Mohsin Raza Khan - Academia.edu (original) (raw)

Papers by Mohsin Raza Khan

Soil samples from different habitats including tanneries, soap industries, garden soil and soil c... more Soil samples from different habitats including tanneries, soap industries, garden soil and soil compost were screened for the presence of alkalophilic Bacillus isolates capable of producing alkaline protease in large quantities. One hundred and eighteen (118) isolates were found having proteolytic activity on skim milk agar plates. Isolates forming larger zones, as a result of casein hydrolysis were further studied for quantitative production of extracellular alkaline protease activity in the shake flask studies. Isolate CEMB10370 gave maximum activity. Time course studies indicated that strain CEMB10370 had the highest protease activity (380 APU/mL) after 48 h of fermentation. The wild type enzyme was biochemically characterized. The enzyme exhibits optimal activity at 50°C and pH 11.5. The protease enzyme was completely inhibited by phenylmethylsulfonyl (PMSF, serine protease inhibitor) and its isoelectric point was ~9.5. The enzyme was purified by ion-exchange chromatography usin...

International Journal of Molecular Sciences

Ischemic injury to the heart causes cardiomyocyte and supportive tissue death that result in adve... more Ischemic injury to the heart causes cardiomyocyte and supportive tissue death that result in adverse remodeling and formation of scar tissue at the site of injury. The dying cardiac tissue secretes a variety of cytokines and chemokines that trigger an inflammatory response and elicit the recruitment and activation of cardiac immune cells to the injury site. Cell-based therapies for cardiac repair have enhanced cardiac function in the injured myocardium, but the mechanisms remain debatable. In this review, we will focus on the interactions between the adoptively transferred stem cells and the post-ischemic environment, including the active components of the immune/inflammatory response that can mediate cardiac outcome after ischemic injury. In particular, we highlight how the adaptive immune cell response can mediate tissue repair following cardiac injury. Several cell-based studies have reported an increase in pro-reparative T cell subsets after stem cell transplantation. Paracrine ...

Circulation Research, 2014

The cardiac influence of chronic ethanol (EtOH) consumption in humans is dictated by the frequenc... more The cardiac influence of chronic ethanol (EtOH) consumption in humans is dictated by the frequency of ethanol ingestion. Whereas moderate consumption (i.e. 1-2 alcoholic drinks/day) imparts a cardiac benefit to patients by reducing adverse cardiovascular event (ACE) occurrences, consumption below or beyond these moderate levels significantly increases the incidence of ACEs. Despite these observations, little is known regarding the functional impact of chronic EtOH consumption on post-myocardial infarct repair or the cellular mechanisms involved in this process. Thus, we investigated the post-AMI functional consequences of chronic ethanol consumption in mice. Mice received chronic ethanol via the Lieber-DeCarli paradigm (i.e. 0%, 1% (moderate) or 5% (high) ethanol v/v) in an isocaloric fashion for 8 weeks. After 8 weeks, mice underwent a 60-minute ischemic/reperfusion injury and the subsequent assessment of their cardiac function for 4 weeks post-AMI. As early as two weeks post-AMI, ...

Journal of Xiangya Medicine, 2021

Background: Concurrent chemoradiotherapy is the mainstay of treatment in locally advanced head an... more Background: Concurrent chemoradiotherapy is the mainstay of treatment in locally advanced head and neck cancer (LAHNC). Several studies have shown better outcome with altered fractionation radiation schedules, especially with hyperfractionation (HF-RT). For the last few decades attempts are being done to combine altered fractionation regimens with concurrent chemotherapy to achieve higher therapeutic gain. This study was done to evaluate the efficacy and toxicity of hyperfractionated concurrent chemoradiation (HF-CRT) in comparison to conventional concurrent chemoradiotherapy (CF-CRT). Methods: This was a prospective trial registered with Clinical Trials Registry-India (REF/2022/01/050552), randomizing LAHNC patients into control group (CF-CRT) (70 Gy/35 fractions/5 fractions per week, 2 Gy/fraction/day) or study group (HF-CRT) (81.6 Gy/68 fractions/10 fractions per week, 1.2 Gy/fraction, twice daily at 6 hours interval). Concurrent chemotherapy consisted of weekly cisplatin (40 mg/m 2). The primary and secondary endpoints were response to therapy and treatment-induced toxicity respectively. Results: A total of 214 eligible patients were recruited: 106 patients in control group & 108 patients in study group. Median follow-up was 7 months. Median overall treatment time was 59 & 63 days in control & study groups respectively. Complete response rates at primary and nodal sites were statistically similar (64% vs. 74%; P=0.1 and 54% vs. 61%; P=0.3 for CF-CRT & HF-CRT respectively). For objective response rate (ORR) and late toxicity rate, again there was no significant difference between the two radiation protocols. However, HF-CRT was associated with significantly higher rate of severe acute mucositis. Conclusions: Combining HF-RT with concurrent chemotherapy did not provide any significant gain in response rate, rather it was associated with higher acute toxicity, inconvenience and logistic issues giving CF-CRT a practical advantage over this protocol especially in resource-restrained settings.

