for liver failure treatment, liver TE is considered a more promising alternative. In this study, we produced a liver tissue equivalent (called ''liver-derived extracellular matrix scaffold [LEMS]-Patch'') by co-culture of human bone marrow stromal cells, human umbilical vein endothelial cells, and a hepatoma cell line, Huh7, within an artificial three-dimensional liverextracellular matrix scaffold. The results showed significant increase in the liver-specific gene expression and hepatic functions, in terms of albumin (ALB) and fibrinogen secretion, urea production, and cytochrome inducibility in the LEMS-Patch compared to controls. In addition, transplanted LEMS-Patch was successfully incorporated into the recipient liver of acute liver failure mice and produced human ALB. Consequently, our data demonstrated that the generated LEMS-Patch could be used as a good platform for functional improvement of hepatic cells in vitro and in vivo.
Fibroblast plays a key role in wound healing, and the advantages of mesenchymal stem cells (MSC) ... more Fibroblast plays a key role in wound healing, and the advantages of mesenchymal stem cells (MSC) secretome in wound healing have previously been reported. In the present study, we investigated the impact of human bone marrow MSC-conditioned media (CM) on skin wound healing in diabetic rats and found that some improvements occurred mainly through fibroblast functions. Then, we scrutinized the impact of MSC-CM treatment on fibroblast cellular behavior by culturing human dermal fibroblasts (HDFs) in a high-glucose (HG) medium, as an in vitro diabetic model. In vivo findings revealed significant improvements in some healing kinetics of diabetic wound which received MSC-CM. Particularly, MSC-CM-treated diabetic wounds reached considerably higher percentages of wound closure. Also, the granulation tissue of these wound had less pronounced inflammatory response, better tissue remodeling, and more vascularization compared with non-treated diabetic ones. Gene expression analyses indicated that MSC-CM treatment leads to upregulation of epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) genes. In addition, a significantly higher cell viability/proliferation, migration, and bFGF gene expression were observed when MSC-CM was used to treat HDFs in HG culture media. Based on these findings, it is suggested that MSC-CM could promote wound repair and skin regeneration, in some major processes, via improvement of cellular behaviors of fibroblasts in the diabetic microenvironment. The beneficial advantages of mesenchymal stem cells-conditioned media on fibroblast cellular behaviors and wound healing may lead to establish a novel approach as an alternative therapeutic procedure to cure chronic wounds in diabetic conditions.
Acute liver failure (ALF) is a lethal disease with limited life-saving therapy. Because lack of w... more Acute liver failure (ALF) is a lethal disease with limited life-saving therapy. Because lack of whole organ donors for liver transplantation, a substitute treatment strategy is needed for these patients. Preclinical and clinical findings have proved that treatment with mesenchymal stem cells (MSCs) is beneficial for recovery from ALF. In this approach, however, the appropriate sources of these cells are unclear. In the present study, we investigated and compared the therapeutic potentials of bone marrow-mesenchymal stem cells (BM-MSC) with those of adipose tissue (AT-MSC) in carbon tetrachloride (CCL4)-induced acute liver failure in mice. Murine BM- and AT-MSCs obtained from normal mice were cultured and labelled. The cells were transplanted to CCL4-induced ALF mice models intravenously. After cell transplantation, blood samples and liver tissues were collected daily for 72 h to analyze liver enzymes and liver histopathology, respectively. We found that survival rate of AT-MSC trans...
Adult cardiomyocytes lack the ability to proliferate and unable to repair the damaged heart tissu... more Adult cardiomyocytes lack the ability to proliferate and unable to repair the damaged heart tissue, therefore differentiation of stem cells to cardiomyocytes represents an exceptional opportunity to study the cardiomyocytes in vitro and potentially provides a valuable source for replacing damaged tissue. However characteristic maturity of the in vitro differentiated cardiomyocytes and methods to achieve it are yet to be optimized. In this study differentiation of human bone marrow-mesenchymal stem cells (hBM-MSCs) into cardiomyocytes is accomplished and the process investigated ultrastructurally. The hBM-MSCs were alternatively treated with 5 µM of 5-azacytidine (5-aza) for eight weeks for differentiation to cardiomyocytes. Expressions of cardiomyocyte-specific genes [cardiac α-actinin, cardiac β-myosin heavy chain (MHC) and connexin-43] and proteins (cardiac α-actinin, cardiac troponin and connexin-43) were confirmed in a time-dependent manner from the first to the fifth weeks post...
An important advantage of employing extracellular matrix (ECM)-derived biomaterials in tissue eng... more An important advantage of employing extracellular matrix (ECM)-derived biomaterials in tissue engineering is the ability to tailor the biochemical and biophysical microenvironment of the cells. This study aims to assess whether three-dimensional (3D) liver-derived ECM hydrogel (LEMgel) promotes physiological function of liver organoids generated by self-organization of human hepatocarcinoma cells together with human mesenchymal and endothelial cells. We have optimized the decellularization method to fabricate liver ECM derived from sheep to preserve the greatest content of glycosaminoglycans, collagen, laminin, and fibronectin in produced LEMgel. During gelation, complex viscoelasticity modulus of the LEMgel (3 mg/mL) increased from 186.7 to 1570.5 Pa and Tan Delta decreased from 0.27 to 0.18. Scanning electron microscopy (SEM) determined that the LEMgel had a pore size of 382 ± 71 µm. Hepatocarcinoma cells in the self-organized liver organoids in 3D LEMgel (LEMgel organoids) showed...
