An American Heart Association fellowship will allow a Binghamton graduate student to further her research in developing 3D heart models. Natalie Weiss is interested in the pharmaceutical implications for treating cardiac fibrosis, an abnormal thickening and scarring of heart tissue that is common with many types of heart diseases and conditions.

The AHA is such a big and well-respected organization, so it is a nice validation to see that they value my research and ideas, said Weiss, a biomedical engineering doctoral student from the Thomas J. Watson College of Engineering and Applied Science who received a competitive two-year pre-doctoral fellowship.

Weiss conducts her work in the lab of Tracy Hookway, assistant professor of biomedical engineering. The team uses cell culture, 3D modeling of stem cells and live imaging of tissue for regenerative medicine therapy.

Natalie has been a huge asset to my lab, Hookway said. Shes incredibly intelligent and very ambitious, and shes not afraid to ask questions.

Weiss research involves creating working models of human hearts and then testing various drugs and therapies with the goal of resolving or improving cardiac fibrosis. She uses stem cells derived from human skin to make heart muscle cells and then combines them with proteins, sugars and a gel polymer, which is then piped into a 3mm donut ring mold (of sorts). The process takes about a week and a half, but once the cells are added to the mold, the ring forms overnight into a simplified, beating human heart model.

By testing on these models, it saves time, money and testing on animals, Weiss said, adding that she often has 40 rings going at a time. What Im hoping to do, once the models are a little more advanced, is replicate the stiffness of cardiac fibrosis in the model and then test a couple of drugs and see if it responds in a positive way.

As a high school student in East Meadow, Long Island, Weiss knew she was interested in the medical field. She volunteered in an emergency room and got her EMT certification.

Ive also always loved problem solving taking things apart and figuring out how they worked, she said. I wasnt aware I could put those two interests together until a biomedical engineering major kept popping up again and again as I was researching college programs.

She received her undergraduate degree in biomedical engineering at Stony Brook University in 2019, and then started her graduate career at Binghamton that fall. She selected the program because she was impressed with Hookway, who would become her advisor.

I wanted someone who I can connect with, Weiss said. Dr. Hookway really seemed like someone who would advocate for her students, so I knew she was going to care about my progress and help me out.

Once Weiss completes her doctorate, she hopes to complete a post-doctoral fellowship and then become a professor and run her own research lab.

This article was originally published in Discover-e.

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Heart Association fellowship to support research - Binghamton

Cardiac Stem Cells Comments Off on Heart Association fellowship to support research – Binghamton | August 26th, 2022

The therapeutic efficacy of intravenous hiPSC-MSCs infusion without intramuscular cellular transplantation

First, we determined whether hiPSC-MSCs could migrate into the ischemic limb after a single intravenous cellular infusion. Our results showed that most of the hiPSC-MSCs engrafted into the liver 12h after infusion (Supplementary Fig.1). The engrafted hiPSC-MSCs gradually migrated into the ischemic limb at day 3 and disappeared at day 14 (Supplementary Fig.1). A few cells engrafted in the ischemic limb, the engraftment rate was extremely low, evidenced by the DiR signal that was 9.8106 at day 7 after a single intravenous administration of 5105 hiPSC-MSCs versus 1.4109 7 days after a single intramuscular injection.

To compare intravenous cellular administration and intramuscular cellular delivery, three groups of mice that received intravenous hiPSC-MSC infusion once, every week or every 3 days without intramuscular administration of hiPSC-MSCs respectively and one group that received intramuscular hiPSC-MSC delivery only were employed (Fig.1a). Intravenous administration of hiPSC-MSCs once, every week or every 3 days without intramuscular administration of hiPSC-MSCs in the Saline-MSC/once, Saline-MSC/week and Saline-MSC/3 days groups significantly improved blood perfusion from day 7 onwards compared with the ischemia group (Fig.1b, all p<0.05). Repeated intravenous administration of hiPSC-MSCs in the Saline-MSC/week and Saline-MSC/3 days groups further increased blood perfusion at day 35 compared with the Saline-MSC/once group (Fig.1b, all p<0.05), although there was no difference between the first two groups (Fig.1b, p>0.05). Nevertheless intramuscular administration of hiPSC-MSCs in the MSC-Saline group achieved a better beneficial effect than intravenous administration of hiPSC-MSCs in the Saline-MSC/once, Saline-MSC/week and Saline-MSC/3 days groups from day 21 onwards (Fig.1b, all p<0.05).

To evaluate blood perfusion in the groups that received intravenous hiPSC-MSCs infusion without intramuscular hiPSC-MSCs transplantation, Laser Doppler imaging analysis was performed immediately and every week following femoral artery ligation (a). A single or repeated intravenous administration of hiPSC-MSCs in the Saline-MSC/once, Saline-MSC/week or Saline-MSC/3 days groups significantly increased blood perfusion from day 7 onwards compared with the ischemia group. Moreover, repeated intravenous hiPSC-MSCs infusion further improved blood perfusion at day 35. Nonetheless intramuscular hiPSC-MSC transplantation in the MSC-Saline group showed a superior beneficial effect over repeated intravenous hiPSC-MSC infusion in the Saline-MSC/week and Saline-MSC/3 days groups (b).

Taken together, our results demonstrated that systemic intravenous administration of hiPSC-MSCs without intramuscular administration of hiPSC-MSCs improved blood perfusion. Repeated intravenous administration of hiPSC-MSCs every week or every 3 days without intramuscular administration of hiPSC-MSCs further increased blood perfusion compared with a single intravenous injection, although there was no significant difference between intravenous administration repeated every week versus every 3 days. Nonetheless intramuscular administration of hiPSC-MSCs achieved a better beneficial effect than intravenous administration of hiPSC-MSCs once, every week or every 3 days.

Five groups of ICR mice were employed in the main experiment (Fig.2): (1) ischemia group receiving intravenous administration of saline immediately after induction of ischemia and intramuscular administration of culture medium at day 7; (2) MSC-Saline group receiving intravenous administration of saline immediately after induction of ischemia and intramuscular administration of 3106 hiPSC-MSCs at day 7; (3) MSC-MSC/once group receiving intravenous administration of 5105 hiPSC-MSCs immediately after induction of ischemia and intramuscular administration of 3106 hiPSC-MSCs at day 7; (4) MSC-MSC/week group receiving repeated intravenous administration of 5105 hiPSC-MSCs immediately and every week following induction of ischemia for 4 weeks and intramuscular administration of 3106 hiPSC-MSCs at day 7; (5) MSC-MSC/3 days group receiving repeated intravenous administration of 5105 hiPSC-MSCs immediately and every 3 days following induction of ischemia for 4 weeks and intramuscular administration of 3106 hiPSC-MSCs at day 7.

There are five groups of ICR mice in main experiment: ischemia group, MSC-Saline group, MSC-MSC/once group, MSC-MSC/week group, MSC-MSC/3 days group.

Serial laser doppler imaging and analysis was performed to evaluate the blood perfusion and monitor the blood flow recovery in the ischemic hind limb (Fig.3a). After induction of ischemia, blood perfusion of the ligated limb significantly decreased to an extremely low level relative to the non-ligated limb in the ischemia group (2.980.56), MSC-Saline group (2.960.30), MSC-MSC/once group (2.950.48), MSC-MSC/week group (3.010.29) and MSC-MSC/3 days group (2.970.30). There was no significant difference between the five groups (Fig.3b, all p>0.05). These results confirmed that acute hind-limb ischemia was induced in all groups. Intramuscular administration of hiPSC-MSCs with intravenous administration of saline or with intravenous administration of hiPSC-MSCs once or every week or every 3 days in the MSC-Saline, MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups resulted in a significant and progressive improvement in the blood perfusion of the ligated limb from day 14 onwards compared with the ischemia group (Fig.3b, all p<0.05). Intravenous administration of hiPSC-MSCs significantly increased blood perfusion in the MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups from day 7 onwards compared with the ischemia and MSC-Saline groups (Fig.3b, all p<0.05). Repeated intravenous administration of hiPSC-MSCs in the MSC-MSC/week and MSC-MSC/3 days groups further increased blood perfusion from day 28 onwards compared with the MSC-MSC/once group (Fig.3b, all p<0.05). Nevertheless there was no significant difference between mice that received repeated intravenous administration of hiPSC-MSCs in the MSC-MSC/week versus MSC-MSC/3 days groups throughout the study period. On day 35, blood perfusion of the ligated hind limb in the ischemia, MSC-Saline, MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups were 30.570.81, 40.560.84, 44.990.75, 50.410.68 and 51.120.86 respectively.

Laser Doppler imaging analysis was performed immediately and every week following femoral artery ligation to evaluate blood perfusion in the ischemic hind limbs (a). After intramuscular transplantation of hiPSC-MSCs, blood perfusion was significantly improved in the MSC-Saline, MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups compared with the ischemia group from day 14 onwards (all p<0.05). A single and repeated intravenous hiPSC-MSC infusion further improved blood perfusion in the MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups compared with MSC-Saline group (all p<0.05). Moreover, the blood perfusion was significantly higher in the MSC-MSC/week and MSC-MSC/3 days groups compared with the MSC-MSC/once group (all p<0.05). There was no significant difference between the MSC-MSC/week and MSC-MSC/3 days groups (p>0.05) (b).

Taken together, our results showed that systemic intravenous administration of hiPSC-MSCs combined with intramuscular transplantation of hiPSC-MSCs improved blood perfusion in a mouse model of hind-limb ischemia relative to intramuscular hiPSC-MSC transplantation without systemic hiPSC-MSC delivery. In addition, repeated intravenous administration of hiPSC-MSCs every week or every 3 days further improved the therapeutic effects of hiPSC-MSC-based therapy compared with a single intravenous injection. No significant difference was observed between repeated intravenous administration of hiPSC-MSCs every week and every 3 days.

To evaluate neovascularization in the ischemic limb, immunohistochemical staining with anti-mouse alpha-smooth muscle antigen (-SMA) and anti-mouse von Willebrand factor (vWF) antibodies were performed to assess arteriogenesis and angiogenesis following cellular transplantation respectively (Fig.4a). On day 14, intramuscular transplantation of hiPSC-MSCs in the MSC-Saline group did not increase arteriogenesis and capillary formation (Fig.4b,c, p>0.05). Nevertheless, systemic intravenous administration of hiPSC-MSCs in the MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups significantly improved arteriogenesis and capillary formation compared with the ischemia group (Fig.4b,c, all p<0.05). On day 35, compared with the ischemia group, intramuscular transplantation of hiPSC-MSCs in the MSC-Saline, MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups significantly increased neovascularization (Fig.4b,c, all p<0.05). Moreover, systemic intravenous administration of hiPSC-MSCs in the MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups further improved neovascularization compared with the MSC-Saline group on day 35 (Fig.4b,c, p<0.05). In addition, repeated intravenous administration of hiPSC-MSCs in the MSC-MSC/week and MSC-MSC/3 days groups further promoted neovascularization compared with the MSC-MSC/once group (Fig.4b,c, all p<0.05). There was no difference in neovascularization between the MSC-MSC/week and MSC-MSC/3 days groups (Fig.4b,c, all p>0.05).

Immunohistochemical staining with anti-mouse vWF (green) and anti-mouse -SMA (red) antibodies was performed to assess angiogenesis and arteriogenesis in ischemic tissues. Massons trichrome staining was performed to evaluate the degree of fibrosis (a). On day 14, neovascularization was markedly increased in the MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups, not in the MSC-Saline group, relative to the ischemia group. On day 35, after intramuscular transplantation of hiPSC-MSCs, neovascularization was significantly improved in the MSC-Saline, MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups compared with the ischemia group (all p<0.05). Intravenous administration of hiPSC-MSCs in the MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups enhanced the therapeutic effects of intramuscularly transplanted hiPSC-MSCs on neovascularization compared with the MSC-Saline group (all p<0.05). Moreover, neovascularization was further enhanced by repeated intravenous hiPSC-MSC infusion in the MSC-MSC/week and MSC-MSC/3 days groups compared with the MSC-MSC/once group (b, c). On day 14, fibrosis was remarkably decreased in the MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups, not in the MSC-Saline group, relative to the ischemia group. On day 35, after intramuscular transplantation of hiPSC-MSCs, fibrosis was significantly reduced in the MSC-Saline, MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups compared with the ischemia group (all p<0.05). Intravenous administration of hiPSC-MSCs in the MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups enhanced the therapeutic effects of intramuscularly transplanted hiPSC-MSCs on reduction of fibrosis compared with the MSC-Saline group (all p<0.05). Moreover, the anti-fibrotic effect was further enhanced by repeated intravenous hiPSC-MSC infusion in the MSC-MSC/week and MSC-MSC/3 days groups compared with the MSC-MSC/once group (d).

To assess the degree of fibrosis in the ischemic limb, Massons Trichrome staining were performed to determine the percentage of fibrotic tissue in the ischemic limb (Fig.4a). On day 14, intramuscular transplantation of hiPSC-MSCs in the MSC-Saline group did not decrease fibrosis (Fig.4d, p>0.05). Nevertheless, systemic intravenous administration of hiPSC-MSCs in the MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups significantly reduced fibrosis compared with the ischemia group (Fig.4d, all p<0.05). Compared with the ischemia group, intramuscular transplantation of hiPSC-MSCs in the MSC-Saline, MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups significantly ameliorated fibrosis on day 35 (Fig.4d, all p<0.05). Moreover, systemic intravenous administration of hiPSC-MSCs in the MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups significantly reduced fibrosis compared with the MSC-Saline group (Fig.4d, all p<0.05). In addition, repeated intravenous administration of hiPSC-MSCs in the MSC-MSC/week and MSC-MSC/3 days groups further decreased fibrosis compared with the MSC-MSC/once group (Fig.4d, all p<0.05). There were no differences in fibrosis between the MSC-MSC/week and MSC-MSC/3 days groups (Fig.4d, all p>0.05).

Taken together, our results showed that systemic intravenous administration of hiPSC-MSCs combined with intramuscular transplantation of hiPSC-MSCs promoted neovascularization and reduced fibrosis in a mouse model of hind-limb ischemia. Repeated intravenous administration of hiPSC-MSCs every week or every 3 days further increased the neovascularization and decreased the fibrosis following cellular transplantation compared with a single intravenous injection. No significant difference was observed between repeated intravenous administration of hiPSC-MSCs every week and every 3 days.