Frontiers in Physiology, 2022

Circulation Research, 2014

Rationale: Embryonic stem cells (ESCs) hold great promise for cardiac regeneration but are suscep... more Rationale: Embryonic stem cells (ESCs) hold great promise for cardiac regeneration but are susceptible to ethical concerns, lack of autologous donors and teratoma formation. Recently, it has been observed that beneficial effects of stem cells are mediated by exosomes secreted out under various physiological conditions. ESCs have the ability to produce exosomes however their effect in the context of the heart is unknown. Objective: Determine the effect of ESC derived exosomes for cardiac repair and modulation of CPCs functions in the heart following myocardial infarction. Methods and Results: Exosomes were isolated from murine ESCs (mES Ex) or embryonic fibroblasts (MEFs) by ultracentrifugation and verified by Flotillin-1 immunoblot analysis. Induction of pluripotent markers, survival and in vitro tube formation was enhanced in target cells receiving ESC exosomes indicating therapeutic potential of mES Ex. mES Ex administration resulted in enhanced neovascularization, cardiomyocyte s...

Circulation, 2014

Rationale: Embryonic heart is characteristic of rapidly dividing cardiomyocytes that give rise to... more Rationale: Embryonic heart is characteristic of rapidly dividing cardiomyocytes that give rise to sufficient numbers required to build a working myocardium. In contrast, cardiomyocytes retain some proliferative capacity in the neonates but lose most of it in adulthood. Embryonic stem cell cycle (ESCC) miRs are a class of microRNAs regulating the unique cell cycle of ESCs and their characteristic pluripotency. Nevertheless, expression of miR-294, a member of the ESCC miRs is lost during developmental transitions from the ESCs to mature cells. Effect of miR-294 to induce cardiac proliferation and heart function has not been previously studied. Objective: To determine whether miR-294 drives cardiomyocyte cell cycle reentry leading to augmentation of cardiac function after myocardial infarction. Methods and Results: miR expression analysis was carried out in the heart during development to determine levels of miR-294. Elevated level of miR-294 was observed in the prenatal heart confirme...

Circulation Research, 2014

We hypothesized that IL-10 regulates miR-375 signaling in EPCs to enhance their survival and func... more We hypothesized that IL-10 regulates miR-375 signaling in EPCs to enhance their survival and function in ischemic myocardium after MI. miR-375 knock down EPC were transplanted intramyocardially after induction of MI. Mice receiving EPC treated with miR-375 inhibitor showed increased number of GFP+EPCs retention that was associated with reduced EPC apoptosis in the myocardium. The engraftment of EPC into the vascular structures and the associated capillary density was significantly higher in miR-375-treated mice. The above findings further correlated with reduced infarct size, fibrosis and enhanced LV function (echocardiography) in miR-375 knock down EPC group as compared to scrambled EPC. Our in vitro studies revealed that the knockdown of miR-375 enhanced EPC proliferation, migration; tube formation ability and inhibited cell apoptosis, while the up-regulation of miR-375 with the mimic had the opposite effects. In addition, we found that miR-375 negatively regulates the expression ...

International Journal of Molecular Sciences, 2021

Metabolism has emerged as a regulator of core stem cell properties such as proliferation, surviva... more Metabolism has emerged as a regulator of core stem cell properties such as proliferation, survival, self-renewal, and multilineage potential. Metabolites serve as secondary messengers, fine-tuning signaling pathways in response to microenvironment alterations. Studies show a role for central metabolite acetyl-CoA in the regulation of chromatin state through changes in histone acetylation. Nevertheless, metabolic regulators of chromatin remodeling in cardiac cells in response to increasing biological age remains unknown. Previously, we identified novel cardiac-derived stem-like cells (CTSCs) that exhibit increased functional properties in the neonatal heart (nCTSC). These cells are linked to a unique metabolism which is altered with CTSC aging (aCTSC). Here, we present an in-depth, RNA-sequencing-based (RNA-Seq) bioinformatic with cluster analysis that details a distinct epigenome present in nCTSCs but not in aCTSCs. Gene Ontology (GO) and pathway enrichment reveal biological process...

