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CuSTOM Organoid Research Evolving From Tool to Treatment – Research Horizons – Research Horizons

Two scientists at Cincinnati Childrens describe the fast-evolving field of organoid medicine as todays research tool, tomorrows organ transplant solution.

A special feature published March 14, 2024, in Science explores advances made by the Cincinnati Childrens Center for Stem Cell and Organoid Medicine (CuSTOM). The article features organoid experts Takanori Takebe, MD, PhD, and Mingxia Gu, MD, PhD.

These 3D formations, grown from induced pluripotent stem cells (iPSCs), are living mini-organs that include the key cell types of full-sized organs.

Already, organoids are showing value as test platforms for preclinical drug testing and ongoing basic studies of human development. Longer term, experts at CuSTOM envision organoids grown from a patients own cells serving as a new method to treat disease and repair organ damage.

Read more about CuSTOM in Science.

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CuSTOM Organoid Research Evolving From Tool to Treatment - Research Horizons - Research Horizons

UCF Researchers Develop Novel Therapy for Incurable Brain Cancer – UCF

College of Medicine researchers are developing a more effective way to treat glioblastoma an aggressive, incurable form of brain cancer. Patients currently live just 12 to 15 months after diagnosis despite surgery, radiation and chemotherapy.

New research led by Kiminobu Sugaya, a stem cell researcher and neuroscientist at UCFs Burnett School of Biomedical Sciences, found that targeting a drug resistant mechanism in cancer stem cells significantly enhanced the efficacy of traditional cancer therapies making them four times more effective against glioblastoma. Current FDA-approved drugs kill less than 25% of glioblastoma cancer stem cells (CSCs).

These cells are a subpopulation of cancer cells that are highly resistant to current therapies. Scientists theorize that cancer returns and spreads because CSCs remain in the body. Thats why they are exploring ways to kill them outright.

Cancer stem cells are bad stem cells that are programed to become a cancer, Sugaya says. They withstand cancer therapies, raise their ugly head, regrow and metastasize.

Sugayas team developed a new drug delivery system by creating a technology that destroys the RNA, or ribonucleic acid, that the stem cells use as a blueprint to produce proteins. This unique strategy inhibits the expression of embryonic stem cell genes that are pivotal in CSCs drug resistance. And because embryonic stem cell genes are not expressed in normal adult cells, this breakthrough approach reduces potential for side effects in healthy cells.

Jonhoi Smith is a doctoral student under Sugaya and the first author on their research paper published in the journal Genes. He said the treatment could increase life expectancy for glioblastoma patients.

This treatment could be a precious gift for glioblastoma patients. When I think about the loved ones Ive lost in my life my father, my grandmother I often wish I could have had more time with them, he says. The idea of offering the potential of a whole new life to people who are facing a death sentence in less than a year means a lot to me.

One of the significant challenges in treating glioblastoma is effectively delivering treatments to the brain. Thats because the brain is protected from external germs and substances by the blood-brain barrier, which can also prevent treatments from reaching brain tissues.

To overcome this obstacle, Sugayas therapy is based on exosomes, nano-sized particles with a lipid membrane that are naturally produced by cells. Exosomes function as cellular communicators, transporting proteins, lipids and genetic material between cells, thereby influencing a wide array of biological processes and functions. Their efficiency in carrying molecules across various parts of the body has inspired scientists to investigate exosomes as potential drug delivery vehicles.

Many current drug delivery systems, including viruses, may cause side effects, Sugaya explains. Were using the bodys natural delivery systems and have developed technologies to modify them to carry therapeutic molecules with targeted delivery to specific tissues.

Marvin Hausman is CEO of Exousia AI, the company that is funding the glioblastoma exosome preclinical research. He heard about Sugayas lab and says that when he visited the lab at UCFs Academic Health Sciences Campus in Lake Nona, he was inspired by its capacity for innovative discoveries.

I have thoroughly analyzed this exosome-based targeted drug delivery system many times, and the potential that this unique technology offers. Hausman says. We are embarking on a revolutionary new development in medicine.

Thanks to funding from Exousia AI, the research is advancing to mouse models carrying human glioblastoma, with preliminary results expected as early as this summer.

Sugaya has dedicated more than 40 years to neuroscience research focused on Alzheimers disease, with an emphasis on stem cells for the last 26 years. He moved to the U.S. after receiving his doctoral degree from the Science University of Tokyo in 1988. He joined UCF as a professor in 2004. His cancer research began in 2010 when he discovered stemness gene expressions, the self-renewing and differentiating property that allows stem cells to grow and spread, in CSCs. He is recognized as an expert in the field of exosome research and recently received Florida Innovation Funding from the State Department of Health for his studies.