Fluorescent imaging of ischemic hind limbs was performed immediately and every week after induction of ischemia to access the cellular engraftment and survival of intramuscularly transplanted hiPSC-MSCs (Fig.5a). To avoid any confusion on the fluorescent signal, intravenous administered hiPSC-MSCs were not labeled with DiR. There was no significant difference in fluorescent signal intensity over the ischemic hind limb after intramuscular cellular transplantation (Fig.5b, all p>0.05). Systemic intravenous administration of hiPSC-MSCs significantly increased cellular engraftment and survival in the MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups from day 14 onwards relative to the MSC-Saline group (Fig.5b, all p<0.05). Moreover, repeated intravenous administration of hiPSC-MSCs in the MSC-MSC/week and MSC-MSC/3 days groups further improved cellular engraftment and survival from day 21 onwards compared with the MSC-MSC/once group (Fig.5b, all p<0.05). There was no significant difference between mice that received repeated intravenous administration of hiPSC-MSCs in the MSC/week and MSC-MSC/3 days groups throughout the study period. On day 35, the estimated survival rates in MSC-Saline, MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups decreased to 2.590.31%, 8.330.54%, 13.560.49% and 14.230.42%, respectively (Supplementary Fig.2 and Supplementary Data1).

A series of fluorescent images of ischemic hind limbs was performed immediately and every week following intramuscular transplantation of hiPSC-MSCs to detect the fate of intramuscularly transplanted hiPSC-MSCs (a). A single or repeated intravenous hiPSC-MSCs infusion in the MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups significantly prolonged the survival of intramuscular transplanted hiPSC-MSCs from day 14 onwards compared with the MSC-Saline group (all p<0.05). Moreover, repeated intravenous hiPSC-MSCs infusion in the MSC-MSC/week and MSC-MSC/3 days groups further improved the survival of intramuscularly transplanted hiPSC-MSCs from day 21 onwards compared with the MSC-MSC/once group (all p<0.05), whereas no significant difference was observed between MSC-MSC/week and MSC-MSC/3 days groups (p>0.05) (b).

Cellular engraftment and survival of intramuscularly transplanted hiPSC-MSCs were further confirmed by immunohistochemical double staining with anti-human GAPDH and anti-human mitochondria antibodies (Fig.6a). Systemic intravenous administration of hiPSC-MSCs significantly increased human GAPDH and human mitochondria positive cells over the ischemic hind limb in the MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups from day 14 onwards relative to the MSC-Saline group (Fig.6b, all p<0.05). Moreover, on day 35, repeated intravenous administration of hiPSC-MSCs in the MSC-MSC/week and MSC-MSC/3 days groups further increased the human GAPDH and human mitochondria positive cells compared with the MSC-MSC/once group (Fig.6b, all p<0.05). No difference between the MSC-MSC/week and MSC-MSC/3 days groups was noted (Fig.6b, all p>0.05).

The engraftment of intramuscularly transplanted hiPSC-MSCs was further confirmed by double immunohistochemical staining with anti-human GAPDH (green) and anti-human mitochondria antibodies (red) at day 14 and 35 (a). A single or repeated intravenous hiPSC-MSC infusion in the MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups significantly improved the engraftment of intramuscularly transplanted hiPSC-MSCs from day 14 onwards (all p<0.05). Repeated intravenous hiPSC-MSC infusion in the MSC-MSC/week and MSC-MSC/3 days groups further improved the engraftment of intramuscular transplanted hiPSC-MSCs at day 35 compared with the MSC-MSC/once group (all p<0.05), whereas no significant difference was observed between the MSC-MSC/week and MSC-MSC/3 days groups (p>0.05) (b).

Taken together, our results demonstrated that systemic intravenous administration of hiPSC-MSCs enhanced engraftment and survival of intramuscularly transplanted hiPSC-MSCs. In addition, repeated intravenous administration every week or every 3 days further increased the cellular engraftment and survival compared with a single intravenous injection. No significant difference was observed between repeated intravenous administration of hiPSC-MSCs every week versus every 3 days.

Immunohistochemical staining with anti-mouse CD68 antibody was performed to calculate the number of macrophages after cellular transplantation and evaluate the infiltration of macrophages (Fig.7a). M2 macrophages were further characterized by immunohistochemical staining with anti-mouse Arginase-1 antibody (Fig.7a). Although there was no significant difference between any of the five groups at day 7 and 14 after induction of ischemia (Fig.7b, all p>0.05), intramuscular administration of hiPSC-MSCs in the MSC-Saline, MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups significantly increased M2 macrophage polarization in the ligated limb from day 14 onwards relative to the ischemia group (Fig.7c, all p<0.05). Moreover, intravenous administration of hiPSC-MSCs remarkedly promoted M2 macrophage polarization in the MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups from day 7 onwards compared with the ischemia and MSC-Saline groups (Fig.7c, all p<0.05). On day 35, intramuscular administration of hiPSC-MSCs in MSC-Saline group had significantly decreased the infiltration of macrophages although the M2 macrophage percentage was similar to that in the ischemia group (Fig.7b,c, all p<0.05). Systemic intravenous administration of hiPSC-MSCs in the MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups significantly decreased macrophage infiltration and increased M2 macrophage polarization relative to the MSC-Saline group (Fig.7b,c, all p<0.05). Repeated intravenous administration of hiPSC-MSCs in the MSC-MSC/week and MSC-MSC/3 days groups further reduced the infiltration of macrophages and increased the polarization of M2 macrophages compared with the MSC-MSC/once group (Fig.7b,c, all p<0.05). There was no noticeable difference in either the infiltration of macrophages or polarization of M2 macrophages between the MSC-MSC/week and MSC-MSC/3 days groups (Fig.7b,c, all p>0.05).

Muscular infiltration of macrophages was determined by immunohistochemical staining with anti-mouse CD68 antibody (green) at day 7, 14, and 35. Number of M2 macrophages was detected by immunohistochemical staining with anti-mouse Arginase-1 antibodies (red) (a). At day 35, after intramuscular transplantation of hiPSC-MSCs, total macrophages were significantly decreased in the MSC-Saline, MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups compared with the ischemia group (all p<0.05). A single or repeated intravenous hiPSC-MSCs infusion in the MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups significantly decreased the muscular infiltration of macrophages compared with the MSC-Saline group (all p<0.05). In addition, repeated intravenous hiPSC-MSCs infusion in the MSC-MSC/week and MSC-MSC/3 days groups further decreased the muscular infiltration of macrophages compared with the MSC-MSC/once group (all p<0.05). Nevertheless no significant difference was observed between groups at day 7 and 14 (all p>0.05) (b). Intramuscular transplantation of hiPSC-MSCs without intravenous hiPSC-MSC infusion significantly increased the polarization of M2 macrophages at day 14 compared with the ischemia group (p<0.05). A single or repeated intravenous hiPSC-MSC infusion in the MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups significantly improved the polarization of M2 macrophages from day 7 onwards (all p<0.05). Repeated hiPSC-MSCs infusion further promoted the polarization of M2 macrophages compared with a single intravenous hiPSC-MSCs infusion in the MSC-MSC/once group at day 35 (all p<0.05) (c).

Taken together, our results demonstrated that systemic intravenous administration of hiPSC-MSCs decreased the infiltration of macrophages and increased the polarization of M2 macrophages. Repeated intravenous administration of hiPSC-MSCs every week or every 3 days further decreased the infiltration of macrophages and increased the polarization of M2 macrophages compared with a single intravenous injection, whereas no significant difference was observed between repeated intravenous administration of hiPSC-MSCs every week and every 3 days.

The limb tissue level of a specific subset-related cytokines was measured using a commercial mouse inflammatory factor array. For anti-inflammatory cytokines, on day 14, there was no significant difference on interleukin (IL)10 and vascular endothelial growth factor (VEGF) among the ischemia, MSC-Saline and MSC-MSC/once groups (Supplementary Fig.3a,b, all p>0.05). Nonetheless, repeated systemic intravenous hiPSC-MSC infusion in the MSC-MSC/week and MSC-MSC/3 days groups significantly increased IL-10 and VEGF compared with the ischemia group (Supplementary Fig.3a,b, all p<0.05). Moreover, an increase of IL-10 was observed in the MSC-MSC/week and MSC-MSC/3 days groups relative to the MSC-Saline group (Supplementary Fig.3a,b, all p<0.05). On day 35, intramuscular transplantation of hiPSC-MSCs in the MSC-Saline group did not significantly improved IL-10 relative to ischemia group. Nevertheless, systemic intravenous hiPSC-MSC infusion in the MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups significantly improved IL-10 compared with the ischemia group (Supplementary Fig.3a, all p<0.05). Moreover, repeated systemic intravenous hiPSC-MSC infusion in the MSC-MSC/week and MSC-MSC/3 days groups further increased IL-10 compared with the MSC-MSC/once group (Supplementary Fig.3a, all p<0.05). No significant difference on VEGF was observed among all five groups on day 35 (Supplementary Fig.3b, all p<0.05).

For inflammatory cytokines, on day 14, intramuscular transplantation of hiPSC-MSCs in the MSC-Saline, MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups significantly decreased IL-1A and IL-17A compared with the ischemia group (Supplementary Fig.3c,d, all p<0.05). Nonetheless, there was no significant difference among the MSC-Saline, MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups (Supplementary Fig.3c,d, all p>0.05). There was no significant difference on IL-2 and macrophage colony-stimulating factor (MCSF) among the ischemia, MSC-Saline and MSC-MSC/once groups (Supplementary Fig.3e,f, all p>0.05). Nonetheless, repeated systemic intravenous hiPSC-MSC infusion in the MSC-MSC/week and MSC-MSC/3 days groups significantly decreased IL-2 and MCSF compared with the ischemia group (Supplementary Fig.3e,f, all p<0.05). On day 35, intramuscular transplantation of hiPSC-MSCs in the MSC-Saline, MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups significantly reduced IL-17A relative to ischemia group (Supplementary Fig.3d, all p<0.05). Moreover, repeated systemic intravenous hiPSC-MSC infusion in the MSC-MSC/week and MSC-MSC/3 days groups further decreased IL-17A compared with the MSC-Saline and MSC-MSC/once groups respectively (Supplementary Fig.3d, all p<0.05). No significant difference on IL-1A, IL-2 and MCSF was observed among all five groups on day 35 (Supplementary Fig.3c,e,f, all p>0.05).

Taken together, our results demonstrated that systemic intravenous administration of hiPSC-MSCs could improve anti-inflammatory cytokines and decreased inflammatory cytokines. Repeated intravenous administration of hiPSC-MSCs every week or every 3 days further improved anti-inflammatory cytokines and decreased inflammatory cytokines compared with a single intravenous injection. No significant difference was observed between repeated intravenous administration of hiPSC-MSCs every week and every 3 days.

Flow cytometry analysis of fresh splenocytes was performed to assess splenic Tregs and natural killer (NK) cells populations and so determine the in vivo immunomodulatory effect of systemic administration of hiPSC-MSCs (Fig.8a). Splenic NK cells were defined as both a CD49b-FITC and NK1.1-APC positive cell population. Our result showed that splenic NK cells progressively decreased following intramuscular hiPSC-MSC transplantation or intravenous hiPSC-MSC infusion in the MSC-Saline, MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups, whereas no significant difference was noted between different time points in the ischemia group (Supplementary Fig.4a). Compared with the ischemia group, intramuscular administration of hiPSC-MSCs in the MSC-Saline, MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups significantly decreased splenic NK cells from day 14 onwards (Fig.8b, all p<0.05). Systemic intravenous hiPSC-MSC infusion in the MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups significantly reduced splenic NK cells from day 7 onwards relative to the ischemia and MSC-Saline groups (Fig.8b, all p<0.05). Repeated systemic intravenous hiPSC-MSC infusion in the MSC-MSC/week and MSC-MSC/3 days groups further reduced splenic NK cells from day 14 onwards compared with the MSC-MSC/once group (Fig.8b, all p<0.05). Nonetheless no significant difference was observed between the MSC-MSC/week and MSC-MSC/3 days groups (Fig.8b, all p>0.05).

Splenic Tregs and NK cells were determined by flow cytometry analysis at day 7, 14 and 35 (a). After intramuscular transplantation of hiPSC-MSCs, splenic NK cells were significantly decreased in the MSC-Saline, MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups from day 14 onwards compared with the ischemia group (all p<0.05). A single or repeated intravenous hiPSC-MSC infusion in the MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups significantly decreased splenic NK cells from day 7 onwards compared with the ischemia and MSC-Saline groups (all p<0.05). Repeated intravenous hiPSC-MSC infusion in the MSC-MSC/week and MSC-MSC/3 days groups further decreased splenic NK cells from day 14 onwards compared with the MSC-MSC/once group (all p<0.05) (b). After intramuscular transplantation of hiPSC-MSCs, splenic Tregs were significantly increased in the MSC-Saline, MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups at day 35 compared with the ischemia group (all p<0.05). A single or repeated intravenous hiPSC-MSC infusion in the MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups significantly increased splenic Tregs compared with the ischemia and MSC-Saline groups (all p<0.05). Moreover, repeated intravenous hiPSC-MSC infusion in the MSC-MSC/week and MSC-MSC/3 days groups further increased splenic Tregs from day 14 onwards compared with the MSC-MSC/once group (all p<0.05) (c).

Splenic Tregs were determined as Foxp3 positive cells in a proportion of pre-gated CD4 positive cells. Our result showed that splenic Tregs reached a peak on day 7 in the MSC-MSC/once group, whereas these immunomodulatory cells continued to increase in the MSC-MSC/week and MSC-MSC/3 days groups. No significant difference was observed between different time points in the ischemia and MSC-Saline groups (Supplementary Fig.4b). Compared with the ischemia group, intramuscular administration of hiPSC-MSCs in the MSC-Saline, MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups significantly increased splenic Tregs on day 35 (Fig.8c, all p<0.05). Intravenous hiPSC-MSC infusion in the MSC-MSC/once, MSC-MSC/week and MSC-MSC/3 days groups significantly improved splenic Tregs from day 7 onwards compared with the ischemia and MSC-Saline groups (Fig.8c, all p<0.05). Repeated systemic intravenous hiPSC-MSCs infusion in the MSC-MSC/week and MSC-MSC/3 days groups further increased splenic Tregs from day 14 onwards compared with the MSC-MSC/once group (Fig.8c, all p<0.05), but there was no significant difference between the MSC-MSC/week and MSC-MSC/3 days groups (Fig.8c, all p>0.05).

Taken together, our results demonstrated that systemic intravenous administration of hiPSC-MSCs could modulate systemic immune cell activation by decreasing splenic NK cells as well as increasing splenic Tregs. Repeated intravenous administration of hiPSC-MSCs every week or every 3 days further decreased splenic NKs and increased splenic Tregs compared with a single intravenous injection. No significant difference was observed between repeated intravenous administration of hiPSC-MSCs every week and every 3 days.

