Abstract 308: CTRP9 Regulates the Fate of Implanted Mesenchymal Stem Cells and Mobilizes Their Protective Effects Against Ischemic Heart Injury via Multiple Novel Signaling Pathways

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Wenjun Yan ◽  
Wayne Lau ◽  
Theodore Christopher ◽  
Bernard Lopez ◽  
Erhe Gao ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Death ◽  
Mesenchymal Stem Cells ◽  
Stem Cell ◽  
Cell Survival ◽  
Therapeutic Efficacy ◽  
Apoptotic Cell ◽  
Biological Effects ◽  
Ischemic Heart ◽  
And Migration

Cell therapy remains the most promising approach against ischemic heart failure. However, the poor survival of engrafted stem cells in the ischemic environment limits their therapeutic efficacy for cardiac repair post-MI. CTRP9 is a novel pro-survival cardiokine with significantly downregulated expression after MI. Here, we tested a hypothesis that CTRP9 might be a cardiokine required for a healthy microenvironment promoting stem cell survival and cardioprotection. Mice were subjected to MI and treated with adipose-derived mesenchymal stem cells (ADSCs, intramyocardial transplantation), CTRP9, or their combination. Administration of ADSCs alone failed to exert significant cardioprotection. However, administration of ADSCs in addition to CTRP9 further enhanced the cardioprotective effect of CTRP9 (P<0.05 vs. CTRP9 alone), suggesting a synergistic effect. CTRP9 significantly increased ADSCs survival and migration after implantation. Conversely, the number of engrafted ADSCs was significantly reduced in the CTRP9KO heart. CTRP9 promoted ADSCs proliferation and migration in vitro, and protected ADSCs against hydrogen peroxide-induced cellular death. Discovery-drive approaches followed by cause-effect analysis identified that CTRP9 enhances ADSCs proliferation/migration by ERK1/2-MMP-9 signaling. CTRP9 promotes anti-apoptotic/cell survival via ERK-Nrf2/anti-oxidative protein expression. Mass spectrometry, immunocytochemistry, and immunoprecipitation identified N-cadherin as the novel CTRP9 binding partner on ADSC. N-cadherin knockdown completely abolished the above noted CTRP9 biological effects. Finally, CTRP9 promotes Sod-3 expression and secretion from ADSCs, protecting cardiomyocytes against oxidative stress-induced cell death. We provide the first evidence that CTRP9 promotes ADSCs proliferation/survival, stimulates ADSCs migration, and attenuates cardiomyocyte cell death by previously unrecognized signaling mechanisms (N-cadherin-ERK/MMP-9 and N-cadherin-ERK/Nrf2-SOD). These results suggest that CTRP9 is a cardiokine critical in maintaining a healthy microenvironment facilitating stem cell engraftment in infarcted myocardial tissue, thereby enhancing stem cell therapeutic efficacy.

scholarly journals BDNF-Overexpressing Engineered Mesenchymal Stem Cells Enhances Their Therapeutic Efficacy against Severe Neonatal Hypoxic Ischemic Brain Injury

2021 ◽  
Vol 22 (21) ◽  
pp. 11395
Author(s):  
So Yoon Ahn ◽  
Dong Kyung Sung ◽  
Yun Sil Chang ◽  
Se In Sung ◽  
Young Eun Kim ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Death ◽  
Mesenchymal Stem Cells ◽  
Brain Injury ◽  
Therapeutic Efficacy ◽  
Inflammatory Responses ◽  
Apoptotic Cell ◽  
Glucose Deprivation

We investigated whether irradiated brain-derived neurotropic factor (BDNF)-overexpressing engineered human mesenchymal stem cells (BDNF-eMSCs) improve paracrine efficiency and, thus, the beneficial potency of naïve MSCs against severe hypoxic ischemic (HI) brain injury in newborn rats. Irradiated BDNF-eMSCs hyper-secreted BDNF > 10 fold and were >5 fold more effective than naïve MSCs in attenuating the oxygen-glucose deprivation-induced increase in cytotoxicity, oxidative stress, and cell death in vitro. Only the irradiated BDNF-eMSCs, but not naïve MSCs, showed significant attenuating effects on severe neonatal HI-induced short-term brain injury scores, long-term progress of brain infarct, increased apoptotic cell death, astrogliosis and inflammatory responses, and impaired negative geotaxis and rotarod tests in vivo. Our data, showing better paracrine potency and the resultant better therapeutic efficacy of the irradiated BDNF-eMSCs, compared to naïve MSCs, suggest that MSCs transfected with the BDNF gene might represent a better, new therapeutic strategy against severe neonatal HI brain injury.