Circulation Research, 2012

The endoplasmic reticulum (ER) is essential for protein homeostasis, or proteostasis, which gover... more The endoplasmic reticulum (ER) is essential for protein homeostasis, or proteostasis, which governs the balance of the proteome. In addition to secreted and membrane proteins, proteins bound for many other cellular locations are also made on ER-bound ribosomes, emphasizing the importance of protein quality and quantity control in the ER. Unlike cytosolic E3 ubiquitin ligases studied in the heart, synoviolin/Hrd1, which has not been studied in the heart, is an ER transmembrane E3 ubiquitin ligase, which we found to be upregulated upon protein misfolding in cardiac myocytes. Given the strategic location of synoviolin in the ER membrane, we addressed the hypothesis that synoviolin is critical for regulating the balance of the proteome, and accordingly, myocyte size. We showed that in vitro, adenovirus-mediated overexpression of synoviolin decreased cardiac myocyte size and protein synthesis, but unlike atrophy-related ubiquitin ligases, synoviolin did not increase global protein degrad...

International Journal of Molecular Sciences, 2021

Ischemic heart disease can lead to myocardial infarction (MI), a major cause of morbidity and mor... more Ischemic heart disease can lead to myocardial infarction (MI), a major cause of morbidity and mortality worldwide. Multiple stem cell types have been safely transferred into failing human hearts, but the overall clinical cardiovascular benefits have been modest. Therefore, there is a dire need to understand the basic biology of stem cells to enhance therapeutic effects. Bmi1 is part of the polycomb repressive complex 1 (PRC1) that is involved in different processes including proliferation, survival and differentiation of stem cells. We isolated cortical bones stem cells (CBSCs) from bone stroma, and they express significantly high levels of Bmi1 compared to mesenchymal stem cells (MSCs) and cardiac-derived stem cells (CDCs). Using lentiviral transduction, Bmi1 was knocked down in the CBSCs to determine the effect of loss of Bmi1 on proliferation and survival potential with or without Bmi1 in CBSCs. Our data show that with the loss of Bmi1, there is a decrease in CBSC ability to prol...

STEM CELLS Translational Medicine, 2020

Cellular replacement in the heart is restricted to postnatal stages with the adult heart largely ... more Cellular replacement in the heart is restricted to postnatal stages with the adult heart largely postmitotic. Studies show that loss of regenerative properties in cardiac cells seems to coincide with alterations in metabolism during postnatal development and maturation. Nevertheless, whether changes in cellular metabolism are linked to functional alternations in cardiac cells is not well studied. We report here a novel role for uncoupling protein 2 (UCP2) in regulation of functional properties in cardiac tissue derived stem-like cells (CTSCs). CTSC were isolated from C57BL/6 mice aged 2 days (nCTSC), 2 month (CTSC), and 2 years old (aCTSC), subjected to bulk-RNA sequencing that identifies unique transcriptome significantly different between CTSC populations from young and old heart. Moreover, results show that UCP2 is highly expressed in CTSCs from the neonatal heart and is linked to maintenance of glycolysis, proliferation, and survival. With age, UCP2 is reduced shifting energy me...

Cells, 2020

Cell-based therapeutics for cardiac repair have been extensively used during the last decade. Pre... more Cell-based therapeutics for cardiac repair have been extensively used during the last decade. Preclinical studies have demonstrated the effectiveness of adoptively transferred stem cells for enhancement of cardiac function. Nevertheless, several cell-based clinical trials have provided largely underwhelming outcomes. A major limitation is the lack of survival in the harsh cardiac milieu as only less than 1% donated cells survive. Recent efforts have focused on enhancing cell-based therapeutics and understanding the biology of stem cells and their response to environmental changes. Stem cell metabolism has recently emerged as a critical determinant of cellular processes and is uniquely adapted to support proliferation, stemness, and commitment. Metabolic signaling pathways are remarkably sensitive to different environmental signals with a profound effect on cell survival after adoptive transfer. Stem cells mainly generate energy through glycolysis while maintaining low oxidative phos...