To compare the survival and engraftment of intramuscularly transplanted hiPSC-MSCs with intervenous infusion of hiPSC-MSCs and subcutaneous administration of cyclosporine A, fluorescent imaging of ischemic hind limb was performed immediately and every week in the MSC-Saline-Cyc, MSC-MSC/once-Cyc and MSC-MSC/week-Cyc groups (Supplementary Fig.5a). There was no significant difference in cellular engraftment between the MSC-MSC/once and MSC-Saline-Cyc groups through this study (Supplementary Fig.5b, p>0.05). Although repeated intravenous infusion of hiPSC-MSCs without subcutaneous administration of cyclosporine A remarkedly increased cell engraftment in the MSC-MSC/week group relative to the MSC-MSC/once group (Supplementary Fig.5b, p<0.05), no significant difference was observed after subcutaneous administration of cyclosporine A between the MSC-MSC/week-Cyc and MSC-MSC/once-Cyc groups (Supplementary Fig.5b, p>0.05). Nonetheless, subcutaneous administration of cyclosporine A did not improve the cell engraftment in the MSC-MSC/once-Cyc and MSC-MSC/week-Cyc groups relative to the MSC-MSC/once and MSC-MSC/week groups respectively (Supplementary Fig.5b, p>0.05).

To compare the therapeutic efficacy of intramuscularly transplanted hiPSC-MSCs with intervenous infusion of hiPSC-MSCs and subcutaneous administration of cyclosporine A, serial laser doppler imaging and analysis was performed to evaluate the blood perfusion and monitor the blood flow recovery in the ischemic hind limb (Supplementary Fig.6a). When comparison between the MSC-MSC/once and MSC-Saline-Cyc groups was performed, intravenous infusion of hiPSC-MSCs significantly improved blood perfusion in the MSC-MSC/once group relative to MSC-Saline-Cyc group during the first 2 weeks (Supplementary Fig.6b, p<0.05). Following intramuscular hiPSC-MSC transplantation at day 7, blood perfusion progressly increased in the MSC-MSC/once and MSC-Saline-Cyc groups. Nevertheless, no significant difference was observed between the MSC-MSC/once and MSC-Saline-Cyc groups from day 21 onwards (Supplementary Fig.6b, p>0.05). Repeated intravenous infusion of hiPSC-MSCs with or without subcutaneous administration of cyclosporine A significantly improved blood perfusion at day 35 in the MSC-MSC/week and MSC-MSC/week-Cyc groups compared with the MSC-MSC/once and MSC-MSC/once-Cyc groups respectively (Supplementary Fig.6b, p<0.05). Nonetheless, subcutaneous administration of cyclosporine A did not improve the blood perfusion in the MSC-MSC/once-Cyc and MSC-MSC/week-Cyc groups relative to the MSC-MSC/once and MSC-MSC/week groups respectively (Supplementary Fig.6b, p>0.05).

Cumulatively, our results demonstrated that no significant difference was observed in cell engraftment between a single or repeated intravenous hiPSC-MSC infusion and subcutaneous administration of cyclosporine A. Although there was no significant difference in blood perfusion between the cyclosporine A and single hiPSC-MSC infusion, a significantly improved blood perfusion was observed in the repeated hiPSC-MSC infusion groups relative to the cyclosporine A group. Furthermore, subcutaneous administration of cyclosporine A did not further increased cell engraftment or therapeutic efficacy in either single or repeated hiPSC-MSC infusion groups.

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Repeated intravenous administration of hiPSC-MSCs enhance the efficacy of cell-based therapy in tissue regeneration | Communications Biology -...

Cardiac Stem Cells Comments Off on Repeated intravenous administration of hiPSC-MSCs enhance the efficacy of cell-based therapy in tissue regeneration | Communications Biology -… | August 26th, 2022

Abstract:Background: One of the best and most effective applied and tolerable approaches for cardioprotecion is the regular exercise. In situation of exercise activity and even cardiac ischemic injury, the activity of the myocardial stem cells and their recruiting factors are changed so that contribute the adaptation and repairment of the myocardium. The aim of this study was to investigate the effect of myocardial preconditioning with high intensive interval training on SDF-1a myocardial levels, CXCR4 receptors and c-kit after acute myocardial infarction in male rats. Methods: 20 male Wistar rats (8 week old ,weight 234.8 5.7 g) were randomly divided into 4 groups of control (C), training (T), myocardial infraction (MI) and training+ myocardial infraction (T+MI). The training groups performed two weeks of high-intensity interval training in four sections. Each section included two or three days of practice sessions and two sessions each per a day. The number or intensity of the intervals increased in each section. SDF-1, CXCR4 and C-Kit proteins were measured by the Western blot method in the myocardial tissue and myocardial injury enzymes (CK, LDH, troponin T) were measured in serum.Results: The results of this study showed that that SDF-1, CXCR4 and C-Kit had a significant increase after two weeks of high intensity interval training and myocardial infraction. Also, serum enzyme measurements showed a positive effect of exercise, so that in the myocardium injury enzymes significantly increased in the myocardial infarction group compared with the other three groups, training and training- myocardial infarction (P<0.001). As well as, there was a significant difference between the groups of training -myocardial infarction in all of the enzymes of the myocardium injury compared to the control and training groups. Conclusions: Even short terms of high intensity interval training can increase the levels of proteins SDF1-a, CXCR4 and C-Kit in order to cardioprotection against myocardial injury through recruitment stem cells.

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High intensity interval training protects the heart against acute myocardial infarction through SDF-1a, CXCR4 receptors and c-kit levels - Newswise

Cardiac Stem Cells Comments Off on High intensity interval training protects the heart against acute myocardial infarction through SDF-1a, CXCR4 receptors and c-kit levels – Newswise | August 26th, 2022

Research led by Muhammad Riaz, PhD, Jinkyu Park, PhD, and Lorenzo Sewanan, MD, PhD, from the Qyang and Campbell laboratories at Yale, provides a mechanism to identify abnormalities linked with a hereditary cardiac condition, hypertrophic cardiomyopathy (HCM), in which walls of the left ventricle become abnormally thick and often stiff. The findings appear in the journal Circulation.

Patients with familial HCM have an increased risk of sudden death, heart failure, and arrhythmias. HCM is the most common inherited cardiac disease, affecting one in 500 people. The disease is thought to be caused by mutations that regulate cardiac muscle contraction, compromising the hearts ability to pump blood. However, the mechanisms behind the disease are poorly understood.

For this multi-model study, the researchers used stem cell approaches to understand the mechanisms that drive inherited HCM. The technology, induced pluripotent stem cells (iPSCs), can accelerate insights into the genetic causes of disease and the development of new treatments using the patients own cells.

This is a humbling experience that a patients disease phenotypes teach researchers fundamental basic knowledge that sets the stage for innovative new therapies. Furthermore, our research has established a great model to assist many physicians at Yale School of Medicine and Yale New Haven Hospital to unravel mechanistic insights into disease progression using the patients own iPSCs and engineered tissues, said Yibing Qyang, PhD, associate professor of medicine (cardiology) and of pathology.

We wanted to understand the disease mechanism and find a new therapeutic strategy, Park said.

Probing the heart disorders mechanismThe concept originated with an 18-month-old patient who suffered from familial HCM. Through a collaboration with Daniel Jacoby, MD, adjunct associate professor of cardiovascular medicine and an expert on HCM, who provided medical care for this patient, Park and the team used stem cell technologies to address a fundamental question, the disease mechanisms behind HCM. They collected 10 cc of the patients blood and introduced stem cell factors into the blood cells to generate self-renewable iPSCs. By applying cardiac knowledge, they coaxed iPSCs into patients own cardiomyocytes (heart cells) for cardiac disease studies. We discovered a general mechanism which explains the disease progression, said Park.

Next, they engineered heart tissues that resembled the early-onset disease scenario of the young patient. The disease was a severe presentation at the age of 18 months, which suggested that the disease started at the fetal/neonatal stage.

The next phase of the study was to recreate a 3-D model that was used to mimic the progression of the disease, including mechanical properties such as contraction and force production of that muscle, to understand how much force is compromised if the mutation is present. This was performed in collaboration with Stuart Campbell, PhD, and Sewanan from Yales Department of Biomedical Engineering. Coupled with computational modeling for muscle contraction, the authors developed robust systems that allowed them to examine the biomechanical properties of the tissue at three-dimensional levels.

Finally, using advanced gene editing technologies, the research team modified these mutations. They discovered that after the mutations were corrected, the disease was reversed. These insights about sarcomeric protein mutations could lead to novel therapeutics for HCM and other diseases. The interaction between mutations could also suggest that the same biomechanical mechanism exists in other conditions such as ischemic heart disease.

Our research has established a great model to assist many physicians at Yale School of Medicine and Yale New Haven Hospital to unravel mechanistic insights into disease progression using the patients own iPSCs and engineered tissues.

Yibing Qyang, PhDWe can apply these findings to cardiac conditions associated with hypertension, diabetes, or aging, said Riaz.

Applying the findings to heart diseaseOne of the fundamental challenges was that we needed to generate iPSCs from the patients family, Riaz added. Using this technology, Park was able to recreate primary cells from the cells of a patient with HCM, a process which takes over a month. Riaz and Park used stem cells to identify the vital role of pathological tissue remodeling, which is caused by sarcomeric hypertrophic cardiomyopathy mutations.

We are hopeful that our findings will be replicated in the scientific community, said Riaz. This is an example of bed to bench research, where scientists extract materials from clinics and conduct the experiment in the laboratory and then discover new methods to treat patients.

The authors also noted that RNA sequencing could be used as a guide to characterize the disease at a molecular level. Scientists may be able to identify more targeted drugs by examining the biomechanical properties of the tissue. We can now screen multiple drugs to see whether any of those drugs are able to rescue the phenotype, they said.

Riaz, now an associate research scientist in the Qyang lab, began as a cancer researcher. He earned a PhD from the Erasmus University Medical Center, based in Rotterdam, Netherlands. He later studied genetic disorders in skeletal muscle disease before joining the lab in 2017.

Park, also from the Qyang lab, graduated from Seoul National University, South Korea in 2013. He completed postdoctoral research at the University of Missouri where he focused on vascular biology and emerging areas in stem cell technology.

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Yale University: Uncovering New Approaches to a Common Inherited Heart Disorder | India Education - India Education Diary

Cardiac Stem Cells Comments Off on Yale University: Uncovering New Approaches to a Common Inherited Heart Disorder | India Education – India Education Diary | August 10th, 2022

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Heart failure in obesity: insights from proteomics in patients treated with or without weight-loss surgery | International Journal of Obesity -...

Cardiac Stem Cells Comments Off on Heart failure in obesity: insights from proteomics in patients treated with or without weight-loss surgery | International Journal of Obesity -… | August 10th, 2022

Raising the dead sounds like science fiction, but a team of medical scientists at Yale University have managed to achieve just thatat least on a cellular level. They successfully revived cells from pigs that were dead for an hour, as a Nature study published August 3 reports. While the study authors emphasize the technology is ages away from being used on people, the work could eventually help keep human tissues alive longer, increasing the supply of viable organs for transplants.

These cells are functioning hours after they should not be, said Nenad Sestan, a professor of neuroscience and comparative medicine at Yale and lead author of the study, in a news briefing per CNN. And what this tells us is that the demise of cells can be halted. And their functionality restored in multiple vital organs. Even one hour after death.

Sestan and his colleagues received 100 pigs from a local breeder. They placed the pigs on ventilators and shocked the animals hearts to induce cardiac arrest. An hour after confirmed death, the Yale scientists used two systems to pump blood back into the bodiesan ECMO machine removed carbon dioxide and added oxygenated blood to one group, while another device, called OrganEx, pumped artificial blood back into the other. That fluid entered the blood vessels of the dead pigs, where synthetic forms of hemoglobin and other molecules protected cells from degradation and stopped blood clots.

After six hours, the researchers recorded signs of oxygen recirculating into the pigs tissues. A heart scan confirmed signs of electrical activity in the heart of pigs on the OrganEx machine, though those organs did not fully restart. Elsewhere, there were signs of business as usual, too: The livers of the deceased pigs resumed production of a protein called albumin. Additionally, the cells of other vital organs were responsive to glucose, suggesting the pigs metabolic processes were working again.

The experiment is not the first time scientists have tried to redefine life and death. In the early 20th century, there were attempts to reboot the brains of deceased monkeys. And in 2019, neuroscientists reanimated the brains of decapitated pigs four hours after they died in a slaughterhouse.

Studies such as these raise questions about what it means to be dead. We presume death is a thing, it is a state of being, Nita Farahany, a Duke law professor who studies ethical, legal and social implications of emerging technologies, told The New York Times. Are there forms of death that are reversible? Or not?

The findings also call into question who is considered legally dead, especially as medicine adapts to make cardiac death one day reversible. People tend to focus on brain death, but theres not much consensus on when cardiac death occurs, Arthur Caplan, a bioethicist at New York University told Nature News. This paper brings that home in an important way.

Ethical challenges abound if technology such as this were applied to people. In 2016 Indias medical research council, citing ethical concerns, blocked a planned clinical trial that aimed to revive brain-dead people to a minimally conscious state using a mix of stem cells and other techniques.

While the current study showed no signs of brain activity in the pigs, the researchers observed the heads, necks, and torsos moved. If brain activity was restored, there is no telling how functional or conscious the pigs would be, making it one of a slew of ethical questions scientists will need to answer as they breach this murky area of science.

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Pigs died after heart attacks. Scientists brought their cells back to life. - Popular Science

Cardiac Stem Cells Comments Off on Pigs died after heart attacks. Scientists brought their cells back to life. – Popular Science | August 10th, 2022

Immediate cord clamping (ICC), within a few seconds after birth, became routine in the latter half of the 20th century, as part of a tranche of medical birth-related interventions that collectively, undoubtedly improved maternal and neonatal survival and outcomes [1]. The trend to ICC (within 15-20 seconds after birth) was partly driven by some early studies suggesting that the most benefit in terms of blood volume is achieved within this time frame [2], and that deferred cord clamping (DCC) increased rates of polycythemia and jaundice [1]. It may also have been partly driven by increased rates of operative deliveries and consequent pressure to minimize surgical times, as well as the increased availability and effectiveness of neonatal resuscitation. Furthermore, ICC was proposed as a means to reduce the risk of maternal exposure to fetal blood group antigens at a time (before RhD immunoprophylaxis) when hemolytic disease of the fetus and newborn was far more common than it is now.