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UCF Researchers Develop Novel Therapy for Incurable Brain Cancer - UCF

BioCardia and StemCardia Announce Biotherapeutic Delivery Partnership – Diagnostic and Interventional Cardiology

March 15, 2024 BioCardia, Inc., a biotechnology company focused on advancing late-stage cell therapy interventions for cardiovascular disorders, andStemCardia, Inc., a biotechnology company focused on cell and gene therapy to re-muscularize the failing heart, today announced a long-term partnership to advance StemCardias investigational pluripotent stem cell product candidate for the treatment of heart failure.

Under the partnership, BioCardia is the exclusive biotherapeutic delivery partner for StemCardias cell therapy candidate through studies expected to result in FDA approval of an investigational new drug application (IND) and the anticipated Phase I/II clinical development to follow.

BioCardia has established safe and minimally invasive delivery of cellular medicines directly into the heart, said Chuck Murry, MD, PhD, StemCardias Founder and CEO. Having worked with BioCardia to successfully deliver our bona fide cardiac muscle cells in large animal models of heart failure, we are excited for this partnership to accelerate clinical development and broaden future commercial access to an off-the-shelf heart regeneration treatment.

StemCardias team encompasses recognized leaders in the field of cardiac regenerative medicine who are pursuing an elegant strategy to repair the failing heart. We look forward to supporting their efforts with our experienced team and proven, proprietary Helix biotherapeutic delivery system, said BioCardia CEO Peter Altman, PhD. This partnership is expected to enhance future treatment options for millions of people suffering from heart failure, offset the costs of biotherapeutic delivery development for our own programs, and provide our investors with meaningful revenue sharing should our efforts together contribute to StemCardias successful therapeutic development.

For more information:www.biocardia.com

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BioCardia and StemCardia Announce Biotherapeutic Delivery Partnership - Diagnostic and Interventional Cardiology

New Positive Data Presented on Briquilimab Conditioning in Patients with Fanconi Anemia – GlobeNewswire

REDWOOD CITY, Calif., March 15, 2024 (GLOBE NEWSWIRE) -- Jasper Therapeutics, Inc. (Nasdaq: JSPR) (Jasper), a biotechnology company focused on development of briquilimab, a novel antibody therapy targeting c-Kit (CD117) to address mast cell driven diseases such as chronic spontaneous urticaria (CSU) and chronic inducible urticaria (CIndU), announced additional positive Phase 1b/2a data on briquilimab as a conditioning agent in the treatment of Fanconi Anemia (FA).

The data was presented at the 2024 Stanford Medicine Center for Definitive and Curative Medicine Symposium on March 13, 2024, in Palo Alto, California.

The ongoing investigator initiated Phase 1b/2a clinical trial is evaluating a conditioning regimen that includes intravenous briquilimab as a potential treatment for FA patients in bone marrow failure. Data from the study show that briquilimab infusion has a promising safety profile and appears to be well tolerated in patients with FA, with all six patients treated achieving full donor engraftment and full blood count recovery.

We continue to be encouraged by the results from Stanford Medicine's Phase 1b/2a study in Fanconi Anemia, which demonstrates the potential of briquilimab to serve as a key component of non-toxic conditioning regimens for stem cell transplant, said Edwin Tucker, Chief Medical Officer of Jasper. Wed like thank our collaborators at Stanford Medicine for their work evaluating briquilimab in this vulnerable patient population.

About Briquilimab

Briquilimab (formerly JSP191) is a targeted aglycosylated monoclonal antibody that blocks stem cell factor from binding to the cell-surface receptor c-Kit, also known as CD117, thereby inhibiting signaling through the receptor. This inhibition disrupts the critical survival signal, leading to the depletion of the mast cells via apoptosis which removes the underlying source of the inflammatory response in mast cell driven diseases such as chronic urticaria. Jasper is currently conducting clinical studies of briquilimab as a treatment in patients with CSU or with CIndU. Briquilimab is also currently in clinical studies as a treatment for patients with LR-MDS and as a conditioning agent for cell and gene therapies for rare diseases. To date, briquilimab has a demonstrated efficacy and safety profile in more than 145 dosed participants and healthy volunteers, with clinical outcomes as a conditioning agent in severe combined immunodeficiency (SCID), acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), FA, and sickle cell disease (SCD).

About Fanconi Anemia

Fanconi Anemia (FA) is a rare but serious blood disorder that prevents the bone marrow from making sufficient new red blood cells. The disorder can also cause the bone marrow to make abnormal blood cells. FA typically presents at birth or early in childhood between five and ten years of age. Ultimately, it can lead to serious complications, including bone marrow failure and severe aplastic anemia. Cancers such as acute AML and MDS are other possible complications. Treatment may include blood transfusions or medicine to create more red blood cells, but a hematopoietic stem cell transplant (HSCT) is currently the only cure.