Circulation, Nov 25, 2014

Background: Recently we have shown that IL-10, an anti-inflammatory cytokine, markedly inhibited ... more Background: Recently we have shown that IL-10, an anti-inflammatory cytokine, markedly inhibited the pressure overload-induced cardiac fibrosis, however, antifibrotic mechanisms of IL-10 are largely unknown. In most organs, including heart, activated fibroblast play critical role in extracellular matrix remodeling, however, very little information is available regarding the origin of myoFBs. Here we hypothesized that IL-10 inhibits stress-induced proliferation and differentiation of nonresident bone marrow-derived fibroblast progenitor cells and therefore, attenuates cardiac fibrosis and improves of heart function. Methods and Results: Cardiac hypertrophy was induced in Wild-type (WT) and IL-10-knockout (KO) mice by transverse aortic constriction (TAC). TAC-induced left ventricular (LV) dysfunction and fibrosis were further exaggerated in KO mice compared to WT. TAC significantly increased TGF-β, collagen Iα and IIIα genes expression. Systemic recombinant mouse IL-10 administration markedly improved LV function, inhibited TAC-induced cardiac fibrosis and fibrosis associated genes expression. To identify the role of fibroblast progenitor cells (FPCs), we measured the mobilization of FPCs (Prominin1 positive cells) from bone marrow to heart by FACs. Exacerbated mobilization of FPCs in peripheral blood and heart in IL-10 KO mice were found 3 and 7 days after aortic constriction. Bone marrow transplantation experiments were performed where WT-GFP positive marrow was transplanted in BM depleted IL-10 KO mice. TAC-induced mobilization was significantly reduced in WT-transplanted marrow as compare to TAC-IL-10 KO mice. To identify the role IL-10 on TGFβ-induced endothelial cells trans-differentiation to myofibroblasts, we treated aortic endothelial cells with IL-10 and TGFβ2 for 96 hrs. Both Immunocytochemistry and Western blot analysis results suggested that TGF-β2-induced EndMT was significantly inhibited by IL-10 treatment. To understand the mechanisms, we found that TGF-β2-induced Notch1 signaling was reduced by IL-10. Conclusion: Taken together our observations suggest that the anti-fibrotic effects of IL-10 treatment are mediated by reduced proliferation and differentiation of non-resident myofibroblasts.

Int J Pept Res Ther, 2010

Circulation, Nov 26, 2013

Circulation, Nov 20, 2012

Circulation, Nov 25, 2014

Despite some encouraging data, the bone marrow progenitor cells (BMPC) mediated clinical trials h... more Despite some encouraging data, the bone marrow progenitor cells (BMPC) mediated clinical trials have only shown a very modest improvement in heart functions. Poor survival and function of transplanted cell in the ischemic and inflamed myocardium likely compromises the full functional benefit of stem cell based therapies. We have earlier reported that co-administration of IL-10 and BMPC not only enhances cell survival but also improved left ventricular (LV) functions after AMI in mice. We identified that microRNA-375 expression is significantly up-regulated in EPCs upon exposure to either inflammatory or hypoxic stimulus. We hypothesized that IL-10 regulates miR-375 signaling in EPCs to enhance their survival and function in ischemic myocardium after MI. miR-375 knock down EPC were transplanted intramyocardially after induction of MI. Mice receiving EPC treated with miR-375 inhibitor showed increased number of EPC retention that was associated with reduced EPC apoptosis in the myocardium. The engraftment o...

Circulation Research, 2016

Stem cell therapy provides immense hope for regenerating the pathological heart, yet has been mar... more Stem cell therapy provides immense hope for regenerating the pathological heart, yet has been marred by issues surrounding the effectiveness, unclear mechanisms, and survival of the donated cell population in the ischemic myocardial milieu. Poor survival and engraftment coupled to inadequate cardiac commitment of the adoptively transferred stem cells compromises the improvement in cardiac function. Various alternative approaches to enhance the efficacy of stem cell therapies and to overcome issues with cell therapy have been used with varied success. Cell-free components, such as exosomes enriched in proteins, messenger RNAs, and miRs characteristic of parental stem cells, represent a potential approach for treating cardiovascular diseases. Recently, exosomes from different kinds of stem cells have been effectively used to promote cardiac function in the pathological heart. The aim of this review is to summarize current research efforts on stem cell exosomes, including their potenti...