Formal evidence that ICC was beneficial was never sought, and recent research summarized in systematic reviews [3-6] has suggested that it may be harmful when compared with DCC for various intervals from 30 seconds until when the cord stops pulsating (defined in some studies as physiological cord clamping). ICC before the onset of breathing exposes the newborn baby to a period of significantly restricted cardiac function, whereas DCC until after the onset of breathing (which often does not occur until late in the first minute after birth) may mean that the expanding pulmonary circulation is able to fill with blood from the placenta, rather than by reverse flow across the ductus arteriosus [7]. This may improve left ventricular preload and stabilize pressures and flows in major vessels [7].

In addition, when cord clamping is deferred, babies may receive a transfusion of blood from the umbilical cord and placenta. A recent systematic review demonstrated that DCC in preterm babies improves peak hematocrit in the first week by 2.7% (95% confidence intervals (CI) 1.88-3.52) and reduced the proportion of babies receiving any subsequent blood transfusion (RD: -0.07, 95%CI -0.11 to -0.04) [6]. Some studies have found a weight increase in the first two minutes after birth when the cord is not clamped, supporting the hypothesis of placental transfusion [8]. Yet, recent evidence shows that placental transfusion may not always occur (Conference abstract: Vijayaselvi R, Abraham A, Kumar M, Kuruvilla A, Mathews J, Duley L. Measuring Umbilical Flow and Placental Transfusion for Preterm Births: Weighing Babies at 33-36 Weeks Gestation with Cord Intact. 1st Congress of Joint European Neonatal Societies; 2015).

The relative roles of cardiovascular stabilization at birth versus placental transfusion in improving outcomes have not been established. Understanding the contributions of these two mechanisms has significant implications for research and practice: for example, if the size of placental transfusion is more important, then prescribing a top-up transfusion soon after birth for babies with lower than average hemoglobin (who are known to be at higher risk of various adverse outcomes) [9] may be justified, especially for the babies for whom DCC has been precluded by maternal or fetal conditions. These include significant maternal bleeding, and monochorionic twins, where deferred cord clamping in the first twin could lead to one twin losing blood to the other. However, if it is the effects on improving cardiovascular stability in the first minutes (with consequential benefits for cardiorespiratory function and reducing severity of illness during the subsequent neonatal intensive care unit (NICU) stay), regardless of the magnitude of transfusion, then early top-up transfusion is unlikely to be helpful.

Observational studies suggest that exposure to blood transfusion itself is harmful to preterm babies, increasing the risk of adverse outcomes [10]. However, this suggestion has not been supported by the small number (to date) of randomized controlled trials of blood (red cell) transfusion thresholds [11-14]. It is unlikely to be the means by which DCC reduced deaths in the largest trial to date of deferred cord clamping in preterm babies, the Australian Placental Transfusion Study (APTS), and in the most recent systematic review on this, because neither showed a difference in rates of other adverse outcomes [6,15].

Another possibility is that it is the umbilical cord blood stem cells received by the baby are the main reason for the observed benefits to both survival and reduced requirement for later blood transfusion [16]. Umbilical cord blood has been demonstrated to be such a good contributor to hematopoiesis that it is a recognized stem cell resource for pediatric and adult hematopoietic stem cell transplant [17]. In addition, umbilical cord blood is a potential regenerative and immunomodulatory agent for a variety of clinical conditions [18], so in this case, the extent of placental transfusion would be critical to the improvement of outcomes, and transfusion with adult red cells would not suffice. There are no established methods to quantify the contribution of umbilical cord stem cells to placental transfusion. However, a larger volume of placental transfusion results in the baby receiving more nucleated cells [19], including more umbilical cord stem cells.

Discerning whether these effects (initial enhanced cardiovascular stability leading to early and sustained reduction in severity of illness or volume of placental transfusion) appear to be the main driver of improved outcomes is likely to contribute to practice change, as well as to informing the design of future research studies into methods to improve outcomes of high-risk newborn babies and reduce their transfusion dependence.

The causal mechanisms of reduced transfusion requirements found in DCC relative to ICC are yet to be resolved. The aim of the study is to address the question; In preterm infants (P) does DCC (I) compared to ICC (C) reduce dependence on red cell transfusion via enhanced cardiovascular stability (mediator 1, M1) or via an increased volume of placental transfusion (M2).

The study is a nested retrospective study, called the Transfusions in the APTS Newborns Study (TITANS) (study registration: ACTRN12620000195954), of the cohort of babies who were enrolled and randomly assigned to ICC or DCC in the Australian and New Zealand (NZ) sites for APTS (study registration: ACTRN12610000633088). This design has been developed to take advantage of the comprehensive dataset already collected for APTS, and because there is currently no suitable prospective study that could address the same research questions in such a large group of participants.

Babies had been considered eligible for APTS if obstetricians or maternal-fetal medicine specialists anticipated that delivery would occur before 30 weeks of gestation. Exclusion criteria included fetal hemolytic disease, hydrops fetalis, twin-twin transfusion, genetic syndromes, and potentially lethal malformations. Further details are available in the original APTS publication [15]. In the present TITANS analysis, we will also exclude any baby with a diagnosis of hemolytic anemia or aplastic/hypoplastic anemia.

There were 1401 babies enrolled for APTS from the 13 Australian and 5 NZ hospital sites [15]. APTS data was provided to the TITANS team on 31 July, 2020. It is planned to collect additional data from Australian and NZ APTS sites using a customised, secure web-based database application (REDCap) [20], which is maintained by the University of Sydney, Sydney, Australia. Data will be obtained from source documents (patient hospital records and laboratory reports) using the electronic data collection application from each study site. The individual participant data collected will correspond to the minimum data required to answer the research questions. Baby identification (ID) and other babies details from APTS will be used to re-identify participants and link them to hospital records. Identified data will be collected, in order to allow linkage between the data newly collected from patient records and hospital laboratories and the existing APTS dataset. The data will be checked with respect to range, internal consistency, consistency with published reports and missing items. After data cleaning and analysis, data will be stored in re-identifiable form, with each participants data being identified with the same study numbering system as used for the APTS study.

We will combine the data already extracted, stored and cleaned from APTS with the additional data obtained from study sites for each participating baby, to determine which factors are most influential in reducing transfusion requirements. The specific objectives are, after adjustment for prior risk factors (listed below), to determine:

1.Whether the effect of the intervention (cord clamping) on the outcome (blood transfusions) is mediated by placental transfusion (measured by hematocrit (Hct)) as seen in Figure 1 (a, c) following the causal path X M1 Y, where X is the intervention, ICC or DCC, Y is the outcome, mediator M1 is placental transfusion, and M2 is initial severity of illness stability

2.Whether the effect of the intervention (cord clamping) on the outcome (blood transfusions) is mediated by initial severity of illness (respiratory support, sampling line yes/no and total duration number, blood pressure, cumulative blood sample volume) as seen in Figure 1 (b, c) following the causal path X M2 Y

3.Whether the effect of cord clamping intervention on the outcome (blood transfusions) is driven by multiple mediators (placental transfusion and initial severity of illness) as seen in Figure 1 (c)

4.Whether cording clamping intervention (ICC or DCC) has a direct effect on the outcome after accounting for the mediators as seen in all panels of Figure 1: X Y.

The protocol was approved by the Northern Sydney Local Health District Human Research Ethics Committee in November 2019 (Version 3.0, Reference 2019/ETH12819), the Mater Misericordiae Ltd Human Research Ethics Committee (Version 1.0, Reference HREC/MML/56247), the Mercy Health Human Research Ethics Committee (Version 2.0, Reference 2020-078), and the Southern Health and Disability Ethics Committee (Version 1.0, Reference 19/STH/195). The ethics committees have granted a waiver of consent. The study is conducted in accordance with the National Health and Medical Research Council Statement on Ethical Conduct in Research Involving Humans.

Intervention

The intervention consisted of either immediate or delayed cord clamping (as assigned in APTS). Immediate clamping was defined as clamping the cord within 10 seconds of delivery. Delayed clamping was defined as clamping the cord at least 60 seconds after delivery, with the infant held as low as possible, below the introitus or placenta, and with no palpation of the cord. Variations in the protocol were allowed if they would aid the mother, baby, or both. If the baby was non-vigorous (heart rate <100 beats per minute, low muscle tone, or lack of breathing, or crying), clinicians were allowed to break protocol using their discretion. Cord milking was not part of the protocol for either intervention. Further details may be sourced from the original APTS publication [15].

Outcomes

The primary outcome is the proportion of babies receiving red cell transfusion (for restoration of hemoglobin or blood volume). The secondary outcomes are number of transfusions per baby, cumulative transfusion volume (mL/kg) per baby, and primary reasons for each transfusion.

Putative Mediators

M1: Indicators of placental transfusion to be assessed will be hematocrit (on admission, highest on the first day, highest in the first week collected before any postnatal transfusion).

M2: Indicators of initial severity of illness to be assessed will be cumulative blood sample volume collected throughout hospital stay (number of blood tests multiplied by hospitals usual sample volume for each type of test), sampling line (umbilical arterial line or peripheral arterial line) - yes/no and total duration, mechanical ventilation or inspired O2, and blood pressure.

Sensitivity Analyses (For the Primary Outcome Analysis Only)

Sensitivity analyses will adjust for the following variables: gender, birth <27 weeks vs. 27 weeks, method of delivery (vaginal versus cesarean), intraventricular hemorrhage (IVH) (yes/no and grade III/IV yes/no), surgery for patent ductus arteriosus (PDA), necrotizing enterocolitis (NEC), and sodium in the first 24 hours of life. We will also test model assumptions relating to sequential ignorability and post-randomization confounding (discussed further in the data analysis plan).

Potential Confounders (Covariates)

The following covariates may be used for adjustment in the analysis: gestational age at randomization before birth and any oral iron supplement pre-transfusion.

Timing of Assessments

Putative mediating variables will only be analyzed if they have been measured before the outcome and will be excluded if there is not adequate time and date information available. If the multiple mediator model is applied, careful consideration of timing information will be evaluated. If there is insufficient empirical information to conclude the causal ordering of mediators (M1 causes M2), we will adjust our analytic approach (as discussed in the analysis plan) and discuss any limitations.

Data Analysis Plan

The analysis will include all babies who were initially randomized in the APTS trial for whom we were able to obtain the relevant data and be based on intention-to-treat. All statistical analyses will be conducted in R version 4.1.3 (2022-03-10; R Foundation for Statistical Computing, Vienna, Austria). Descriptive characteristics for continuous data will be presented as means or medians, as appropriate, and categorical data will be presented as frequencies and percentages.

A model-based inference approach will be applied to estimate the average causal mediation effect (ACME), average direct effect (ADE), and the average total effect as recommended [23-25]. This approach will be applied with the R mediation package [26]. We will initially fit two models, one model with mediation as the dependent variable and intervention as the independent variable (mediator model), and a second model with the outcome as the dependent variable, and both mediation and intervention as independent variables (outcome model). To account for the clustering of multiples, estimates will be calculated with generalized estimating equations with a compound symmetric correlation structure to account for within subject correlations. Depending on the outcome (binary, count, skew) these will be modelled with the appropriate family and link functions.

A counterfactual framework will be applied to the mediator and outcome models to simulate the values of the mediator and outcome to estimate the potential values of the mediator. This process is used to estimate the ACME, ADE, and average total effects; 95%CI will be estimated with 1000 bootstrap simulations.

We will apply single mediator models on both placental transfusion variables and initial severity of illness variables if mediators are statistically independent, as seen in Table 1. Independence will be tested using linear regression and any appropriate link functions. If both mediators are not statistically independent, we will investigate the possibility of multiple mediator models, which require an expanded framework for analysis [21]. Here we assume that initial severity of illness is causally related to placental transfusion. For this process, we will use the method developed by Imai and Yamamoto [21] to estimate the ACME and ADE. Following this, 95%CI will be estimated with 1000 bootstrap simulations. If theoretical and empirical timing data and sensitivity analyses suggest that M1 and M2 have non-causal correlation and may be affected by an unmeasured latent mediator, we will adjust our approach to estimate interventional direct and path-specific indirect effects [27,28].

Sensitivity analyses have been limited to a set of biologically plausible and clinically meaningful groups that will be explored by including them for adjustment with covariates, and with the introduction of interaction terms if appropriate. Missing data will be described, reasons for missing data will be explored, and the impact of missing data on conclusions about the treatment effect on the primary outcome will also be explored where possible (e.g., using sensitivity analyses and multiple imputation techniques).

Methodological Assumptions

The causal mediation approach assumes sequential ignorability: that the treatment effect on the outcome is not confounding and that the mediator effect on the outcome is not confounded. As treatment was randomly allocated to neonates, we will assume that the treatment-mediator relationship is not confounded. However, the mediator itself has not been randomized. Thus, unknown confounders may be driving a spurious effect in the mediator-outcome relationship. We will employ additional sensitivity analyses to estimate whether any mediation effects are sensitive to the violation of the assumption of sequential ignorability. To test the possibility of unmeasured confounders we will examine the correlation between residuals in the mediator model and the outcome model. If there is no correlation this would suggest there is no unmeasured confounding, if there is correlation between the residuals, an unmeasured mediator may be affecting both the measured mediator and the outcome. We will apply the method developed by Imai et al. andTingley et al. [23,26] that uses sensitivity analyses to evaluate if the ACME estimate is sensitive to unmeasured confounding.

Post-randomization confounders are dependent on the treatment allocated, affect both mediator and outcome, and can corrupt the mediation estimate. In the context of the present trial, it is possible that non-adherence to the intervention is a post-randomization confounder. We are analyzing our data based on intention to treat principles; however, a sensitivity analysis based on the actual time of cord clamping to assess the influence of non-adherence with the treatment protocol on our estimates may be performed.

Blood transfusions of neonates have been associated with a number of serious adverse outcomes [29]. Nevertheless, there are few evidence-based methods to reduce transfusion exposure [30]. The APTS study found that DCC was associated with a statistically significant reduced need for red cell transfusions by about 10% compared to ICC [15]. However, the mechanism remains unclear.

The study will, at a minimum, provide further information that should increase clinicians understanding of the pathways by which DCC (or other methods to accomplish placental transfusion) results in beneficial patient outcomes. Since one of the main barriers to implementation is lack of understanding about the mechanisms by which such a simple practice change should have such dramatic effects, this should improve adherence to recommendations to defer cord clamping for most babies, thereby reducing mortality and transfusion incidence.

By elaborating on the mechanisms, it may also provide good evidence for how other routine neonatal intensive care practices and interventions affect likelihood of needing to transfuse. Better understanding of these effects may lead to other testable hypotheses or improvements in other aspects of practice, further reducing transfusion exposure and improving other outcomes.