About Phase 1/2 clinical trial (NCT04784052)

The Stanford sponsored, investigator initiated Phase 1/2 study is an open-label clinical trial evaluating briquilimab as a potential treatment for FA patients in bone marrow failure (BMF) requiring allogeneic transplant. Utilizing briquilimab, the regimen eliminates the need for busulfan chemotherapy or total body irradiation. Participants with FA with BMF receive allo-HCT with TCR+ T-cell/CD19+ B-cell depleted hematopoietic grafts from 10/10 unrelated, 9/10 unrelated or haploidentical family donors. A 0.6 mg/kg dose of briquilimab is administered in combination with standard FA dosing of anti-thymocyte globulin (ATG), cyclophosphamide, fludarabine, and rituximab as lymphodepletion. The primary outcomes include safety, efficacy, and engraftment success.

About Jasper

Jasper is a clinical-stage biotechnology company developing briquilimab, a monoclonal antibody targeting c-Kit (CD117) as a therapeutic for chronic mast and stem cell diseases such as chronic urticaria and lower to intermediate risk MDS and as a conditioning agent for stem cell transplants for rare diseases such as SCD, FA and SCID. To date, briquilimab has a demonstrated efficacy and safety profile in more than 145 dosed participants and healthy volunteers, with clinical outcomes as a conditioning agent in SCID, acute myeloid leukemia, MDS, FA, and SCD. For more information, please visit us atwww.jaspertherapeutics.com.

Forward-Looking Statements

Certain statements included in this press release that are not historical facts are forward-looking statements for purposes of the safe harbor provisions under the United States Private Securities Litigation Reform Act of 1995. Forward-looking statements are sometimes accompanied by words such as believe, may, will, estimate, continue, anticipate, intend, expect, should, would, plan, predict, potential, seem, seek, future, outlook and similar expressions that predict or indicate future events or trends or that are not statements of historical matters. These forward-looking statements include, but are not limited to, statements regarding briquilimabs potential, including its potential as a conditioning agent in the treatment of FA and FA patients in bone marrow failure and its safety profile, its potential to serve as a key component of non-toxic conditioning regimens for stem cell transplant and its potential to address mast cell driven diseases such as CSU and CIndU. These statements are based on various assumptions, whether or not identified in this press release, and on the current expectations of Jasper and are not predictions of actual performance. These forward-looking statements are provided for illustrative purposes only and are not intended to serve as, and must not be relied on by an investor as, a guarantee, an assurance, a prediction or a definitive statement of fact or probability. Many actual events and circumstances are beyond the control of Jasper. These forward-looking statements are subject to a number of risks and uncertainties, including general economic, political and business conditions; the risk that the potential product candidates that Jasper develops may not progress through clinical development or receive required regulatory approvals within expected timelines or at all; the risk that clinical trials may not confirm any safety, potency or other product characteristics described or assumed in this press release; the risk that Jasper will be unable to successfully market or gain market acceptance of its product candidates; the risk that prior study results may not be replicated; the risk that Jaspers product candidates may not be beneficial to patients or successfully commercialized; patients willingness to try new therapies and the willingness of physicians to prescribe these therapies; the effects of competition on Jaspers business; the risk that third parties on which Jasper depends for laboratory, clinical development, manufacturing and other critical services will fail to perform satisfactorily; the risk that Jaspers business, operations, clinical development plans and timelines, and supply chain could be adversely affected by the effects of health epidemics; the risk that Jasper will be unable to obtain and maintain sufficient intellectual property protection for its investigational products or will infringe the intellectual property protection of others; and other risks and uncertainties indicated from time to time in Jaspers filings with the SEC, including its Annual Report on Form 10-K for the year ended December 31, 2023 and subsequent Quarterly Reports on Form 10-Q. If any of these risks materialize or Jaspers assumptions prove incorrect, actual results could differ materially from the results implied by these forward-looking statements. While Jasper may elect to update these forward-looking statements at some point in the future, Jasper specifically disclaims any obligation to do so. These forward-looking statements should not be relied upon as representing Jaspers assessments of any date subsequent to the date of this press release. Accordingly, undue reliance should not be placed upon the forward-looking statements.

Contacts:

Joyce Allaire (investors) LifeSci Advisors 617-435-6602 jallaire@lifesciadvisors.com

Alex Gray (investors) Jasper Therapeutics 650-549-1454 agray@jaspertherapeutics.com

Lauren Walker (media) Real Chemistry 646-564-2156 lbarbiero@realchemistry.com

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New Positive Data Presented on Briquilimab Conditioning in Patients with Fanconi Anemia - GlobeNewswire

Notoginsenoside R1 promotes Lgr5+ stem cell and epithelium renovation in colitis mice via activating Wnt/-Catenin … – Nature.com

Chemicals and reagents

Notoginsenoside R1 (NGR1, BP1010, C47H80O18, purity 98%, CAS No 80418-24-2, MW: 933.13Da) was purchased from Chengdu Purifa Technology Development Co. Ltd (Chengdu, China). Dextran sulfate sodium salt (DSS, 0216011010, MW: 36kDa50kDa) was purchased from MP Biomedicals (Shanghai, China). Salicylazosulfapyridine (SASP, S0883, C18H14N4O5S, CAS No 599-79-1, MW: 398.39Da) and FITC-dextran (FD4, CAS No 60842-46-8) was purchased from Sigma-Aldrich (Darmstadt, Germany). ICG-001 (T6113, C33H32N4O4, purity 98%, CAS No 780757-88-2, MW: 548.64Da) was acquired from TOPSCIENCE (Shanghai, China). Water-DEPC treated (693520) and DMSO (D8418) were obtained from MilliporeSigma (Burlington, MA, USA).