Circulation, Nov 26, 2013

Soil samples from different habitats including tanneries, soap industries, garden soil and soil c... more Soil samples from different habitats including tanneries, soap industries, garden soil and soil compost were screened for the presence of alkalophilic Bacillus isolates capable of producing alkaline protease in large quantities. One hundred and eighteen (118) isolates were found having proteolytic activity on skim milk agar plates. Isolates forming larger zones, as a result of casein hydrolysis were further studied for quantitative production of extracellular alkaline protease activity in the shake flask studies. Isolate CEMB10370 gave maximum activity. Time course studies indicated that strain CEMB10370 had the highest protease activity (380 APU/mL) after 48 h of fermentation. The wild type enzyme was biochemically characterized. The enzyme exhibits optimal activity at 50°C and pH 11.5. The protease enzyme was completely inhibited by phenylmethylsulfonyl (PMSF, serine protease inhibitor) and its isoelectric point was ~9.5. The enzyme was purified by ion-exchange chromatography usin...

International Journal of Molecular Sciences

Ischemic injury to the heart causes cardiomyocyte and supportive tissue death that result in adve... more Ischemic injury to the heart causes cardiomyocyte and supportive tissue death that result in adverse remodeling and formation of scar tissue at the site of injury. The dying cardiac tissue secretes a variety of cytokines and chemokines that trigger an inflammatory response and elicit the recruitment and activation of cardiac immune cells to the injury site. Cell-based therapies for cardiac repair have enhanced cardiac function in the injured myocardium, but the mechanisms remain debatable. In this review, we will focus on the interactions between the adoptively transferred stem cells and the post-ischemic environment, including the active components of the immune/inflammatory response that can mediate cardiac outcome after ischemic injury. In particular, we highlight how the adaptive immune cell response can mediate tissue repair following cardiac injury. Several cell-based studies have reported an increase in pro-reparative T cell subsets after stem cell transplantation. Paracrine ...

Circulation Research, 2014

The cardiac influence of chronic ethanol (EtOH) consumption in humans is dictated by the frequenc... more The cardiac influence of chronic ethanol (EtOH) consumption in humans is dictated by the frequency of ethanol ingestion. Whereas moderate consumption (i.e. 1-2 alcoholic drinks/day) imparts a cardiac benefit to patients by reducing adverse cardiovascular event (ACE) occurrences, consumption below or beyond these moderate levels significantly increases the incidence of ACEs. Despite these observations, little is known regarding the functional impact of chronic EtOH consumption on post-myocardial infarct repair or the cellular mechanisms involved in this process. Thus, we investigated the post-AMI functional consequences of chronic ethanol consumption in mice. Mice received chronic ethanol via the Lieber-DeCarli paradigm (i.e. 0%, 1% (moderate) or 5% (high) ethanol v/v) in an isocaloric fashion for 8 weeks. After 8 weeks, mice underwent a 60-minute ischemic/reperfusion injury and the subsequent assessment of their cardiac function for 4 weeks post-AMI. As early as two weeks post-AMI, ...

Journal of Xiangya Medicine, 2021

Background: Concurrent chemoradiotherapy is the mainstay of treatment in locally advanced head an... more Background: Concurrent chemoradiotherapy is the mainstay of treatment in locally advanced head and neck cancer (LAHNC). Several studies have shown better outcome with altered fractionation radiation schedules, especially with hyperfractionation (HF-RT). For the last few decades attempts are being done to combine altered fractionation regimens with concurrent chemotherapy to achieve higher therapeutic gain. This study was done to evaluate the efficacy and toxicity of hyperfractionated concurrent chemoradiation (HF-CRT) in comparison to conventional concurrent chemoradiotherapy (CF-CRT). Methods: This was a prospective trial registered with Clinical Trials Registry-India (REF/2022/01/050552), randomizing LAHNC patients into control group (CF-CRT) (70 Gy/35 fractions/5 fractions per week, 2 Gy/fraction/day) or study group (HF-CRT) (81.6 Gy/68 fractions/10 fractions per week, 1.2 Gy/fraction, twice daily at 6 hours interval). Concurrent chemotherapy consisted of weekly cisplatin (40 mg/m 2). The primary and secondary endpoints were response to therapy and treatment-induced toxicity respectively. Results: A total of 214 eligible patients were recruited: 106 patients in control group & 108 patients in study group. Median follow-up was 7 months. Median overall treatment time was 59 & 63 days in control & study groups respectively. Complete response rates at primary and nodal sites were statistically similar (64% vs. 74%; P=0.1 and 54% vs. 61%; P=0.3 for CF-CRT & HF-CRT respectively). For objective response rate (ORR) and late toxicity rate, again there was no significant difference between the two radiation protocols. However, HF-CRT was associated with significantly higher rate of severe acute mucositis. Conclusions: Combining HF-RT with concurrent chemotherapy did not provide any significant gain in response rate, rather it was associated with higher acute toxicity, inconvenience and logistic issues giving CF-CRT a practical advantage over this protocol especially in resource-restrained settings.