Porpose:To evaluate the development of cardiomyocyte-like cells derived from human bone marrow me... more Porpose:To evaluate the development of cardiomyocyte-like cells derived from human bone marrow mesenchymal stem cells induced by 5-azacytidine (5-aza) under in vitro condition. Materials and Methods: Human bone marrow mesenchymal stem cells (BMMSCs) were purified, then the cells were induced by 5µM 5-aza for 5 weeks. To transdifferentiate into cardiomyocyte, the culture medium of human BMMSCs was changed every 24 hours, in the way that the cells were put in the culture medium containing 5-aza for 24 hours and, then were put in a culture medium free of the said material for another 24 hours, and this process continued until sampling. RT-PCR assay was performed to detect the expression of specific myocardium genes including α-actinin, myosin heavy chain (MHC) and connexin-43 each weeks after first induction. Fluocytometry was used to determine the expression of specific myocardium proteins including α-actinin, troponin and connexin-43 at 3 rd and 5 th weeks after the first induction. Results: The expression of all three myocardium genes was detected 1 to 5 weeks after induction in a time-dependent manner. There was a continuous increase in expression of α-actinin and connexin-43 genes from the 1 st to the 5 th week, while mRNA of MHC gene was at the highest level in the forth week. The expression of α-actinin and troponin proteins was equal after three and five weeks, whereas that of the connexin-43 was higher after five weeks in comparison to the 3 rd week. Conclusion: The current study indicated that stimulating human bone marrow mesenchymal stem cells by 5-aza with the concentration of 5µM under in vitro condition can lead to differentiating cardiomyocyte-like cells. Furthermore prolonged culture duration may lead to more differentiated cells.
New severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant, Omicron, contains 32 mu... more New severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant, Omicron, contains 32 mutations that have caused a high incidence of breakthrough infections or re-infections. These mutations have reduced vaccine protection against Omicron and other new emerging variants. This highlights the need to find effective treatment, which is suggested to be stem cell-based therapy. Stem cells could support respiratory epithelial cells and they could restore alveolar bioenergetics. In addition, they can increase the secretion of immunomodulatory cytokines. However, after transplantation, cell survival and growth rate are low because of an inappropriate microenvironment, and stem cells face ischemia, inflammation, and oxidative stress in the transplantation niche which reduces the cells’ survival and growth. Exercise-training can upregulate antioxidant, anti-inflammatory, and anti-apoptotic defense mechanisms and increase growth signaling, thereby improving transplanted cells’ surviva...
Cell therapy and tissue engineering (TE) are considered alternative therapeutic approaches to org... more Cell therapy and tissue engineering (TE) are considered alternative therapeutic approaches to organ transplantation. Since cell therapy approaches achieved little success for liver failure treatment, liver TE is considered a more promising alternative. In this study, we produced a liver tissue equivalent (called ''liver-derived extracellular matrix scaffold [LEMS]-Patch'') by co-culture of human bone marrow stromal cells, human umbilical vein endothelial cells, and a hepatoma cell line, Huh7, within an artificial three-dimensional liverextracellular matrix scaffold. The results showed significant increase in the liver-specific gene expression and hepatic functions, in terms of albumin (ALB) and fibrinogen secretion, urea production, and cytochrome inducibility in the LEMS-Patch compared to controls. In addition, transplanted LEMS-Patch was successfully incorporated into the recipient liver of acute liver failure mice and produced human ALB. Consequently, our data demonstrated that the generated LEMS-Patch could be used as a good platform for functional improvement of hepatic cells in vitro and in vivo.
Fibroblast plays a key role in wound healing, and the advantages of mesenchymal stem cells (MSC) ... more Fibroblast plays a key role in wound healing, and the advantages of mesenchymal stem cells (MSC) secretome in wound healing have previously been reported. In the present study, we investigated the impact of human bone marrow MSC-conditioned media (CM) on skin wound healing in diabetic rats and found that some improvements occurred mainly through fibroblast functions. Then, we scrutinized the impact of MSC-CM treatment on fibroblast cellular behavior by culturing human dermal fibroblasts (HDFs) in a high-glucose (HG) medium, as an in vitro diabetic model. In vivo findings revealed significant improvements in some healing kinetics of diabetic wound which received MSC-CM. Particularly, MSC-CM-treated diabetic wounds reached considerably higher percentages of wound closure. Also, the granulation tissue of these wound had less pronounced inflammatory response, better tissue remodeling, and more vascularization compared with non-treated diabetic ones. Gene expression analyses indicated that MSC-CM treatment leads to upregulation of epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) genes. In addition, a significantly higher cell viability/proliferation, migration, and bFGF gene expression were observed when MSC-CM was used to treat HDFs in HG culture media. Based on these findings, it is suggested that MSC-CM could promote wound repair and skin regeneration, in some major processes, via improvement of cellular behaviors of fibroblasts in the diabetic microenvironment. The beneficial advantages of mesenchymal stem cells-conditioned media on fibroblast cellular behaviors and wound healing may lead to establish a novel approach as an alternative therapeutic procedure to cure chronic wounds in diabetic conditions.