NCM460 human intestinal epithelial cells and CT26 murine colon carcinoma cells were obtained from the American Type Culture Collection (ATCC, Manassas, VA, USA). NCM460 and CT26 cells were cultured in Roswell Park Memorial Institute (RPMI)-1640 culture medium (11875085, Gibco, NY, USA) supplemented with 10% fetal bovine serum (10099158, Gibco, NY, USA). The culture conditions included a humidified atmosphere containing 5% CO2, with a constant temperature maintained at 37C.

The Laboratory Animal Center of Shanghai University of Traditional Chinese Medicine provided female C57BL/6 mice weighing 202g. These mice were housed in a specific pathogen-free facility under meticulously controlled conditions, including a temperature range of 2325C, humidity maintained at 60%70%, and a well-regulated 12-h light-dark cycle. The Animal Experimentation Ethics Committee of Shanghai University of Traditional Chinese Medicine granted approval (PZSHUTCM2307310004) for experimental procedures conducted on the animals. All experiments were conducted in accordance with institutional animal care guidelines and protocols approved by the committee.

According to the method reported by Yue [26], we established the acute colitis mouse model. Briefly, female C57BL/6 mice were divided randomly into four groups: Control, DSS, DSS+SASP, and DSS+NGR1. Acute colitis was induced by administering 3% DSS in the drinking water of mice for a period of 8 days. Mice in the DSS+SASP group were treated orally with SASP (260mg/kg) once per day for the same duration. The DSS+NGR1 group received NGR1 (25, 50, 125mg/kg) by oral gavage once per day for 10 days. Mice in the Control and DSS groups were administered the same volume of Control. Daily monitoring of body weight and rectal bleeding was conducted throughout the 10-day period. At the end of the experiment, mice were euthanized, and the colon was collected for further analysis.

Female C57BL/6 mice were randomly divided into four groups: DSS, DSS+ICG-001, DSS+NGR1 and DSS+ICG-001+NGR1. To establish an acute enteritis model, mice were subjected to the protocol described above. Mice in the DSS+NGR1 and DSS+ICG-001+NGR1 group were given NGR1 (25mg/kg) orally once daily for 10 consecutive days. Meanwhile, mice in the DSS+ICG-001 and DSS+ICG-001+NGR1 groups were given ICG-001 (20mg/kg) via intraperitoneal injection three times per week. The DSS and DSS+NGR1 groups received the same volume of Control.

Male BALB/c mice were acclimated for 1 week in a specific pathogen-free environment. Subsequently, CT26 cells (2105 cells/mouse) were subcutaneously transplanted into the left axillary region of each mouse. Once the tumor size reached 200mm3, the mice were randomly assigned to the vehicle group or the NGR1 group based on tumor size. Throughout the 18-day experiment, mice in the vehicle group received 0.5% CMC-Na, while those in the NGR1 group were administered 25mg/kg NGR1. Tumor volume=0.5length (mm)width (mm)2.

C57BL/6 mice were fasted for 4h before execution. Mice were then orally administered 60mg/100g body weight of FITC-dextran in 200L of sterile saline. After 4h, blood samples were collected via retro-orbital bleeding, and serum was separated by centrifugation. The serum FITC-dextran levels were measured at an excitation wavelength of 485nm and an emission wavelength of 528nm using a fluorometer (VARIOSKAN FLASH, Thermo Fisher, MA, USA).

Colonic tissues were collected from mice and fixed in 4% paraformaldehyde. Tissues were then dehydrated, embedded in paraffin, and sectioned into 4m thick slices. The sections were then stained with hematoxylin and eosin (H&E) using standard protocols. Stained sections were analyzed under a light microscope (BX61VS, Olympus, Tokyo, Japan), and images were captured for further analysis.

The concentrations of DAO (CSB-E10090m) and LPS (CSB-E13066m) in mouse serum samples were determined using the respective ELISA kit (Wuhan Huamei Biological Engineering Co., Ltd, Wuhan, China). Specifically, serum samples were added to a 96-well plate coated with DAO or LPS-specific antibodies, followed by incubation with detection reagents and substrate solution. Absorbance was measured at 450nm, and concentrations were calculated using standard curves.