Frontiers in Physiology, 2022

Circulation Research, 2014

Rationale: Embryonic stem cells (ESCs) hold great promise for cardiac regeneration but are suscep... more Rationale: Embryonic stem cells (ESCs) hold great promise for cardiac regeneration but are susceptible to ethical concerns, lack of autologous donors and teratoma formation. Recently, it has been observed that beneficial effects of stem cells are mediated by exosomes secreted out under various physiological conditions. ESCs have the ability to produce exosomes however their effect in the context of the heart is unknown. Objective: Determine the effect of ESC derived exosomes for cardiac repair and modulation of CPCs functions in the heart following myocardial infarction. Methods and Results: Exosomes were isolated from murine ESCs (mES Ex) or embryonic fibroblasts (MEFs) by ultracentrifugation and verified by Flotillin-1 immunoblot analysis. Induction of pluripotent markers, survival and in vitro tube formation was enhanced in target cells receiving ESC exosomes indicating therapeutic potential of mES Ex. mES Ex administration resulted in enhanced neovascularization, cardiomyocyte s...

Circulation, 2014

Rationale: Embryonic heart is characteristic of rapidly dividing cardiomyocytes that give rise to... more Rationale: Embryonic heart is characteristic of rapidly dividing cardiomyocytes that give rise to sufficient numbers required to build a working myocardium. In contrast, cardiomyocytes retain some proliferative capacity in the neonates but lose most of it in adulthood. Embryonic stem cell cycle (ESCC) miRs are a class of microRNAs regulating the unique cell cycle of ESCs and their characteristic pluripotency. Nevertheless, expression of miR-294, a member of the ESCC miRs is lost during developmental transitions from the ESCs to mature cells. Effect of miR-294 to induce cardiac proliferation and heart function has not been previously studied. Objective: To determine whether miR-294 drives cardiomyocyte cell cycle reentry leading to augmentation of cardiac function after myocardial infarction. Methods and Results: miR expression analysis was carried out in the heart during development to determine levels of miR-294. Elevated level of miR-294 was observed in the prenatal heart confirme...

Circulation Research, 2014

We hypothesized that IL-10 regulates miR-375 signaling in EPCs to enhance their survival and func... more We hypothesized that IL-10 regulates miR-375 signaling in EPCs to enhance their survival and function in ischemic myocardium after MI. miR-375 knock down EPC were transplanted intramyocardially after induction of MI. Mice receiving EPC treated with miR-375 inhibitor showed increased number of GFP+EPCs retention that was associated with reduced EPC apoptosis in the myocardium. The engraftment of EPC into the vascular structures and the associated capillary density was significantly higher in miR-375-treated mice. The above findings further correlated with reduced infarct size, fibrosis and enhanced LV function (echocardiography) in miR-375 knock down EPC group as compared to scrambled EPC. Our in vitro studies revealed that the knockdown of miR-375 enhanced EPC proliferation, migration; tube formation ability and inhibited cell apoptosis, while the up-regulation of miR-375 with the mimic had the opposite effects. In addition, we found that miR-375 negatively regulates the expression ...

International Journal of Molecular Sciences, 2021

Metabolism has emerged as a regulator of core stem cell properties such as proliferation, surviva... more Metabolism has emerged as a regulator of core stem cell properties such as proliferation, survival, self-renewal, and multilineage potential. Metabolites serve as secondary messengers, fine-tuning signaling pathways in response to microenvironment alterations. Studies show a role for central metabolite acetyl-CoA in the regulation of chromatin state through changes in histone acetylation. Nevertheless, metabolic regulators of chromatin remodeling in cardiac cells in response to increasing biological age remains unknown. Previously, we identified novel cardiac-derived stem-like cells (CTSCs) that exhibit increased functional properties in the neonatal heart (nCTSC). These cells are linked to a unique metabolism which is altered with CTSC aging (aCTSC). Here, we present an in-depth, RNA-sequencing-based (RNA-Seq) bioinformatic with cluster analysis that details a distinct epigenome present in nCTSCs but not in aCTSCs. Gene Ontology (GO) and pathway enrichment reveal biological process...