Potential limitations of the study include the dependence on some routinely collected clinical data, which were not collected at the time by the original study according to predefined research definitions. However, we have no reason to think that potential problems of data quality would have been influenced by study group allocation and so do not anticipate that this will be a source of bias.

Originally posted here:
Protocol for a Nested, Retrospective Study of the Australian Placental Transfusion Study Cohort - Cureus

Cardiac Stem Cells Comments Off on Protocol for a Nested, Retrospective Study of the Australian Placental Transfusion Study Cohort – Cureus | August 10th, 2022

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Autologous Cell Therapy Market 2021-2025: Scope

The autologous cell therapy market report covers the following areas:

Autologous Cell Therapy Market 2021-2025: Segmentation

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Autologous Cell Therapy Market 2021-2025: Vendor Analysis

We provide a detailed analysis of around 25 vendors operating in the autologous cell therapy market, including Bayer AG, Brainstorm Cell Therapeutics Inc., Daiichi Sankyo Co. Ltd., FUJIFILM Holdings Corp., Holostem Terapie Avanzate Srl, Osiris Therapeutics Inc., Takeda Pharmaceutical Co. Ltd., Teva Pharmaceutical Industries Ltd., Sumitomo Chemical Co. Ltd., and Vericel Corp. among others. The key offerings of some of these vendors are listed below:

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Autologous Cell Therapy Market 2021-2025: Key Highlights

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Autologous Cell Therapy Market Scope

Report Coverage

Details

Page number

120

Base year

2020

Forecast period

2021-2025

Growth momentum & CAGR

Accelerate at a CAGR of 14.16%

Market growth 2021-2025

USD 4.11 billion

Market structure

Fragmented

YoY growth (%)

13.5

Regional analysis

North America, Europe, APAC, and South America

Performing market contribution

North America at 43%

Key consumer countries

US, UK, Germany, Canada, and Japan

Competitive landscape

Leading companies, competitive strategies, consumer engagement scope

Companies profiled

Bayer AG, Brainstorm Cell Therapeutics Inc., Daiichi Sankyo Co. Ltd., FUJIFILM Holdings Corp., Holostem Terapie Avanzate Srl, Osiris Therapeutics Inc., Takeda Pharmaceutical Co. Ltd., Teva Pharmaceutical Industries Ltd., Sumitomo Chemical Co. Ltd., and Vericel Corp.

Market Dynamics

Parent market analysis, market growth inducers and obstacles, fast-growing and slow-growing segment analysis, COVID-19 impact and future consumer dynamics, market condition analysis for the forecast period

Customization purview

If our report has not included the data that you are looking for, you can reach out to our analysts and get segments customized.

Table Of Contents :

Executive Summary

Market Landscape

Market Sizing

Five Forces Analysis

Market Segmentation by Product

Customer landscape

Geographic Landscape

Vendor Landscape

Vendor Analysis

Appendix

About Us

Technavio is a leading global technology research and advisory company. Their research and analysis focus on emerging market trends and provide actionable insights to help businesses identify market opportunities and develop effective strategies to optimize their market positions. With over 500 specialized analysts, Technavio's report library consists of more than 17,000 reports and counting, covering 800 technologies, spanning across 50 countries. Their client base consists of enterprises of all sizes, including more than 100 Fortune 500 companies. This growing client base relies on Technavio's comprehensive coverage, extensive research, and actionable market insights to identify opportunities in existing and potential markets and assess their competitive positions within changing market scenarios.

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Autologous Cell Therapy Market Size to Grow by USD 4.11 billion, Bayer AG and Brainstorm Cell Therapeutics Inc. Among Key Vendors - Technavio - PR...

Cardiac Stem Cells Comments Off on Autologous Cell Therapy Market Size to Grow by USD 4.11 billion, Bayer AG and Brainstorm Cell Therapeutics Inc. Among Key Vendors – Technavio – PR… | August 2nd, 2022

Dr. Jennifer Lang splits most of her work life treating patients at Gates Vascular Institute and conducting research in her lab several floors up in the same building.

UB medical physics students Simon Wu and Emily Vanderbelt work with flow-through 3D-printed aneurysm models using X-rays in the Canon Stroke & Vascular Research Center, part of the University at BuffaloClinical and Translational Research Center on the Buffalo Niagara Medical Campus.

The arrangement suits her well as she continues promising research to learn if a stem cell-derived treatment can repair damaged heart tissue.

Lang, a cardiologist, and her University at Buffalo team, face a dilemma: The immune system revs into high gear when the heart suffers a serious setback, limiting the power of stem cells to heal.

The daunting task seems more surmountable these days because she works in a building filled with researchers of all stripes.

I do collaborations with groups that I otherwise wouldn't have. Its led to some really new, interesting results, said Lang, assistant professor in the UB Jacobs School of Medicine and Biomedical Sciences who practices with UBMD Internal Medicine and at the Buffalo VA Medical Center.

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This day, a surgical team worked seamlessly to monitor her vital signs and feather a medical device through a catheter into the left side of her damaged heart. The procedure slowed her heartrate so her organs could take a couple of days to re-collect themselves and give her a fighting chance to recover.

UB-fueled research unfolds on floors five through eight of the building at 875 Ellicott St., alongside Buffalo General Medical Center.

Ten years ago, the university invested $118 million into its Clinical and Translational Research Center, and about $25 million for equipment came from industry partners who wanted to join forces with physicians, engineers and others in the science fields.

The center became the first major pieceof the UB medical school to move onto the downtown Buffalo Niagara Medical Campus, followed in late 2017 by the $375 million Jacobs School teaching and research complex, around the corner at Main and High streets.

Both foster translational medicine, which combines disciplines, resources and techniques to move benchtop research to the patient bedside, eventually strengthening community health.

Langs work symbolizes the approach.

The Buffalo native can see her high school alma mater, City Honors, from her workplace. She went to Cornell University as an undergraduate and returned to Buffalo to go to medical school. Buoyed by fellow UB students, faculty and mentors, she chose to stay in the city for her internal medicine residency and cardiology fellowship.

Lang did her classroom work and research on the UB South Campus and most of her clinical work 8 miles away, on the downtown Medical Campus.

Stairs and elevators are the only things that separate her from most of her collaborators and patients today.

I moved into this building when it opened 10 years ago, she said. At the time, I was completing my cardiology fellowship. There was a physical divide, so I was thrilled with the new arrangement. Things can happen in parallel now.

Dr. Timothy Murphy, left, director of theUB Clinical and Translational Research Center in Buffalo, works with research technician Charmaine Kirkham in their lab, which focuses on potential treatments forchronic obstructive pulmonary disease (COPD).

That was the plan, said Dr. Timothy Murphy, director of the UB Clinical and Translational Research Center.

Clinical research and health care have become more and more seamlessly integrated, he said. The building contributed to that.

Murphy, another regional native, was among those who shared and helped carry out the vision of Gates Vascular Institute founder Dr. L. Nelson Nick Hopkins III, who chaired the UB Department of Neurosurgery from 1989 to 2013 and wanted to create a more innovative vascular center.

Murphy moved his lab in 2006 from the VA Medical Center near South Campus to the UB Center for Bioinformatics and Life Sciences on the Medical Campus, so he could be involved in the design of the UB research center, on floors above Gates Vascular, as well as at the Jacobs School particularly its labs.

They always talked about physicians and researchers bumping into each other, talking to each other, and having graduate students and postdocs and technicians talk to each other, Murphy said. Having done it now for all these years, I see it really does work.

He and his research team continue a 20-year study on the bacterial infection that causes COPD in hopes it will help lead to vaccines that prevent the infection and new treatments to clear the bacteria from the lower airway.

As senior associate dean forclinical and translational researchat the Jacobs School, he is also the point person for coordinating UB-related clinical trials and encouraging collisions between health care researchers on the Medical Campus and around the world.

There were 70 such trials on the Medical Campus in 2015, when the building where he works was in its infancy. Today, there are more than 200.

"Things can happen in parallel now," says Dr. Jennifer Lang, a cardiologist, researcher and University at Buffalo assistant professor who splits her research and clinical time in the same building on the Buffalo Niagara Medical Campus.

Labs focused on obstetric and gynecological advances and keys to healthy aging occupy space near his seventh-floor lab.

The Clinical and Translational Research Center was established in 2012. UB added a biobank in 2019 to store medical specimens for ongoing clinical studies.

Its collaborative framework helped UB land a $15 million Clinical and Translational Science Awardin 2015 from the National Institutes of Health (NIH) to encourage research efforts across university departments and specialties to boost innovation, speed development of medical treatments, and reduce health disparities in poor, rural and minority communities.

The five-year grant was renewed in 2020 with nearly $22 million more, encouraging Buffalo-based researchers to work with others who got awards, including researchers with Harvard, Johns Hopkins, Stanford and Yale universities.

A printer creates a 3D model, slice by slice, at the Canon Stroke & Vascular Research Center in the University at Buffalo Clinical and Translational Research Center. Lab researchers experiment with different mixtures of six polymers to make the most malleable and useful models for medical research.

Throughout the building, the goal is to improve medical devices and treatments that make an impact in the clinics and catheter suites in the Gates Vascular Institute on the floors below the research center and provide data and education that informs others, including patients.

The eighth-floor Canon Stroke & Vascular Research Center, which tops the UB research center, is a case in point.

Ciprian Chip Ionita, its director, came to UB from Romania in 1999 and worked his first dozen years on the South Campus.

We were the first ones to move in, said Ionita, assistant professor of biomedical engineering and member of the medical school's Department of Neurosurgery.

The lab was designed to help innovate and improve medical devices and neurovascular procedures.

Part of its work involves using MRIs, CT scans and other radiological images of Gates Vascular patients to create 3D-printed models of the circulatory system and heart.

3D printing created this replica of part of a patient's spinal column at the Canon Stroke & Vascular Research Center. Researchers there push the boundaries until their findings are refined to the point where they can be applied to model-making on two highly calibrated 3D printers in the Jacobs Institute downstairs from the lab that meet FDA standards. We fail up here about 90% of the time, says Ciprian Chip Ionita, lab director. They fail maybe 1%, so were testing everything that's possible.

Medical school and other lab researchers use the models produced here to better understand how anatomy and disease of former and current patients led to poor health and, in some cases, poor surgical outcomes.

Gates Vascular surgeons also can use 3D models that replicate the anatomy of patients awaiting surgery to practice feathering catheters and medical devices through bends, nooks and crannies of the blood vessels, and deploy medical devices in spines and the circulatory system as they maneuver past muscles, bones, blockages and other obstructions that might come into play.

During practice interventions, we analyze everything, Ionita said, because we can go into these models with sensors to measure blood flow, blood pressure and more.

You can create a model that says, Here's somebody who has a carotid artery that's 50% (blocked) and he's 50 years old, Ionita said. Or we can say, 'Here is a young person in their 20s, and is fully compliant, no stenosis or whatever.' And those mechanical properties are translated by the printer.

Even cadaver donors cant do that.

The goal is to lower the rate of complications and be successful in one shot during a procedure, said Ionita, who supervises up to 10 graduate biomedical engineering students, and roughly 20 undergraduate, graduate and medical school students.

Those who pay close attention to 3D models and other medical research based on data from patients treated in the building include Dr. Elad Levy, co-director of the Gates Vascular Stroke Center; Dr. Adnan Siddiqui, director of neurological and stroke services at Kaleida Health; and Dr. Vijay Iyer, medical director of cardiology and the Structural Heart Program at Kaleida. All three have ties to UB.

Even here, Ionita said, physician-scientists and other researchers see the damage that smoking, high blood pressure and living in ZIP codes where poverty is rampant can create complications that lead to worse health and surgical outcomes.

Eric Wozniak, a senior research and development technician in the Idea to Reality lab at the Jacobs Institute, uses a microscope as he works to improve catheter technology.

Doctors and staff improve treatment protocols and surgical prowess with help from those who work on the top half of the building for UB and the Jacobs Institute. The latter is named for Dr. Lawrence D. Jacobs, a Buffalo neurosurgeon whose research led to the first treatments for multiple sclerosis.

Four years after Jacobs died in 2001, his brother Jeremy, chair of the Delaware North Cos. and the UB Council, approached the university about creating a lasting memorial for the respected physician. He later signed on to the concept of creating a multidisciplinary vascular center, starting with a $10 million donation for the institute that bears the family name.

The institute includes an atrium, caf and glass-walled spaces that overlook procedure rooms on the floor below. It has 50 employees, including more than 30 biomedical and electrical engineers, who seek company-sponsored research funding, help collect data and make prototypes for clinical trials, and work with researchers to publish their work in medical journals.

In 2016, the institute was designated a 3D Printing Center of Excellence in Health Care by Israeli-based Stratasys Ltd., a leading 3D printing-maker. In early 2018, it created a proof-of-concept Idea to Reality Center, known as i2R, to further improve medical devices and surgical techniques in the vascular space.

This is our secret sauce lab, said Siddiqui, Jacobs Institute CEO. There's nothing we do downstairs that we could not do better.

This is a device designed and built in the Idea 2 Reality lab at the Jacobs Institute in Buffalo. The lab improves medical devices and technology used in vascular procedures and treatments.

Dr. Carlos Pena, who ran the FDA Neurologic Devices Division for 15 years, joined the institute staff last year to improve the chances technology conceived and designed with help from the institute gets to market.

Every company wants to talk to him, Siddiqui said. He tells them what testing needs to be done. Some of that gets done in-house. A lot of it goes to the university or, when they have a clinical trial, that gets done downstairs so the entire ecosystem is functioning, I think better than Nick Hopkins ever imagined.

Lang, the cardiologist, doesnt miss her former workday commutes. She loves the design and location of the building that sets the standard for vascular care.

Most of her days mix benchtop research in her lab and patient visits and procedures on the floors below. When there is time, she can visit her husband, Fraser Sim, neuroscience director and associate professor at the medical school.

Because we're in such close proximity to the Jacobs School now, we're also really able to engage the medical students earlier in their careers and encourage more research, Lang said. And because we're so close to the hospital, we're able to involve medical residents and fellows in our research projects much more than ever before.

University at Buffalo medical school postdoctoral research associateToubaTarvirdizadeh focuses on cardiac research in the lab of Dr. Jennifer Lang at the UB Clinical and Translational Research Center in Buffalo.

She has spent a decade trying to find better ways for a stem cell derivative that can withstand an immune response and rejuvenate heart tissue without major complications, a result that could help patients recover from a heart attack and lessen the strain of heart failure.

Four years ago, Lang and her doctoral student researcher, Kyle Mentkowski, discovered a way that lowered the immune response in mice that received the derivative.