Colonic tissues were fixed in 4% paraformaldehyde, embedded in OCT compound, and sectioned into 5-m slices. After permeabilization and blocking, sections were incubated with primary antibodies against ZO-1 (#13663, Cell Signaling Technology, CST, MA, USA) and Occludin (#91131, CST, MA, USA), followed by secondary antibodies conjugated to fluorophores (9300039001, ABclonal, Wuhan, China). Nuclei were counterstained with DAPI (#4083, CST, MA, USA), and images were obtained using a fluorescence microscope (BX61VS, Olympus, Tokyo, Japan). Quantification of ZO-1 and Occludin expression was performed using ImageJ software (NIH, Bethesda, MD, USA).

Colonic tissue samples were obtained from mice, fixed, dehydrated, embedded in paraffin blocks, sectioned, and stained with Alcian blue using a commercial kit. Under a light microscope (BX61VS, Olympus, Tokyo, Japan), the stained sections were examined and images were captured for subsequent analysis.

RNA was extracted using the TRIzol method, and RNA quantity and purity were measured by NanoDrop spectrophotometer (Thermo Fisher Scientific). The RNA was then reverse-transcribed using an Evo M-MLV RT Premix for qPCR kit (AG11706, Accurate Biotechnology Co., Ltd., Chengdu, China), and qPCR was performed using a SYBR Green Premix Pro Taq HS qPCR Kit (AG11718, Accurate Biotechnology Co., Ltd., Chengdu, China) (Table1). The amplification was carried out using an ABI Prism 7900HT Sequence Detection System (Life Technologies, CA, USA), and data were analyzed using the 2Ct method.

Colonic tissues were extracted and homogenized, and protein was obtained using RIPA lysis buffer with phosphatase and protease inhibitors. Protein concentration was measured using a BCA assay kit (20201ES76, Yeasen Biotech Co., Ltd, Shanghai, China). Equal amounts of protein were loaded onto SDS-PAGE (sodium dodecyl sulfate polyacrylamide gel electrophoresis) gels and separated by electrophoresis. Subsequently, the separated proteins were transferred onto PVDF membranes (000025736, Milipore, MA, USA). The membrane was then blocked with 5% BSA solution for 2h. After blocking, the membrane was incubated with primary antibodies overnight at 4C, followed by incubation with HRP-conjugated secondary antibodies for 1h at room temperature. Protein bands were visualized using ECL reagents (WBKLS0500, Millipore) and imaged with a GS-700 imaging densitometer (Bio-Rad, CA, USA). Protein expression levels were quantified using ImageJ software (NIH, Bethesda, MD, USA). The following primary antibodies were used: rabbit anti--Catenin (1:1000, #8480, CST, MA, USA), rabbit anti-p-GSK-3 (1:1000, #5558, CST, MA, USA), rabbit anti-GSK-3 (1:1000, #12456, CST, MA, USA), rabbit anti-Cyclin D1 (1:1000, #2922, CST, MA, USA), rabbit anti-c-Myc (1:1000, #5605, CST, MA, USA) and rabbit anti--actin (1:1000, #4970, CST, MA, USA).

Colonic tissue sections were fixed in 4% paraformaldehyde, embedded in paraffin, and sliced into 5m thick sections. Antigen retrieval was performed using citrate buffer solution (pH=6.0) and heating in a microwave oven. Non-specific binding was blocked with 5% goat serum for 30min. Sections were incubated overnight at 4C with primary antibodies, followed by incubation with a secondary antibody and staining with DAB (3,3-diaminobenzidine). Hematoxylin was used for counterstaining before the sections were examined microscopically and images were captured.

Total RNA was extracted from mouse intestinal tissues using TRIzol reagent according to the manufacturers instructions. The extracted RNA was evaluated for quality using a NanoDrop spectrophotometer (Thermo Fisher). RNA sequencing libraries were then constructed with the NEBNext Ultra RNA Library Prep Kit for Illumina, and sequencing was performed on an Illumina HiSeq platform. The differential gene was carried out on the cloud platform of majorbio (https://www.majorbio.com/).

Caco-2 cells were seeded in Millicell inserts of 24-well plates at a density of 5104 cells/400L per well. The outer chamber was filled with 600L DMEM medium (2323012, Gibco, NY, USA) and replaced every other day. TEER values were measured using a MERS00002 volt-ohm meter system (Milipore), and the electrode was sterilized with 70% ethanol and rinsed with sterile phosphate-buffered saline (PBS) before each measurement. Monolayer formation was assumed at TEER values of 400/cm2. Measurements were taken at regular intervals using the same electrode and recorded.