Circulation Research, 2012

The endoplasmic reticulum (ER) is essential for protein homeostasis, or proteostasis, which gover... more The endoplasmic reticulum (ER) is essential for protein homeostasis, or proteostasis, which governs the balance of the proteome. In addition to secreted and membrane proteins, proteins bound for many other cellular locations are also made on ER-bound ribosomes, emphasizing the importance of protein quality and quantity control in the ER. Unlike cytosolic E3 ubiquitin ligases studied in the heart, synoviolin/Hrd1, which has not been studied in the heart, is an ER transmembrane E3 ubiquitin ligase, which we found to be upregulated upon protein misfolding in cardiac myocytes. Given the strategic location of synoviolin in the ER membrane, we addressed the hypothesis that synoviolin is critical for regulating the balance of the proteome, and accordingly, myocyte size. We showed that in vitro, adenovirus-mediated overexpression of synoviolin decreased cardiac myocyte size and protein synthesis, but unlike atrophy-related ubiquitin ligases, synoviolin did not increase global protein degrad...

International Journal of Molecular Sciences, 2021

Ischemic heart disease can lead to myocardial infarction (MI), a major cause of morbidity and mor... more Ischemic heart disease can lead to myocardial infarction (MI), a major cause of morbidity and mortality worldwide. Multiple stem cell types have been safely transferred into failing human hearts, but the overall clinical cardiovascular benefits have been modest. Therefore, there is a dire need to understand the basic biology of stem cells to enhance therapeutic effects. Bmi1 is part of the polycomb repressive complex 1 (PRC1) that is involved in different processes including proliferation, survival and differentiation of stem cells. We isolated cortical bones stem cells (CBSCs) from bone stroma, and they express significantly high levels of Bmi1 compared to mesenchymal stem cells (MSCs) and cardiac-derived stem cells (CDCs). Using lentiviral transduction, Bmi1 was knocked down in the CBSCs to determine the effect of loss of Bmi1 on proliferation and survival potential with or without Bmi1 in CBSCs. Our data show that with the loss of Bmi1, there is a decrease in CBSC ability to prol...

STEM CELLS Translational Medicine, 2020

Cellular replacement in the heart is restricted to postnatal stages with the adult heart largely ... more Cellular replacement in the heart is restricted to postnatal stages with the adult heart largely postmitotic. Studies show that loss of regenerative properties in cardiac cells seems to coincide with alterations in metabolism during postnatal development and maturation. Nevertheless, whether changes in cellular metabolism are linked to functional alternations in cardiac cells is not well studied. We report here a novel role for uncoupling protein 2 (UCP2) in regulation of functional properties in cardiac tissue derived stem-like cells (CTSCs). CTSC were isolated from C57BL/6 mice aged 2 days (nCTSC), 2 month (CTSC), and 2 years old (aCTSC), subjected to bulk-RNA sequencing that identifies unique transcriptome significantly different between CTSC populations from young and old heart. Moreover, results show that UCP2 is highly expressed in CTSCs from the neonatal heart and is linked to maintenance of glycolysis, proliferation, and survival. With age, UCP2 is reduced shifting energy me...

Cells, 2020

Cell-based therapeutics for cardiac repair have been extensively used during the last decade. Pre... more Cell-based therapeutics for cardiac repair have been extensively used during the last decade. Preclinical studies have demonstrated the effectiveness of adoptively transferred stem cells for enhancement of cardiac function. Nevertheless, several cell-based clinical trials have provided largely underwhelming outcomes. A major limitation is the lack of survival in the harsh cardiac milieu as only less than 1% donated cells survive. Recent efforts have focused on enhancing cell-based therapeutics and understanding the biology of stem cells and their response to environmental changes. Stem cell metabolism has recently emerged as a critical determinant of cellular processes and is uniquely adapted to support proliferation, stemness, and commitment. Metabolic signaling pathways are remarkably sensitive to different environmental signals with a profound effect on cell survival after adoptive transfer. Stem cells mainly generate energy through glycolysis while maintaining low oxidative phos...