Mentkowski, now a post-doctorate researcher at Harvard-affiliated Massachusetts General Hospital, was talking with another group of student researchers in the building when they thought it might be a good idea to bring Dr. Jessica Reynolds, an immunologist and UB medical school associate professor, into the research.

The collaboration created robust, reproducible results in mice models, Lang said, and the start of testing in human immune cells she and her colleagues hope can benefit patients within the next decade.

Collaborators now regularly get together to chat at the Jacobs Institute.

The NIH seems very interested in this as a potential clinical therapy, Lang said, but the field as a whole is still in the beginning stages of understanding where we need to go next.

Dr. Aaron Hoffman, left, University at Buffalo medical school associate professor of surgery, and Dr. Kenneth Snyder, UB associate professor of neurosurgery, chat during a break in the Jacobs Institute atrium.

UB researchers have shared some of their findings with researchers making similar inroads elsewhere, she said, and the work spawned other collaborations with Reynolds, her research team and scientists in the UB Department of Biomedical Engineering.

This type of unplanned interaction is not a unique occurrence in this building, Lang said. Our story is just one of many.

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Buffalo center fuels research that can save your life from heart disease and stroke - Buffalo News

Cardiac Stem Cells Comments Off on Buffalo center fuels research that can save your life from heart disease and stroke – Buffalo News | August 2nd, 2022

The British Heart Foundation announced the winner of its $36 million Big Beat Challenge, one of the largest non-commercial awards ever given for heart research.

The winning team, CureHeart, brings together researchers from the U.K., U.S. and Asia, including Eric Olson, professor and chair of the Department of Molecular Biology at UT Southwestern Medical Center.

Olson is the founding chair of the department and directs the Hamon Center for Regenerative Science and Medicine and the Wellstone Center for Muscular Dystrophy Research. He holds the Robert A. Welch Distinguished Chair in Science and the Annie and Willie Nelson Professorship in Stem Cell Research.

He has spent his career investigating heart and muscle development and disease, leading to his participation on the CureHeart team. The Olson Lab at UTSW has been incredibly successful in muscular research, most recently providing a new way to correct the mutation that causes Duchenne muscular dystrophy through gene editing.

CureHeart made the top of the list with its gene editing therapy aimed at curing inherited heart muscle diseases, known as cardiomyopathies.

A BHF release said the technology will seek to develop the first cures for inherited heart muscle diseases by pioneering revolutionary and ultra-precise gene therapy technologies that could edit or silence the faulty genes that cause these deadly conditions.

The project will use gene-editing technology CRISPR to complete base and prime editing in the heart for the first time.

It works by correcting or silencing a faulty gene in the pumping machinery of the heart, either by re-writing the DNA at a single location or by switching off the entire copy of the faulty gene.

The technique was described as molecules that act like tiny pencils to rewrite the single mutations that are buried within the DNA of heart cells in people with heart conditions.

It can also help the heart produce enough proteins to function normally, again by fixing or stimulating the faulty gene.

With ultra-precise base editing technology, we hope to be able to correct a single letter and larger errors in the genetic code. This would mark a breakthrough for not only genetic cardiomyopathies, but for many heart conditions, said Olson in the release.

The project is the next step toward a real-world application, having already proved successful in animals with cardiomyopathies and in human cells. Members of the team believe therapies could be delivered through an arm injection, slowing or stopping the progression of cardiomyopathies, or even curing the disease entirely.

If successful, the research could have enormous impacts.

Every year in the US, around 2,000 people under the age of 25 die of a sudden cardiac arrest, often caused by one of these inherited muscle diseases, said the release. Current treatments do not prevent the condition from progressing, and around half of all heart transplants are needed because of cardiomyopathy.

The researchers believe it could also be successful in preventing the disease from being expressed if inherited. Children who receive the faulty gene from their parents could receive the injection and never develop cardiomyopathy in the first place.

Over the last 30 years, we have made extraordinary advancements in our understanding of the genetic mistakes that cause cardiomyopathy. CureHeart is a once-in-a-generation opportunity to transform this knowledge into a cure, said Olson in the release.

The technology is still in the research and development phase, but Olson said the funds will be used to optimize the method and expand it to a larger number of genetic diseases of the heart, and could move to clinical trials in the next few years.

See the article here:
UTSW researcher part of team awarded $36 million heart research grant - The Dallas Morning News

Cardiac Stem Cells Comments Off on UTSW researcher part of team awarded $36 million heart research grant – The Dallas Morning News | August 2nd, 2022

Abstract: Diabetes mellitus with hyperglycaemia is a major risk factor for malignant cardiac dysrhythmias. However, the underlying mechanisms remain unclear, especially during the embryonic developmental phase of the heart. This study investigated the effect of hyperglycaemia on the pulsatile activity of stem cell-derived cardiomyocytes. Mouse embryonic stem cells (mESCs) were differentiated into cardiac-like cells through embryoid body (EB) formation, in either baseline glucose or high glucose conditions. Action potentials (APs) were recorded using a voltage-sensitive fluorescent dye and gap junction activity was evaluated using scrape-loading lucifer yellow dye transfer assay. Molecular components were detected using immunocytochemistry and immunoblot analyses. High glucose decreased the spontaneous beating rate of EBs and shortened the duration of onset of quinidine-induced asystole. Furthermore, it altered AP amplitude, but not AP duration, and had no impact on the expression of the hyperpolarisation-activated cyclic nucleotide-gated isoform 4 (HCN4) channel nor on the EB beating rate response to ivabradine nor isoprenaline. High glucose also decreased both the intercellular spread of lucifer yellow within an EB and the expression of the cardiac gap junction protein connexin 43 as well as upregulated the expression of transforming growth factor beta 1 (TGF1) and phosphorylated Smad3. High glucose suppressed the autorhythmicity and gap junction conduction of mESC-derived cardiomyocytes, via mechanisms probably involving TGF1/Smad3 signalling. The results allude to glucotoxicity related proarrhythmic effects, with potential clinical implications in foetal diabetic cardiac disease.

Read more:
Hyperglycaemia-Induced Impairment of the Autorhythmicity and Gap Junction Activity of Mouse Embryonic Stem Cell-Derived Cardiomyocyte-Like Cells -...

Cardiac Stem Cells Comments Off on Hyperglycaemia-Induced Impairment of the Autorhythmicity and Gap Junction Activity of Mouse Embryonic Stem Cell-Derived Cardiomyocyte-Like Cells -… | July 25th, 2022

NASA and Cedars-Sinai Medical Center are launching stem cells into space. In the study, funded by NASA and being conducted by scientists at Cedars-Sinai Medical Center in Los Angeles, the stem cells have been sent into space and will orbit for just over a months time to determine whether they grow differently without G-force.

A remotely controlled container of cells, with reagents and equipment needed to remotely sustain the cells, arrived at the International Space Station over the weekend. Two queries are presented alongside the launch details: do cells age differently in low orbit and can the Earthly challenges of stem cell growth amplification be overcome in space?

The human body is comprised of a full library of cell types, cataloged by specialty and location such as the striated cardiac muscles or the branching neurons in the brain. Each of these cells began as a raw stem cell and has developed in a particular manner. The cells can multiply to become a plentiful stem cell line under the correct conditions, but laboratory settings that would generate the quantity needed for medicinal purposes pose challenges that require innovative thinking.

Despite being featured in many biologic candidates currently under research and development and in clinical trials, mass-producing stem cells for use in these therapeutics isnt feasible. To prevent conglomeration or losing the stem cells at the bottom of a reactor tank, the bioreactor must be stirred at a rate that causes probable cell death. The end result is very few stem cells suitable for therapeutic and research use. By launching stem cells into space, the Cedars-Sinai research team is hoping to overcome these production limitations.

With stem cells, the possibilities and applications are increasing each day. They can work as models for testing drug safety and efficacy, thus reducing the burden placed on animal model research, be used as regenerative cells for those that have suffered damage as a result of injury or disease and even as a basic tool to help researchers further understand the human body.

By pushing the boundaries like this, its knowledge and its science and its learning, Clive Svendsen, executive director at the Cedars-Sinai Regenerative Medicine Institute, commented. Svendsen has sent a part of himself along with the project, as the donor of the stem cells.

Various other studies are being conducted by research teams around the globe in an effort to better understand the potential of stem cells.

Just last week, researchers from the University of Malta announced the launch of a similar mission that will be conducted aboard a SpaceX craft. The Maleth II project is the second installment of the Maleth Program that is designed to evaluate how human skin tissue cell genetics react to low earth orbit. A remotely controlled biocube will orbit the Earth for 60 days while the single cells are analyzed for changes.

The student researchers at the university are being directly supported by Maltas national Research, Innovation, Development Trust and the study itself is in collaboration with the Ministry of Foreign and European Affairs, Singleron Biotechnologies

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NASA's Solution to Stem Cell Production is Out of this World - BioSpace

Cardiac Stem Cells Comments Off on NASA’s Solution to Stem Cell Production is Out of this World – BioSpace | July 25th, 2022

Human samples

Rapid harvesting of cadaveric pancreatic tissues was obtained with informed consent from next of kin, from heart-beating, brain-dead donors, with research approval from the Human Research Ethics Committee at St Vincents Hospital, Melbourne. Pancreas from individuals without and with diabetes, islet, acinar and ductal samples were obtained as part of the research consented tissues through the National Islet Transplantation Programme (at Westmead Hospital, Sydney and the St Vincents Institute, Melbourne, Australia), HREC Protocol number: 011/04. The donor characteristics of islet cell donor isolations are presented in Table 1.

Islets were purified by intraductal perfusion and digestion of the pancreases with collagenase AF-1.24 (SERVA/Nordmark, Germany) followed by purification using Ficoll density gradients.25 Purified islets, from low-density gradient fractions and acinar/ductal tissue, from high-density fractions, were cultured in Miami Media 1A (Mediatech/Corning 98021, USA) supplemented with 2.5% human serum albumin (Australian Red Cross, Melbourne, VIC, Australia), in a 37C, 5% CO2 incubator.

Total RNA from human ex vivo pancreatic cells was isolated using TRIzol (Invitrogen) and RNeasy Kit (QIAGEN) including a DNase treatment. First-strand cDNA synthesis was performed using a high-capacity cDNA Reverse Transcription Kit (Applied Biosystems) according to the manufacturers instructions. cDNA primers were designed using oligoperfect designer (Thermo Fisher Scientific), as shown in Table 2. Briefly, quantitative RT-PCR analyses were undertaken using the PrecisionFast 2 qPCR Master Mix (Primerdesign) and primers using Applied Biosystems 7500 Fast Real-Time PCR System. Each qPCR reaction contained: 6.5l qPCR Master Mix, 0.5l of forward and reverse primers, 3.5l H2O and 2l of previously synthesised cDNA, diluted 1/20. Expression levels of specific genes were tested and normalised to 18s ribosomal RNA housekeeping gene.

Modification of Histone H3 and histone-associated Ezh2 protein signals were quantified in human pancreatic ductal epithelial cells (AddexBio) by the LI-COR Odyssey assay. The cells were treated with 5 or 10M of GSK 126 (S7061, Selleckchem) for 48h. Histones and their associated proteins were examined using an acid extraction and immunoblotting as described previously.18 Protein concentrations were determined using Coomassie Reagent (Sigma) with BSA as a standard. Equal amounts (3g) of acid extract were separated by Nu-PAGE (Invitrogen), transferred to a PVDF membrane (Immobilon-FL; Millipore) and then probed with antibodies against H3K27me3 (07449, Millipore), H3K27ac (ab4729, Abcam), H3K9me3 (ab8898, Abcam), H3K9me2 (ab1220, Abcam), H3K4me3 (39159, Active Motif), Ezh2 (#4905, Cell Signaling Technology), and total histone H3 (#14269, Cell Signaling Technology). Protein blotting signals were quantified by an infra-red imaging system (Odyssey; LI-COR). Modification of Histone H3 and histone-associated Ezh2 signals were quantified using total histone H3 signal as a loading control.

Chromatin immunoprecipitation assays in human exocrine cells were performed previously described.26,27 Cells were fixed for 10min with 1% formaldehyde and quenched for 10min with glycine (0.125M) solution. Fixed cells were resuspended in sodium dodecyl (lauryl) sulfate (SDS) lysis buffer (1% SDS, 10mM EDTA, 50mM Tris-HCl pH 8.1) including a protease inhibitor cocktail (Roche Diagnostics GmBH, Mannheim, Germany) and homogenised followed by incubation on ice for 5min. Soluble samples were sonicated to 200600bp and chromatin was resuspended in ChIP Dilution Buffer (0.01% SDS, 1.1% Triton X-100, 1.2mM EDTA, 16.7mM Tris-HCl pH 8.0, and 167mM NaCl) and 20l of Dynabeads Protein A (Invitrogen, Carlsbad, CA, USA) was added and pre-cleared. H3K27me3 antibody was used for immunoprecipitation of chromatin and incubated overnight at 4C as previously described.28 Immunoprecipitated DNA were collected by magnetic isolation, washed low salt followed by high salt buffers and eluted with 0.1M NaHCO3 with 1% SDS. Protein-DNA cross-links were reversed by adding Proteinase K (Sigma, St. Louis, MO, USA) and incubation at 62C for 2h. DNA was recovered using a Qiagen MinElute column (Qiagen Inc., Valencia, CA, USA). H3K27me3 content at the promoters of the INS, INS-IGF2, NGN3 and PDX1 genes were assessed by qPCR using primers designed from the integrative ENCODE resource.29 ChIP primers are shown in Table 3.

Insulin and glucagon localisation in human islets were assessed using paraffin sections (5m thickness) of human pancreas tissue fixed in 10% neutral-buffered formalin and stained with hematoxylin and eosin (H&E) or prepared for immunohistochemistry. Insulin and glucagon were detected using Guinea Pig anti-insulin (1/100, DAKO) or mouse anti-glucagon (1/50) mAbs (polyclonal Abs, Sigma-Aldrich).

Pharmacological inhibition of EZH2, human pancreatic exocrine cells were kept untreated or stimulated with 10M GSK-126 (S7061, Selleckchem) at a cell density of 1105 per well for 24h. After 24h of treatment, fresh Miami Media was added to the cells, which were treated again with 10 GSK-126 and cultured for a further 24h. All cell incubations were performed in Miami Media 1A (Mediatech/Corning 98-021, USA) supplemented with 2.5% human serum albumin (Australian Red Cross, Melbourne, VIC, Australia), in a cell culture incubator at 37C in an atmosphere of 5% CO2 for 48h using non-treated six-well culture plates (Corning).