The intestinal crypts were isolated from the small intestine of C57BL/6 mice (6- to 8-week-old). The small intestine was removed and flushed with ice-cold PBS. The intestine was opened longitudinally and cut into 2- to 3-mm pieces. The pieces were then washed with ice-cold PBS and incubated in 3mM EDTA solution at 4C for 20min with gentle shaking. After incubation, the crypts were released by vigorously shaking the tubes. The supernatant containing the crypts was collected and filtered through a 70-m cell strainer. The crypts were then centrifuged at 1200r/min for 5min and resuspended in Matrigel (Corning, NA, USA). The crypt-Matrigel mixture was plated in 24-well plates and incubated at 37C for 30min to allow the Matrigel to solidify. The IntestCultTM OGM Mouse Basal Medium (#06005, STEMCELL, Vancouver, Canada) was then added to the wells and changed every other day.

After cultured 2 days in a 24 well plate, the intestinal crypts were randomly divided into control, DSS model group and DSS+NGR1 group. Then, the organoids were administered DSS (20g/mL), DSS (20g/mL) plus NGR1 (100M) for 4 days. The organoid growth conditions were recorded by the microscope (Olympus CKX4, Tokyo, Japan). IHC assay was conducted to examine the fluorescent protein expression of Lgr5 and -Catenin (refer to the above method of IHC).

The molecular docking was performed using AutoDock Vina software. The 3D crystal structure of -Catenin protein (PDB: 1JDH) was obtained from the Protein Data Bank (PDB) database. The structure of NGR1 was drawn and optimized using ChemDraw software and converted to a PDB file using Open Babel software. The protein and ligand files were prepared using AutoDock Tools. Docking simulations were performed and the conformation with the lowest binding energy was selected as the final docking result. The docking results were analyzed using PyMOL software.

The TOPFlash assay was performed as previously described with slight modifications [27]. HEK293T cells were seeded in 24-well plates and cultured overnight. The cells were transfected with the 500ng TOPFlash luciferase reporter plasmids (Beyotime Biotechnology, Shanghai, China) and 50ng Renilla luciferase (Promega GmbH, Mannheim, Germany) using Lipofectamine 3000 (Thermo Fisher). After 24h, the cells were treated with NGR1 (50M) and BIO (0.5M) for 24h, separately. Subsequently, cells were lysed in 150L/well passive phenylbenzothiazole (PPBT) buffer, and the luciferase activity was measured using a Dual-LuciferaseTM Reporter Assay System (Promega Corporation, WI, USA). The firefly luciferase activity was normalized to Renilla luciferase activity.

A scratch wound was created using a plastic pipette (10L) tip. NCM460 cells were then washed with PBS to remove any debris and treated with either DSS (20g/mL) or DSS (20g/mL)+NGR1 (100M) for 24h. The width of the scratch was measured using microscopy at 0 and 24h post-dosing, and the percentage of wound closure was calculated by comparing the scratch width at 24h to the initial scratch width.

NCM460 cells were treated with either DSS (20g/mL) or DSS (20g/mL)+NGR1 (100M) for 24h. Then, NCM460 cells were harvested and washed with PBS after experimental treatment. Cells were then suspended in a binding buffer containing Annexin V-fluorescein isothiocyanate (FITC) and propidium iodide (PI), and incubated in the dark at room temperature for 15min. Flow cytometry analysis was performed to detect apoptotic cells. The data were analyzed using Guava software, and the percentage of apoptotic cells was expressed.

Statistical analysis was performed using GraphPad Prism 9.0 software. Data were presented as meanstandard deviation (SD). Differences between groups were analyzed using one-way analysis of variance (ANOVA). P<0.05 was considered statistically significant. All experiments were repeated at least three times.

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Notoginsenoside R1 promotes Lgr5+ stem cell and epithelium renovation in colitis mice via activating Wnt/-Catenin ... - Nature.com

Lawsuit over League City stem-cell treatment headed for trial – Galveston County Daily News

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Lawsuit over League City stem-cell treatment headed for trial - Galveston County Daily News

BioCardia and StemCardia Announce Biotherapeutic Delivery Partnership – Diagnostic and Interventional Cardiology

March 15, 2024 BioCardia, Inc., a biotechnology company focused on advancing late-stage cell therapy interventions for cardiovascular disorders, andStemCardia, Inc., a biotechnology company focused on cell and gene therapy to re-muscularize the failing heart, today announced a long-term partnership to advance StemCardias investigational pluripotent stem cell product candidate for the treatment of heart failure.

Under the partnership, BioCardia is the exclusive biotherapeutic delivery partner for StemCardias cell therapy candidate through studies expected to result in FDA approval of an investigational new drug application (IND) and the anticipated Phase I/II clinical development to follow.

BioCardia has established safe and minimally invasive delivery of cellular medicines directly into the heart, said Chuck Murry, MD, PhD, StemCardias Founder and CEO. Having worked with BioCardia to successfully deliver our bona fide cardiac muscle cells in large animal models of heart failure, we are excited for this partnership to accelerate clinical development and broaden future commercial access to an off-the-shelf heart regeneration treatment.