Acute liver failure (ALF) is a lethal disease with limited life-saving therapy. Because lack of w... more Acute liver failure (ALF) is a lethal disease with limited life-saving therapy. Because lack of whole organ donors for liver transplantation, a substitute treatment strategy is needed for these patients. Preclinical and clinical findings have proved that treatment with mesenchymal stem cells (MSCs) is beneficial for recovery from ALF. In this approach, however, the appropriate sources of these cells are unclear. In the present study, we investigated and compared the therapeutic potentials of bone marrow-mesenchymal stem cells (BM-MSC) with those of adipose tissue (AT-MSC) in carbon tetrachloride (CCL4)-induced acute liver failure in mice. Murine BM- and AT-MSCs obtained from normal mice were cultured and labelled. The cells were transplanted to CCL4-induced ALF mice models intravenously. After cell transplantation, blood samples and liver tissues were collected daily for 72 h to analyze liver enzymes and liver histopathology, respectively. We found that survival rate of AT-MSC trans...
Adult cardiomyocytes lack the ability to proliferate and unable to repair the damaged heart tissu... more Adult cardiomyocytes lack the ability to proliferate and unable to repair the damaged heart tissue, therefore differentiation of stem cells to cardiomyocytes represents an exceptional opportunity to study the cardiomyocytes in vitro and potentially provides a valuable source for replacing damaged tissue. However characteristic maturity of the in vitro differentiated cardiomyocytes and methods to achieve it are yet to be optimized. In this study differentiation of human bone marrow-mesenchymal stem cells (hBM-MSCs) into cardiomyocytes is accomplished and the process investigated ultrastructurally. The hBM-MSCs were alternatively treated with 5 µM of 5-azacytidine (5-aza) for eight weeks for differentiation to cardiomyocytes. Expressions of cardiomyocyte-specific genes [cardiac α-actinin, cardiac β-myosin heavy chain (MHC) and connexin-43] and proteins (cardiac α-actinin, cardiac troponin and connexin-43) were confirmed in a time-dependent manner from the first to the fifth weeks post...
An important advantage of employing extracellular matrix (ECM)-derived biomaterials in tissue eng... more An important advantage of employing extracellular matrix (ECM)-derived biomaterials in tissue engineering is the ability to tailor the biochemical and biophysical microenvironment of the cells. This study aims to assess whether three-dimensional (3D) liver-derived ECM hydrogel (LEMgel) promotes physiological function of liver organoids generated by self-organization of human hepatocarcinoma cells together with human mesenchymal and endothelial cells. We have optimized the decellularization method to fabricate liver ECM derived from sheep to preserve the greatest content of glycosaminoglycans, collagen, laminin, and fibronectin in produced LEMgel. During gelation, complex viscoelasticity modulus of the LEMgel (3 mg/mL) increased from 186.7 to 1570.5 Pa and Tan Delta decreased from 0.27 to 0.18. Scanning electron microscopy (SEM) determined that the LEMgel had a pore size of 382 ± 71 µm. Hepatocarcinoma cells in the self-organized liver organoids in 3D LEMgel (LEMgel organoids) showed...
Porpose:To evaluate the development of cardiomyocyte-like cells derived from human bone marrow me... more Porpose:To evaluate the development of cardiomyocyte-like cells derived from human bone marrow mesenchymal stem cells induced by 5-azacytidine (5-aza) under in vitro condition. Materials and Methods: Human bone marrow mesenchymal stem cells (BMMSCs) were purified, then the cells were induced by 5µM 5-aza for 5 weeks. To transdifferentiate into cardiomyocyte, the culture medium of human BMMSCs was changed every 24 hours, in the way that the cells were put in the culture medium containing 5-aza for 24 hours and, then were put in a culture medium free of the said material for another 24 hours, and this process continued until sampling. RT-PCR assay was performed to detect the expression of specific myocardium genes including α-actinin, myosin heavy chain (MHC) and connexin-43 each weeks after first induction. Fluocytometry was used to determine the expression of specific myocardium proteins including α-actinin, troponin and connexin-43 at 3 rd and 5 th weeks after the first induction. Results: The expression of all three myocardium genes was detected 1 to 5 weeks after induction in a time-dependent manner. There was a continuous increase in expression of α-actinin and connexin-43 genes from the 1 st to the 5 th week, while mRNA of MHC gene was at the highest level in the forth week. The expression of α-actinin and troponin proteins was equal after three and five weeks, whereas that of the connexin-43 was higher after five weeks in comparison to the 3 rd week. Conclusion: The current study indicated that stimulating human bone marrow mesenchymal stem cells by 5-aza with the concentration of 5µM under in vitro condition can lead to differentiating cardiomyocyte-like cells. Furthermore prolonged culture duration may lead to more differentiated cells.
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Papers by Mona Saheli