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Inhibition of pancreatic EZH2 restores progenitor insulin in T1D donor | Signal Transduction and Targeted Therapy - Nature.com

Cardiac Stem Cells Comments Off on Inhibition of pancreatic EZH2 restores progenitor insulin in T1D donor | Signal Transduction and Targeted Therapy – Nature.com | July 25th, 2022

Stem Cells Market: Introduction

According to the report, the globalstem cells marketwas valued at US$11.73Bn in 2020 and is projected to expand at a CAGR of10.4%from 2021 to 2028. Stem cells are defined as specialized cells of the human body that can develop into various different kinds of cells. Stem cells can form muscle cells, brain cells and all other cells in the body. Stem cells are used to treat various illnesses in the body.

North America was the largest market for stem cells in 2020. The region dominated the global market due to substantial investments in the field, impressive economic growth, increase in incidence of target chronic diseases, and technological progress. Moreover, technological advancements, increase in access to healthcare services, and entry of new manufacturers are the other factors likely to fuel the growth of the market in North America during the forecast period.

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Asia Pacific is projected to be a highly lucrative market for stem cells during the forecast period. The market in the region is anticipated to expand at a high CAGR during the forecast period. High per capita income has increased the consumption of diagnostic and therapy products in the region. Rapid expansion of the market in the region can be attributed to numerous government initiatives undertaken to improve the health care infrastructure. The market in Asia Pacific is estimated to expand rapidly compared to other regions due to shift in base of pharmaceutical companies and clinical research industries from developed to developing regions such as China and India. Moreover, changing lifestyles and increase in urbanization in these countries have led to a gradual escalation in the incidence of lifestyle-related diseases such as cancer, diabetes, and heart diseases.

Technological Advancements to Drive Market

Several companies are developing new approaches to culturing or utilizing stem cells for various applications. Stem cell technology is a rapidly developing field that combines the efforts of cell biologists, geneticists, and clinicians, and offers hope of effective treatment for various malignant and non-malignant diseases. The stem cell technology is progressing as a result of multidisciplinary effort, and advances in this technology have stimulated a rapid growth in the understanding of embryonic and postnatal neural development.

Adult Stem Cells Segment to Dominate Global Market

In terms of product type, the global stem cells market has been classified into adult stem cells, human embryonic stem cells, and induced pluripotent stem cells. The adult stem cells segment accounted for leading share of the global market in 2020. The capability of adult stem cells to generate a large number of specialized cells lowers the risk of rejection and enables repair of damaged tissues.

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Autologous Segment to Lead Market

Based on source, the global stem cells market has been bifurcated into autologous and allogenic. The autologous segment accounted for leading share of the global market in 2020. Autologous stem cells are used from ones own body to replace damaged bone marrow and hence it is safer and is commonly being practiced.

Regenerative Medicines to be Highly Lucrative

In terms of application, the global stem cells market has been categorized into regenerative medicines (neurology, oncology, cardiology, and others) and drug discovery & development. The regenerative medicines segment accounted for major share of the global market in 2020, as regenerative medicine is a stem cell therapy and the medicines are made using stem cells in order to repair an injured tissue. Increase in the number of cardiac diseases and other health conditions drive the segment.

Therapeutics Companies Emerge as Major End-users

Based on end-user, the global stem cells market has been divided into therapeutics companies, cell & tissue banks, tools & reagents companies, and service companies. The therapeutics companies segment dominated the global stem cells market in 2020. The segment is driven by increase in usage of stem cells to treat various illnesses in the body. Therapeutic companies are increasing the utilization of stem cells for providing various therapies. However, the cell & tissue banks segment is projected to expand at a high CAGR during the forecast period. Increase in number of banks that carry out research on stem cells required for tissue & cell growth and elaborative use of stem cells to grow various cells & tissues can be attributed to the growth of the segment.

Regional Analysis

In terms of region, the global stem cells market has been segmented into North America, Europe, Asia Pacific, Latin America, and Middle East & Africa. North America dominated the global stem cells market in 2020, followed by Europe. Emerging markets in Asia Pacific hold immense growth potential due to increase in income levels in emerging markets such as India and China leading to a rise in healthcare spending.

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Competition Landscape

The global stem cells market is fragmented in terms of number of players. Key players in the global market include STEMCELL Technologies, Inc., Astellas Pharma, Inc., Cellular Engineering Technologies, Inc., BioTime, Inc., Takara Bio, Inc., U.S. Stem Cell, Inc., BrainStorm Cell Therapeutics, Inc., Cytori Therapeutics, Inc., Osiris Therapeutics, Inc., and Caladrius Biosciences, Inc.

Stem Cells Market, by Application

Stem Cells Market, by End-user

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About Us

Transparency Market Research, a global market research company registered at Wilmington, Delaware, United States, provides custom research and consulting services. The firm scrutinizes factors shaping the dynamics of demand in various markets.The insights and perspectives on the markets evaluate opportunities in various segments. The opportunities in the segments based on source, application, demographics, sales channel, and end-use are analysed, which will determine growth in the markets over the next decade.

Our exclusive blend of quantitative forecasting and trends analysis provides forward-looking insights for thousands of decision-makers, made possible by experienced teams of Analysts, Researchers, and Consultants. The proprietary data sources and various tools & techniques we use always reflect the latest trends and information. With a broad research and analysis capability, Transparency Market Research employs rigorous primary and secondary research techniques in all of its business reports.

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Stem Cells Market to Expand at a CAGR of 10.4% from 2021 to 2028 Travel Adventure Cinema - Travel Adventure Cinema

Cardiac Stem Cells Comments Off on Stem Cells Market to Expand at a CAGR of 10.4% from 2021 to 2028 Travel Adventure Cinema – Travel Adventure Cinema | July 25th, 2022

Shortly after I was told I would need a heart transplant, in August 2014, a cardiac nurse visited my house. She scanned the room and noticed my exercise equipment. "You're not going to use that are you?", she asked me. "Yes", I replied, "why?"

My heart was operating at 13 percent and I was firmly told I couldn't be doing that sort of thing in my condition. The nurse said she would send round a physiotherapist called Nikki Simpson to tell me what I could and couldn't do while doctors tried to figure out what was going on with my heart.

"Nikki Simpson?" I asked. It couldn't be. The woman I had once known with the same name was training to be a hairdresser, plus she'd married and moved away.

We had first met as teenagers at a club in the north of England in 1984. I had wavy shoulder length hair and she always had some sort of red leather gear on. Usually, I'm not the sharpest knife in the drawer when it comes to flirting, but I could tell she liked me straight away.

We dated for about six months. I didn't drink much so we would go on long drives and spend time with mutual friends, but for some reason the relationship just fizzled out. Nothing bad happened, we just drifted apart.

I lived a bachelor life for a while. Eventually I got married and had my son, Robert. Nikki got married and had a baby girl. We only lived a village away from each other but I never saw her once.

When my son was eight my first marriage broke down and I cared for Robert. It was the hardest thing to do, but we had the best time of our lives. I did date when my son was younger, but nobody seemed to understand that Robert came first.

For years I'd been extremely fit, I was a plasterer by trade and had always had physical jobs. But in February, 2014, when I was doing some work putting up billboards in Leeds, I couldn't breathe and kept falling to my knees.

I visited the emergency room with my sister. I was told I had pneumonia and given a course of antibiotics. I took them for two weeks but still couldn't breathe properly, so I was told it was likely I had a respiratory condition and to visit my doctor.

After months of being referred to and from the hospital, my doctor told me he thought I had heart failure. He organized an MRI scan which showed my heart was globally dilated and operating at a fraction of its normal function. They said it was likely down to a virus, but had no idea which one.

I went back the next week and the doctor sat there, clicking away on his keyboard. He glanced across at me and said: "We need to discuss a heart transplant." There I was, this strapping Yorkshireman who doesn't drink, doesn't smoke, doesn't do anything untoward, who has a dodgy heart. I stopped listening to anything he said. I went back to my doctor who told me to stop whatever I was doing, go home and watch TV on the sofa.

I started going for various scans and a cardiac nurse began to visit me and curate my drugs, which is when she mentioned about a physio helping me.

One day in August 2014, this nurse she knocked on the door and said "The physio is on her way, but I need to ask your permission for her to treat you because you have a history." I said it was fine.

When Nikki knocked on my door, I swung it open and shouted "f*** off!" I grabbed her, sat her on the kitchen table and gave her a big kiss on the cheek.

It just sort of took off from there. We started seeing each other when she came round to treat me. I would go to the gym with her to do exercises and she would call round for a cup of tea in the evenings.

Robert was doing his first year at university studying aeronautical engineering and I was concerned because he was driving a fair distance home every day just so I wasn't at home by myself. Eventually, Nikki said she'd move in with me so Robert could go and live the dream.

It was ace having her around. Even at this point, when I thought I was dying and there was no cure for me, it was like this angel had walked through the door and made my life better.

The relationship with Nikki was great, but I was going to the hospital a lot. The tablets used to steady you and make you comfortable I just couldn't tolerate. I got to the stage where I spent so much time in the hospital the porters recognised me.

It looked like I was going to die. I had a mate who had his suit washed three times for my funeral. Whenever I saw him he would say: "Are you still here?"

In October 2017, we were watching TV when an interview with the Heart Cells Foundation came on. They'd created a stem-cell procedure which took bone marrow from a patient's pelvis then injected it straight into the heart. I wanted it.

The next day I phoned them and they said to come down for some tests. I qualified for the procedure and in November 2018 went down to St Bartholomew's Hospital in London and had the treatment. It changed my life overnight.

This horrific thing I was thinking about; someone dying and me taking their heart, wasn't going to happen anymore. That was three and a half years ago. I had thought I was going to be dead in months without a transplant.

From day one of leaving the hospital, I haven't had any problems at all. I go down for a yearly check up and the consultant wants me to have the treatment again. They've never done it twice but think they might get some good results.

Nikki has been ace throughout all of this. We're looking to get married next year. I didn't want to get married before the treatment. I didn't want to be pushed down the aisle in a wheelchair or go for a meal after and end up in an ambulance. But, now, I'm getting fit, strong and strapping, so we want to go with it.

Looking back, it seems so strange that Nikki and I parted ways. I don't know if I believe in fate, but since I was first told I'd need a heart transplant we've lost my dad, my brother, two aunties and Nikki's dad. All these people who have gone, I was supposed to go before them. My perspective on life has always been to live it today, because you don't know what's going to come tomorrow.

Barry Newman, 55, from Wakefield, was a plasterer before undergoing pioneering treatment with the Heart Cells Foundation, an independent charity which has run a small unit at St Bartholomew's Hospital since 2016. Earlier this year he carried the baton at the Commonwealth Games relay.

All views expressed in this article are the author's own.

As told to Monica Greep

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'My Teen Sweetheart And I Drifted Apart. 30 Years Later I Made a Shocking Discovery' - Newsweek

Cardiac Stem Cells Comments Off on ‘My Teen Sweetheart And I Drifted Apart. 30 Years Later I Made a Shocking Discovery’ – Newsweek | July 25th, 2022

In brief

In 2020, the European Commission began a review of the EUs rules on blood, tissues and cells (BTC) used for medical treatments and therapies. Now the Commission haspublisheda draft legislative proposal to amend the rules.

The proposal does not recommend a complete overhaul: the EU will not change its definitions of blood, tissue and cell products. Yet it does promise a significant update to the two Directives published in the early 2000s that continue to govern the use of BTC components in the EU. Most importantly, the proposed legislation would be packaged as a Regulation rather than a Directive, meaning it would have a direct effect in the Member States.

The legislation sets out quality and safety requirements for allactivitiesfrom donation to human application (unless the donations are used to manufacture medicinal products or medical devices, in which case the legislation only applies to donation, collection and testing).

In its press release, the European Commission states that every year, EU patients are treated with 25 million blood transfusions (during surgery, emergency, cancer or other care), a million cycles of medically assisted reproduction, over 35,000 transplants of stem cells (mainly for blood cancers) and hundred thousands of replacement tissues (e.g., for orthopedic, skin, cardiac or eye problems). These therapies are only available thanks to the willingness of fellow citizens to make altruistic donations.

In the EU, the collection, processing and supply of each individual unit is typically organized on a local small-scale by public services, (academic) hospitals and non-profit actors.

Afteralmost 20years in place, the legislationno longer addressesthe scientific and technicalstate of the art and needs to be updated to take into account developments that have taken place in the sector.

How is the Commission planning to change BTC legislation in the EU? Here are three key takeaways from the draft proposal.

Compensating Doctors

The tissue and cell directive currently in force explicitly permits the Member States to compensate donors of tissue and cell products for their trouble. The corresponding blood Directive, however, contains no such provision: in its absence, different countries have developed their own guidelines on blood donor compensation.

That disparity is addressed in the draft Regulation, which would allow the Member States to reimburse donors of all human-derived products for losses related to their participation in adonation through fixed-rate allowances. Improving access to plasma donation, advocates of compensation schemes hope, could help the EU to bolster its patchy stockpiles of the essential fluid.

Emergency Planning

The Covid-19 pandemic demonstrated the fragility of healthcare networks that rely heavily on external sources for their products. Supply chain disruptions are a particular threat to the availability of plasma-derived medicines in the bloc since much of the EUs plasma is imported from the USA.

With this in mind, the Commission wants the Member States to develop emergency plans to cope with supply shocks. Countries would be required to maintain lines of communication that could be used in emergencies, establish authorities responsible for distribution in critical situations, and detect risks to their continued access to substances of human origin.

Detecting Risks

As might be expected, the draft Regulation introduces measures to protect the health and privacy of donors and donees. Screening is mandated to prevent patients from receiving diseased blood or cancerous cells. Technical systems should be in place to preserve the anonymity of all parties to a BTC transfer.

The burden of safeguarding is particularly heavy where assisted reproduction is concerned. It would be up to the Member States, under the draft legislation, to detect and mitigate genetic risks posed by donated reproductive cells.

If approved, it is thought that the revisions will be endorsed by 2023, with implementation beginning in 2024.

For further information, please contact Julia Gillert of our London office.

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EU: New Blood? Proposed Revisions to the EUs Blood, Tissues and Cells Rules - GlobalComplianceNews

Cardiac Stem Cells Comments Off on EU: New Blood? Proposed Revisions to the EUs Blood, Tissues and Cells Rules – GlobalComplianceNews | July 25th, 2022

Wilmington, Delaware, United States, July 18, 2022 (GLOBE NEWSWIRE) -- Transparency Market Research Inc.: The market value of the global cell separation technologies market is estimated to be over US$ 20.3 Bn by 2031, according to a research report by Transparency Market Research (TMR). Hence, the market is expected expand at a CAGR of 11.9% during the forecast period, from 2022 to 2031.