StemCardias team encompasses recognized leaders in the field of cardiac regenerative medicine who are pursuing an elegant strategy to repair the failing heart. We look forward to supporting their efforts with our experienced team and proven, proprietary Helixbiotherapeutic delivery system, said BioCardia CEO Peter Altman, PhD. This partnership is expected to enhance future treatment options for millions of people suffering from heart failure, offset the costs of biotherapeutic delivery development for our own programs, and provide our investors with meaningful revenue sharing should our efforts together contribute to StemCardias successful therapeutic development.

For more information:www.biocardia.com

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BioCardia and StemCardia Announce Biotherapeutic Delivery Partnership - Diagnostic and Interventional Cardiology

Developing Stem Cell Therapy to Halt Critical Limb Amputations – Mirage News

Critical limb ischemia is a condition in which the main blood vessels supplying blood to the legs are blocked, causing blood flow to gradually decrease as atherosclerosis progresses in the peripheral arteries. It is a severe form of peripheral artery disease that causes progressive closure of arteries in the lower extremity, leading to the necrosis of the leg tissue and eventual amputation. Current treatments include angioplasty procedures such as stent implantation and anti-thrombotic drugs, but there is a risk of blood vessel damage and recurrence of blood clots, which is why there is a strong interest in developing a treatment using stem cells.

A research team led by Dr. Sangheon Kim of the Center for Biomaterials Research at the Korea Institute of Science and Technology (KIST) announced that they have developed a three-dimensional stem cell therapy to treat critical limb ischemia through a self-assembling platform technology using a new material microgel. By using collagen microgels, a new biocompatible material, the researchers were able to easily transplant stem cells into the body and increase cell survival rate compared to 3D stem cell therapies made of cells alone.

Stem cell therapies have high tissue regeneration capabilities, but when stem cells are transplanted alone, hypoxia at the site of injury, immune responses, and other factors can reduce cell viability and prevent the desired therapeutic effect. Therefore, it is necessary to develop a material that delivers stem cells using biodegradable polymers or components of extracellular matrix as a support to increase cell viability.

The team processed collagen hydrogels to micro-scale to create porous, three-dimensional scaffolds that are easy to inject in the body and have a uniform cell distribution. Collagen, a component of the extracellular matrix, has excellent biocompatibility and cellular activity, which can induce cell self-assembly by promoting interactions between the microgel particles and collagen receptors on stem cells. In addition, the spacing between microgel particles increased the porosity of the three-dimensional constructs, improving delivery efficiency and cell survival.

The microgel-cell constructs developed by the researchers expressed more pro-angiogenic factors and exhibited higher angiogenic potential than cell-only constructs. When microgel-cell constructs were injected into the muscle tissue of mice with critical limb ischemia, blood perfusion rate increased by about 40% and limb salvage ratio increased by 60% compared to the cell-only constructs, confirming their effectiveness in increasing blood flow and preventing necrosis in the ischemic limb.

The new stem cell therapy is expected to provide a new alternative for patients with critical limb ischemia who have limited treatment options other than amputation due to its excellent angiogenic effect. Furthermore, since angiogenesis is an essential component of various tissue regeneration processes, it can be extended to other diseases with similar mechanisms to peripheral arterial disease.

"The collagen microgel developed in this study is a new biomaterial with excellent biocompatibility and high potential for clinical applications," said Dr. Sangheon Kim of KIST. "We plan to develop technologies for administration methods required in the medical field, as well as conduct follow-up research to clarify the clear mechanism of action of the treatment and discover target factors."

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Developing Stem Cell Therapy to Halt Critical Limb Amputations - Mirage News

Unlocking the Secrets of Aging: Researchers Reveal Key to Intestinal Balance – SciTechDaily

University of Helsinki researchers discovered that the capacity of intestinal stem cells to maintain cellular balance in the gut diminishes with age, and identified a new mechanism linking nutrient adaptation of these stem cells to aging. This insight could lead to methods for preserving gut function in the elderly.

The ability of intestinal stem cells to preserve the cellular equilibrium in the gut diminishes with age. Scientists at the University of Helsinki have identified a novel interaction between the adaptation of intestinal stem cells to nutrients and the aging process. The finding may make a difference when seeking ways to maintain the functional capacity of the aging gut.

The cellular balance of the intestine is carefully regulated, and it is influenced, among other things, by nutrition: ample nutrition increases the total number of cells in the gut, whereas fasting decreases their number. The relative number of different types of cells also changes according to nutrient status.

The questions of how the nutrition status of the gut controls stem cell division and differentiation, and how the nutrient adaptation of stem cells changes as during aging have not been comprehensively answered. Nutrient adaptation refers to the way in which nutrients guide cell function.