scholarly journals Role of Insulin-like Growth Factor 1 Receptor Signaling in Stem Cell Stemness and Therapeutic Efficacy

2018 ◽  
Vol 27 (9) ◽  
pp. 1313-1319 ◽  
Author(s):  
Chiao-Fang Teng ◽  
Long-Bin Jeng ◽  
Woei-Cherng Shyu
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Stem Cell ◽  
Growth Factor ◽  
Therapeutic Efficacy ◽  
Functional Markers ◽  
Insulin Like Growth Factor ◽  
Self Renewal ◽  
Placental Mesenchymal Stem Cells ◽  
Igf1r Signaling

Evidence has emerged that stem cells represent a promising therapeutic tool for tissue engineering and regenerative medicine. Thus, identifying functional markers for selecting stem cells capable of superior self-renewal and pluripotency (or multipotency) and maintaining stem cell identity under appropriate culture conditions are critical for guiding the use of stem cells toward clinical applications. Many investigations have implicated the insulin-like growth factor 1 receptor (IGF1R) signaling in maintenance of stem cell characteristics and enhancement of stem cell therapy efficacy. IGF1R-expressing stem cells display robust pluripotent or multipotent properties. In this review, we summarize the essential roles of IGF1R signaling in self-renewal, pluripotency (or multipotency), and therapeutic efficacy of stem cells, including human embryonic stem cells, neural stem cells, cardiac stem cells, bone marrow mesenchymal stem cells, placental mesenchymal stem cells, and dental pulp mesenchymal stem cells. Modifying IGF1R signaling may thus provide potential strategies for maintaining stem cell properties and improving stem-cell-based therapeutic applications.

Genetic Modification of Human Mesenchymal Stem Cells Enables Contribution to the Cardiac Progenitor Pool and Developing Myocardium In Vivo.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3730-3730
Author(s):  
Evan J Colletti ◽  
Melisa Soland ◽  
Stephen St. Jeor ◽  
Esmail D Zanjani ◽  
Christopher D Porada ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Death ◽  
Mesenchymal Stem Cells ◽  
Stem Cell ◽  
Nk Cells ◽  
Myocardial Damage ◽  
Cardiac Stem Cell ◽  
Cell Pool ◽  
Npt Ii ◽  
Stem Cell Pool