Circulation, Nov 25, 2014

Background: Recently we have shown that IL-10, an anti-inflammatory cytokine, markedly inhibited ... more Background: Recently we have shown that IL-10, an anti-inflammatory cytokine, markedly inhibited the pressure overload-induced cardiac fibrosis, however, antifibrotic mechanisms of IL-10 are largely unknown. In most organs, including heart, activated fibroblast play critical role in extracellular matrix remodeling, however, very little information is available regarding the origin of myoFBs. Here we hypothesized that IL-10 inhibits stress-induced proliferation and differentiation of nonresident bone marrow-derived fibroblast progenitor cells and therefore, attenuates cardiac fibrosis and improves of heart function. Methods and Results: Cardiac hypertrophy was induced in Wild-type (WT) and IL-10-knockout (KO) mice by transverse aortic constriction (TAC). TAC-induced left ventricular (LV) dysfunction and fibrosis were further exaggerated in KO mice compared to WT. TAC significantly increased TGF-β, collagen Iα and IIIα genes expression. Systemic recombinant mouse IL-10 administration markedly improved LV function, inhibited TAC-induced cardiac fibrosis and fibrosis associated genes expression. To identify the role of fibroblast progenitor cells (FPCs), we measured the mobilization of FPCs (Prominin1 positive cells) from bone marrow to heart by FACs. Exacerbated mobilization of FPCs in peripheral blood and heart in IL-10 KO mice were found 3 and 7 days after aortic constriction. Bone marrow transplantation experiments were performed where WT-GFP positive marrow was transplanted in BM depleted IL-10 KO mice. TAC-induced mobilization was significantly reduced in WT-transplanted marrow as compare to TAC-IL-10 KO mice. To identify the role IL-10 on TGFβ-induced endothelial cells trans-differentiation to myofibroblasts, we treated aortic endothelial cells with IL-10 and TGFβ2 for 96 hrs. Both Immunocytochemistry and Western blot analysis results suggested that TGF-β2-induced EndMT was significantly inhibited by IL-10 treatment. To understand the mechanisms, we found that TGF-β2-induced Notch1 signaling was reduced by IL-10. Conclusion: Taken together our observations suggest that the anti-fibrotic effects of IL-10 treatment are mediated by reduced proliferation and differentiation of non-resident myofibroblasts.

Int J Pept Res Ther, 2010

Circulation, Nov 26, 2013

Circulation, Nov 20, 2012

Circulation, Nov 25, 2014

Despite some encouraging data, the bone marrow progenitor cells (BMPC) mediated clinical trials h... more Despite some encouraging data, the bone marrow progenitor cells (BMPC) mediated clinical trials have only shown a very modest improvement in heart functions. Poor survival and function of transplanted cell in the ischemic and inflamed myocardium likely compromises the full functional benefit of stem cell based therapies. We have earlier reported that co-administration of IL-10 and BMPC not only enhances cell survival but also improved left ventricular (LV) functions after AMI in mice. We identified that microRNA-375 expression is significantly up-regulated in EPCs upon exposure to either inflammatory or hypoxic stimulus. We hypothesized that IL-10 regulates miR-375 signaling in EPCs to enhance their survival and function in ischemic myocardium after MI. miR-375 knock down EPC were transplanted intramyocardially after induction of MI. Mice receiving EPC treated with miR-375 inhibitor showed increased number of EPC retention that was associated with reduced EPC apoptosis in the myocardium. The engraftment o...

Circulation Research, 2016

Stem cell therapy provides immense hope for regenerating the pathological heart, yet has been mar... more Stem cell therapy provides immense hope for regenerating the pathological heart, yet has been marred by issues surrounding the effectiveness, unclear mechanisms, and survival of the donated cell population in the ischemic myocardial milieu. Poor survival and engraftment coupled to inadequate cardiac commitment of the adoptively transferred stem cells compromises the improvement in cardiac function. Various alternative approaches to enhance the efficacy of stem cell therapies and to overcome issues with cell therapy have been used with varied success. Cell-free components, such as exosomes enriched in proteins, messenger RNAs, and miRs characteristic of parental stem cells, represent a potential approach for treating cardiovascular diseases. Recently, exosomes from different kinds of stem cells have been effectively used to promote cardiac function in the pathological heart. The aim of this review is to summarize current research efforts on stem cell exosomes, including their potenti...

Circulation, Nov 26, 2013