According to the TMR insights on the cell separation technologies market, the prevalence of chronic disorders including obesity, diabetes, cardiac diseases, cancer, and arthritis is being increasing around the world. Some of the key reasons for this situation include the sedentary lifestyle of people, increase in the older population, and rise in cigarette smoking and alcohol consumption across many developed and developing nations. These factors are expected to help in the expansion of the cell separation technologies market during the forecast period.

Players in the global cell separation technologies market are increasing focus on the launch of next-gen products. Hence, they are seen increasing investments in R&Ds. Moreover, companies are focusing on different strategies including acquisitions and strengthening their distribution networks in order to stay ahead of the competition.

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As per the Imperial College London, chronic diseases are expected to account for approximately 41 million deaths per year, which seven out of 10 demises worldwide. Of these deaths, approximately 17 million are considered to be premature. Hence, surge in cases of chronic diseases globally is resulting into increased need for cellular therapies in order to treat such disease conditions, which, in turn, is boosting the investments toward R&Ds, creating sales opportunities in the cell separation technologies market.

Cell Separation Technologies Market: Key Findings

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Cell Separation Technologies Market: Growth Boosters

Cell Separation Technologies Market: Regional Analysis

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Cell Separation Technologies Market: Key Players

Some of the key players profiled in the report are:

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Cell Separation Technologies Market Segmentation

Modernization of healthcare in terms of both infrastructure and services have pushed the healthcare industry to new heights, Stay Updated with Latest Healthcare Research Reports by Transparency Market Research:

Cell Culture Market: Rise in outsourcing activities and expansion of biopharmaceutical manufacturers are expected to drive the cell culture market during the forecast period

Cell Culture Media, Sera, and Reagents Market: The global cell culture media, sera, and reagents market is majorly driven by growth and expansion of biotechnology & pharmaceutical companies and academic & research institutes.

Stem Cells Market: The global stem cells market is majorly driven by rising applications of stem cells in regenerative medicines. Increase in the number of chronic diseases such as cardiac diseases, diabetes, cancer, etc.

Cell Line Authentication and Characterization Tests Market: Increase in the geriatric population and surge in incidence of chronic diseases are projected to drive the global cell line authentication and characterization tests market.

CAR T-cell Therapy Market: The CAR T-cell therapy market is expected to clock a CAGR of 30.6% during the assessment period. The CAR T-cell therapy is known as a revolutionary treatment option for cancer, owing to its remarkably effective and durable clinical responses.

Cell & Tissue Preservation Market: Rise in investments in the field of regenerative medicine research is estimated to propel the market. Human blood, tissues, cells, and organs own the capability to heal damaged tissues and organs with long-term advantages.

Placental Stem Cell Therapy Market: Placental stem cell therapy market is driven by prominence in treatment of age-related disorders/diseases and increase in awareness about stem cell therapies are projected to drive the global market in the near future.

Biotherapeutics Cell Line Development Market: The market growth will be largely driven by research and development activities due to which, new solutions and technologies have gradually entered the market.

About Transparency Market Research

Transparency Market Research, a global market research company registered at Wilmington, Delaware, United States, provides custom research and consulting services. Our exclusive blend of quantitative forecasting and trends analysis provides forward-looking insights for thousands of decision makers. Our experienced team of Analysts, Researchers, and Consultants use proprietary data sources and various tools & techniques to gather and analyze information.

Our data repository is continuously updated and revised by a team of research experts, so that it always reflects the latest trends and information. With a broad research and analysis capability, Transparency Market Research employs rigorous primary and secondary research techniques in developing distinctive data sets and research material for business reports.

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Rohit BhiseyTransparency Market Research Inc.CORPORATE HEADQUARTER DOWNTOWN,1000 N. West Street,Suite 1200, Wilmington, Delaware 19801 USATel: +1-518-618-1030USA Canada Toll Free: 866-552-3453Website:https://www.transparencymarketresearch.comBlog:https://tmrblog.comEmail:sales@transparencymarketresearch.com

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Cell Separation Technologies Market Expands with Rise in Prevalence of Chronic Diseases, States TMR Study - GlobeNewswire

Cardiac Stem Cells Comments Off on Cell Separation Technologies Market Expands with Rise in Prevalence of Chronic Diseases, States TMR Study – GlobeNewswire | July 25th, 2022

WILMINGTON, Del., July 21, 2022 /PRNewswire/ --An in-depth demand analysis of dental membrane and bone graft substitutes found that massive demand for resorbable bone grafting materials presents value-grab opportunity. Companies in the dental membrane and bone graft substitutes market are actively leaning on development of novel biomaterials to meet the needs of bone grafting procedures. The TMR study projects the size of the market to surpass worth of US$ 1,337 Mn by 2031.

Advancements in periodontology are catalyzing introduction of new soft tissue regeneration, as emerging trends of the dental membrane and bone graft substitutes market underscore. Moreover, dental membrane and bone graft substitutes market projections in the TMR study have found that the use of xenograft for dental bone regeneration is anticipated to rise rapidly, and will unlock lucrative avenues. The fact that xenografts are cost-effective and show good results in bone tissue regeneration will spur the popularity of products in the segment.

Increasing number of bone regeneration procedures has led to the commercialization of novel biomaterials and dental bone grafts. The application of human cell sources in bone graft substitutes is growing, thus extending the canvas for companies in the dental membrane and bone graft substitutes market. Rise in oral disorders and injuries has impelled the need for bone substitute materials that can promise long-term survival rates in the patients.

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Key Findings of Dental Membrane and Bone Graft Substitutes Market Study

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Dental Membrane and Bone Graft Substitutes Market: Key Drivers

Dental Membrane and Bone Graft Substitutes Market: Regional Growth Dynamics

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Dental Membrane and Bone Graft Substitutes Market: Key Players

High degree of fragmentation has characterized the competition landscape in the dental membrane and bone graft substitutes market, mainly due to presence of several prominent players. Some of the key players are Zimmer Biomet, OPKO Health, Inc., NovaBone Products, LLC., Nobel Biocare Services AG, Geistlich Pharma AG, Dentsply Sirona, Collagen Matrix, Inc., BioHorizons, and Institut Straumann AG.

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Dental Membrane and Bone Graft Substitutes Market Segmentation

Regions Covered

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Modernization of healthcare in terms of both infrastructure and services have pushed the healthcare industry to new heights, Stay Updated withLatest Healthcare Research Reportsby Transparency Market Research:

Non-Invasive Prenatal Testing Market: Non-invasive prenatal testing market was worth around US$ 1.3 Bn in 2018. The market is likely to develop at a CAGR of 16.4% during the forecast period, from 2019 to 2027.

Cell Culture Media, Sera, and Reagents Market: The global cell culture media, sera, and reagents market is majorly driven by growth and expansion of biotechnology & pharmaceutical companies and academic & research institutes.

Stem Cells Market: The global stem cells market is majorly driven by rising applications of stem cells in regenerative medicines. Increase in the number of chronic diseases such as cardiac diseases, diabetes, cancer, etc.

Cell Line Authentication and Characterization Tests Market: Increase in the geriatric population and surge in incidence of chronic diseases are projected to drive the global cell line authentication and characterization tests market.

CAR T-cell Therapy Market: The CAR T-cell therapy market is expected to clock a CAGR of 30.6% during the assessment period. The CAR T-cell therapy is known as a revolutionary treatment option for cancer, owing to its remarkably effective and durable clinical responses.

Cell & Tissue Preservation Market: Rise in investments in the field of regenerative medicine research is estimated to propel the market. Human blood, tissues, cells, and organs own the capability to heal damaged tissues and organs with long-term advantages.

mHealth Monitoring Diagnostic Medical Devices Market: The global mHealth monitoring diagnostic medical devices market was valued at US$ 29.05 Bn in 2018 and is projected to expand at a CAGR of 20.5% from 2019 to 2027.

Pediatric Medical Devices Market: The global pediatric medical devices market was valued at US$ 21,000 Mn in 2017 and is projected to expand at a CAGR of 8.0% from 2018 to 2026.

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Dental Membrane and Bone Graft Substitutes Market to Exceed Value of US$ 1,337 Mn by 2031 - PR Newswire UK

Cardiac Stem Cells Comments Off on Dental Membrane and Bone Graft Substitutes Market to Exceed Value of US$ 1,337 Mn by 2031 – PR Newswire UK | July 25th, 2022

Almost one out of 100 babies are born with a heart defect each year in the United States. Many of these babies will need surgery within weeks of birth, followed by more surgeries throughout their lives. Now, doctors are turning to stem cells to give big hope for little hearts.

Hypoplastic left heart syndrome is a complex congenital heart disease. It is where the left ventricle does not develop, Sunjay Kaushal, MD, Ph.D., Chief of Pediatric Cardiac Surgery at Lurie Childrens Hospital in Chicago, explained.

Hypoplastic left heart syndrome

Those newborns depend solely on their right ventricles to pump blood throughout their bodies.

Kaushal emphasizes, These babies need surgical intervention in the first weeks of life.

Between 15% and 20% of those babies will not live to see their first birthday. For the little ones who do, medications and implanted devices can help, but ultimately, those children will need a heart transplant to survive.

That right ventricle becomes tired. It doesn't pump blood efficiently, Kaushal further explains.

The latest news from around North Texas.

Pediatric cardiac surgeons at Lurie Childrens Hospital are injecting stem cells directly into the heart to revitalize the worn-out right ventricle.

We're trying to see if we can actually put stem cells in there in order to remodel, rejuvenate that right ventricle in order to pump blood more efficiently for that baby, Kaushal said.

In the long run, stem cell therapy could possibly prevent those children from needing a heart transplant at all.

Kaushal added, I think that these studies could be game-changing for our babies.

They said 38 patients will be enrolled at seven clinical sites across the United States for a phase two clinical trial this year. Researchers hope that eventually, the stem cell injections will not have to be given as an injection into the heart, but as an intravenous injection like other medicine.

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Stem Cells Used to Repair Heart Defects in Children - NBC 5 Dallas-Fort Worth

Cardiac Stem Cells Comments Off on Stem Cells Used to Repair Heart Defects in Children – NBC 5 Dallas-Fort Worth | July 16th, 2022

Affecting one in 5,000 male births worldwide, Duchenne Muscular Dystrophy (DMD) is a fatal genetic disorder that currently doesnt have a cure, but published research conducted at the University of Nevada, Reno School of Medicine shows promise and may lead to the eventual development of a new molecular therapeutic.

The latest, significant research finding, published in Human Molecular Genetics, February 2022, involves the small-molecule sunitinib which has been shown to mitigate DMD-related skeletal muscle disease in a number of ways.

As patients with DMD grow older, muscular dystrophy worsens, causing respiratory and cardiac muscle failure resulting in premature death. There are no effective treatments to prevent DMD-related cardiac failure, however continued research in the lab of UNR Med Professor of Pharmacology Dean Burkin is pointing to protein and molecular-based solutions, including sunitinib which is already FDA approved and used in cancer treatments.

Burkin conducted the latest research with Ph.D. student Ariany Oliveira-Santos. Based on a mouse model, they found that sunitinib improved major negative symptoms that stem from DMD, such as cardiac muscle damage, without depressing the immune system completely. Oliveira-Santos was lead author on the published results. The study was supported by a grant from the Muscular Dystrophy Association and the National Institutes of Health.

Burkins lab focuses mainly on studying two key proteins 71 integrinand laminin and understanding the role they play in muscle development and disease. The lab primarily studies two muscle-damaging diseases: DMD and Laminin-2 related congenital muscular dystrophy (LAMA2-CMD).

Were interested in the biology of the 71 integrin, that's really the central focus of [our research], Burkin said. But we also have other big interests in these muscle diseases where the integrin [protein] is normally found.

Burkin explains that through this translational research, which he also calls the lab bench to bedside approach, researchers attempt to understand the biology of a system as much as possible, and then continue through the development steps that lead to therapeutic treatments.

Patients with DMD lack dystrophin which causes progressive muscle degeneration and weakness. This means the more these muscles are used, the more damage occurs. While there are repair cells in muscles, these cells eventually tire out. Burkin and Oliveira-Santos noted that the heart, an organ being used all the time, does not have this repair system, making the damage severe in cardiac muscles as well. Currently some therapeutic approaches have been beneficial for skeletal muscles but not for the heart; therefore, its important to have a drug or treatment that can target and be beneficial to skeletal and cardiac muscle at the same time, Oliveira-Santos explained.

We looked to the electrical and mechanical function of the heart and both were improved, Oliveira-Santos said. Sunitinib helped the cardiac function [and reduced] cardiac damage, and inflammation. I don't think theres really many drugs out there that do that right now.

Oliveira-Santos remembers wanting to be a scientist as early as eight years old. She went on to earn degrees in Brazil, including a bachelors in biomedicine and a masters in the scientific fields of immunology and pharmacology as they relate to transplant rejection. While earning her masters degree, Burkin was invited to Brazil by Oliveira-Santoss supervisor to give a talk, and the two met in-person and discussed her masters project. At the time, they were studying the same molecule, but in different models, so Oliveira-Santos had read some of Burkins papers.

Oliveira-Santos had always been interested in the physiology and pathology of disease and thought it would be a great area to study for a doctoral degree. She knew Burkin was working in this field, so about five years after their in-person meeting, Oliveira-Santos reached out to Burkin. He told her about an open position in his lab for a Ph.D. student, and their project of understanding the role of an FDA-approved small molecule for the treatment of DMD cardiomyopathy. She felt this project was a good match for what she was looking for and joined the lab in January 2019.

Oliveira-Santos said the mentorship and support shes received from Burkin and the rest of the lab has been invaluable.

Dean is always available to discuss and very happy to help [the lab members] with everything we need, Oliveira-Santos said. Everyone had an important opinion about the project and that was essential for the projects success.

While working in science oftentimes can come with struggles, Oliveira-Santos expressed how much these experiences have taught her.

Being in science is a big challenge, because you have to learn how to deal with problems all the time, she said. There are more failures than success [so] it teaches you how to deal with failure. Failure is normal. You just need to try to find a way around to get a solution.

Oliveira-Santos is set to finish her Ph.D. in Cellular and Molecular Pharmacology & Physiology in the fall 2022.

When I bring a student to the lab, I say I can supply everything but enthusiasm. And that's one thing that Ariany brings in abundance, Burkin said. I'm putting my students in contact with other principal investigators that I know to try and make sure that the next level on their career is achieved. She can go anywhere right now and move forward. The world is her oyster.

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Promising solution to fatal genetic-disorder complications discovered by University professor and Ph.D. candidate - Nevada Today

Cardiac Stem Cells Comments Off on Promising solution to fatal genetic-disorder complications discovered by University professor and Ph.D. candidate – Nevada Today | July 16th, 2022