Abstract Abstract 3730 Although a great deal of attention has been focused on developing cell based therapies for cardiac repair, only limited success has been achieved to date. Controversy still remains as to which specific type of cells should be transplanted and what role they play in the repair of damaged areas. Human autologous mesenchymal stem cells (MSC) are currently being used in clinical trials, and early results show improvement in the overall cardiac function. This improvement is mediated by inhibition of inflammatory signaling, fibroblast recruitment, and scar tissue development; however, little to none of the transplanted cells contribute to the working myocardium. It is likely that the extensive rate of cell death observed within cells efficiently delivered to the heart constitutes a key event precluding success of cell-based myocardial repair. Cytotoxic T lymphocytes (CTL), important mediators of allograft rejection, have also been implicated in immune responses against cardiac self-antigens subsequent to myocardial damage after myocardial infarction. Likewise, Natural Killer (NK) cells play an important role in targeting and destroying allogeneic and autologous cells undergoing distress. Therefore, it is possible that, in the event of myocardial damage, CTL and NK cells present at the site of injury contribute significantly to the death of the cells delivered for myocardial rescue, reducing their therapeutic effectiveness. We have shown that MSC transduced with a viral vector encoding the human cytomegalovirus unique short region 6, (hMSC-US6), are less susceptible to both NK killing and induction of CTL proliferation when compared to untransduced MSC, and to MSC transduced with a vector encoding only NPT-II (MSC-E). Therefore, in these studies we compared the ability of hMSC-US6 and hMSC-E to give rise to cardiac cells upon transplantation in a xenogeneic sheep fetal model. 5.6×104 of each cell population was transplanted into fetal sheep at 60 days of gestation (n=4). Two months after transplant, heart tissues were collected and the contribution of transplanted MSC to the fetal hearts was evaluated by confocal microscopy and NPT-II immunofluorescence. Examination of hearts from animals transplanted with MSC-US6 showed that engrafted cells contributed not only to the myocardium, as demonstrated by co-localization of NPT-II and Troponin-I (TNI), but were also able to contribute to the cardiac stem cell pool, as evidenced by co-localization of NPT-II and c-kit positivity. In the myocardium, MSC-US6 contributed to 2.6% of total TNI+ cardiomyocytes (53.9% of all cells in the heart are TNI+ at this stage of fetal gestation). Furthermore, at this stage in development, the c-kit+ cardiac progenitor pool constitutes 12.7% of the total cells in the heart, with the majority of the c-kit population localizing perivascularly. Upon examination, 4.5% of these c-kit+ cells were also NPT-II+, demonstrating the contribution of MSC-US6 to the heart stem cell pool. By contrast, the heart of animals that received MSC-E did not contain NPT-II+/TNI+ cardiomyocytes or NPT-II+/c-kit+ cardiac stem cells; the transplanted cells only contributed to the Purkinje fiber system in the heart. Although the transplantation model used is a non-injury model, MSC are still able to elicit an immune response in this non-autologous setting, activating CTL and NK cells already present in the recipient at the time of transplant. In conclusion, our results show that expression of US-6 protein allows transplanted human MSC to evade existing CTL- and NK-mediated immunity and contribute to the myocardial tissue through integration into the cardiac stem cell pool in the chimeric fetal heart. Therefore, engineering MSC to evade resident immune cells may decrease post-infusion cell death and allow these cells to contribute directly to the repair/regeneration of the injured myocardium. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Vitrification of Dog Skin Tissue as a Source of Mesenchymal Stem Cells

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Young-Bum Son ◽  
Yeon Ik Jeong ◽  
Sang-Yun Lee ◽  
Yeon Woo Jeong ◽  
Ki-June Lee ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Stem Cell ◽  
Mitochondrial Membrane ◽  
Apoptotic Cell ◽  
Pcr Analysis ◽  
Stem Cell Markers ◽  
Proliferation And Apoptosis ◽  
Conservation Of Genetic Resources ◽  
Histological Appearance

The purpose of this study was to develop an efficient vitrification system for cryopreservation of dog skin tissues as a source of stable autologous stem cells. In this study, we performed vitrification using four different cryoprotectants, namely, ethylene glycol (EG), dimethyl-sulfoxide (Me2SO), EG plus Me2SO, and EG plus Me2SO plus sucrose, and analyzed the behaviors of cells established from warmed tissues. Tissues vitrified with 15% EG, 15% Me2SO, and 0.5 M sucrose had a normal histological appearance and the highest cell viability after cell isolation, and thus, this cocktail of cryoprotectants was used in subsequent experiments. We evaluated proliferation and apoptosis of cells derived from fresh and vitrified tissues. These cells had a normal spindle-like morphology after homogenization through subculture. Dog dermal skin stem cells (dDSSCs) derived from fresh and vitrified tissues had similar proliferation capacities, and similar percentages of these cells were positive for mesenchymal stem cell markers at passage 3. The percentage of apoptotic cell did not differ between dDSSCs derived from fresh and vitrified tissues. Real-time PCR analysis revealed that dDSSCs at passage 3 derived from fresh and vitrified tissues had similar expression levels of pluripotency (OCT4, SOX2, and NANOG), proapoptotic (BAX), and antiapoptotic (BCL2 and BIRC5) genes. Both types of dDSSCs successfully differentiated into the mesenchymal lineage (adipocytes and osteocytes) under specific conditions, and their differentiation potentials did not significantly differ. Furthermore, the mitochondrial membrane potential of dDSSCs derived from vitrified tissues was comparable with that of dDSSCs derived from fresh tissues. We conclude that vitrification of dog skin tissues using cocktail solution in combination of 15% EG, 15% Me2SO, and 0.5 M sucrose allows efficient banking of these tissues for regenerative stem cell therapy and conservation of genetic resources.

Sign in / Sign up

Export Citation Format

Share Document