On the left: Model organism fruit fly (Drosophila melanogaster), gastrointestinal tract highlighted in green. On the right: Microscope images of the fruit fly intestine where cell nuclei are stained (cyan). The intestine on the top is from well-fed animal, and the intestine below from an animal kept on a restricted diet. Credit: Jaakko Mattila

Researchers at the University of Helsinki identified a new regulatory mechanism that directs the differentiation of intestinal stem cells under a changing nutrient conditions. Cell signaling activated by nutrients increases the size of stem cells in the fruit fly intestine. The size of the stem cells, in turn, controls the cell type into which the stem cells differentiate. For stem cell function, flexible regulation of their size is essential.

In other words, the size of the cells dynamically increases or decreases, depending on the dietary conditions. Such flexibility enables stem cells to differentiate in accordance with the prevailing nutrient status. By utilizing intestine-wide cell imaging, the researchers found that the nutrient adaptation of stem cell size and the resulting differentiation vary in different regions of the gut.

Our observations demonstrate that the regulation of intestinal stem cells is much more region-specific than previously understood. This may be relevant to, for example, how we think about the pathogenetic mechanisms of intestinal diseases, says Jaakko Mattila, the corresponding author of the research article from the Faculty of Biological and Environmental Sciences, University of Helsinki.

The researchers also observed that the ability of intestinal stem cells to react to a changing nutrient status is greatly reduced in older animals. They also found that, in older animals, stem cells are in a state where they are constantly large in size, which restricts their ability to differentiate. With aging, flexible regulation of stem cell size was markedly better preserved in animals that had been kept under a diet regime that is known as intermittent fasting. In the past, intermittent fasting has been shown to prolong the lifespan of animals, and the results now obtained indicate that the improved preservation of stem cell function may underlie this prolongation.

According to the researchers, the mechanisms associated with the functioning, nutrient adaptation, and aging of human and fruit fly stem cells are fairly similar.

We believe that these findings have a broader significance towards understanding how to slow down the loss of tissue function caused by aging by controlling the nutrient adaptation of stem cells. However, more information is needed on the effect of the mechanism on human intestinal stem cells. Our work on the nutrient adaptation of stem cells continues, says Professor Ville Hietakangas from the Faculty of Biological and Environmental Sciences and the Institute of Biotechnology, University of Helsinki.

Reference: Stem cell mTOR signaling directs region-specific cell fate decisions during intestinal nutrient adaptation by Jaakko Mattila, Arto Viitanen, Gaia Fabris, Tetiana Strutynska, Jerome Korzelius and Ville Hietakangas, 9 February 2024, Science Advances. DOI: 10.1126/sciadv.adi2671

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Unlocking the Secrets of Aging: Researchers Reveal Key to Intestinal Balance - SciTechDaily

Human stem-cell-based therapy for Parkinson’s disease proven safe PET – BioNews

A small clinical trial involving 12 patients with Parkinson's disease has reported no safety concerns with a newly developed human stem-cell-based therapy.

The therapy called TED A9 was delivered as a cell transplant injected directly into the brain of the participants as part of a Phase 1/2a clinical trial, which is principally concerned with assessing safety and dosing requirements.

The drug's developer, S.Biomedics, in Seoul, South Korea, claimed in a press release: 'According to Professor Jin-Woo Chang, [the principal investigator of the transplant conducted at Severance Hospital, Seoul,] none of the 12 Parkinson's disease participants had any side effects, complications, or unusual adverse reactions following the transplantation of TED-A9'.

The trial participants were aged between 50 and 75 years old, had been diagnosed with Parkinson's disease for more than five years, and had already motor complications such as freezing of gait or dyskinesia.

To ensure and monitor the safety of the treatment, an initial three patients were injected with a low dose (3.15 million cells) and monitored for three months, before another three patients were treated at high dose (6.3 million cells) and also monitored for three months.

No side effects, complications, or unusual adverse reactions were seen in either group during the three-month assessment period. Therefore, the clinical trial continued by adding three further patients to each of the low-dose and high-dose groups. Again, no safety concerns were seen.

Parkinson's symptoms are caused by the progressive loss of neurons that produce dopamine, a major chemical messenger in the brain. The TED-A9 therapy contains dopaminergic progenitor (precursor) cells, which had themselves been derived in the lab from embryonic stem cells.

The drug developers at S.Biomedics hope that the dopaminergic precursor cells in TED-A9 will treat Parkinson's disease by replacing the mature dopamine-producing nerve cells that are lost in patients.

Professor Dong-Wook Kim, a neurosurgeon and the principal developer of TED-A9, said: 'We have developed a fundamental therapeutic mechanism that directly replaces dopaminergic neurons lost in patients with Parkinson's disease. TED-A9 could represent a fundamental treatment that surpasses current therapies, which only temporarily alleviate the symptoms of Parkinson's disease,'.

The trial is expected to continue until February 2026, allowing safety of the therapy to be monitored for a total of five years. As part of the study, exploratory efficacy will also be examined for two years using clinical measures of motor symptoms and a patient questionnaire of daily life quality.

More Information is available at ClinicalTrials.gov.

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Human stem-cell-based therapy for Parkinson's disease proven safe PET - BioNews