Stem Cell Clinic

Duke team completes ten-year study on gene expression in stem cells – Duke Chronicle

By Induced Pluripotent Stem Cells

How do cells acquire their identities? In hopes of answering this question, a Duke team recently completed a study explaining the expression of stem cells after a decade of research.

Stem cells are found in every living organism, including humans and plants. They are initially unspecialized and can develop into almost any cell type while dividing to produce new cells over time. At this point, theyre faced with a choice: divide to make copies of themselves or create something new.

To explore how stem cells make this decision, the group researched the expression of stem cells in plants by developing a specialized microscope that takes precise photographs through a technique called light sheet microscopy.

Cara Winter, associate research professor in biology, and postdoctoral associate Pablo Szekely began working on the project in the lab of Philip Benfey, former Paul Kramer distinguished professor of biology who passed away last year.

This eventually grew to a collaboration with the California Institute of Technology, which included a microscopist, a computer scientist, graduate students and undergraduate student assistants. Winter emphasized that the project was a collaborative effort.

There's no one person that knows all of the information that you need to know to make the microscope and the project work. So you really have to work together to figure out how to get to the goal, Winter said.

Researchers at the California Institute of Technology visited the Duke lab to help construct the microscope. Compared to traditional imaging, this specialized light sheet microscope caused less toxicity and photobleaching, which allowed the team to image cells for longer. This was key because the microscope needed a long observation period to collect enough data on the cells.

The microscope tracked the changing colors of the root cells, which indicated whether the cell would divide and the type of division that would occur. The researchers then connected this data with the level of proteins in the cells to explore how those proteins were associated with cell division. The level of high-resolution imaging of stem cells over such a significant period has never been done before.

Szekely noted that this was made possible by using machine learning and other technological tools to answer these biological questions.

The study allowed the team to photograph the expression of multiple genes in the context of a living organism and connect that gene expression to cell division. They were also able to use that data to test a model of a gene regulatory network, which allowed them to gain insight into asymmetric cell division and how it interfaces with the cell cycle.

The groups results were published in Nature. The study's findings connect to further research for humans and other animals in cancer therapies, drugs, and other aspects of the cell cycle.

I'm hoping to continue following with the next steps of this project, following up on sort of the ideas that came out of the paper, trying to understand exactly what these two regulators are doing early in the cell cycle, Winter said. I'm hoping to stick with imaging, continuing imaging and developing new imaging technologies to ask questions that couldn't be asked.

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Aseel Ibrahim is a Trinity first-year and a staff reporter for the news department.

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Duke team completes ten-year study on gene expression in stem cells - Duke Chronicle

HOIL-1L deficiency induces cell cycle alteration which causes immaturity of skeletal muscle and cardiomyocytes … – Nature.com

By Induced Pluripotent Stem Cells

hiPSC culture

hiPSCs were generated from an Asian female HOIL-1L-deficient patient and healthy controls and kindly donated by the Center for iPS Cell Research and Application (Kyoto University, Kyoto, Japan). Patient-specific (HOIL-1L_1, CiRA-j-0154B and HOIL-1L_2, CiRA-j-0154D) and healthy control hiPSCs (Control_1, CiRA-j-1616-A, Asian female volunteer) were established from the peripheral blood mononuclear cells (PBMCs) using episomal vectors containing reprograming factors30. Another control hiPSC line from Asian male (Control_2, 110F5) was established as described previously31. Each cell line stored in liquid nitrogen using STEM-CELLBANKER (Takara, Cat.# 11924) and once thawed in 37C water bath, it was maintained in mTeSR1 medium (Stem Technologies, Cat.# 85,850) as previously reported32. Each cell was stocked at less than 15 passages, and all experimentations were done between 20 and 45 passages. The sequence of RBCK1 gene was confirmed by Sanger sequencing at the beginning of key experiments. Pluripotency of CiRA-j-1616-A, CiRA-j-0154B and CiRA-j-0154D was evaluated by OCT3/4 and NANOG mRNA expression by TaqMan qPCR and pluripotency of control_2 was evaluated by quantitative PCR analysis of Oct 3/4, Sox2, Klf4, and c-Myc using SYBR green. Cells were passaged every 45days at 1:10 or 1:12 ratio using accutase (Nacalai Tesque, Cat.# 12679-54). Dissociated cells were seeded on Matrigel-coated 6-well plates. The medium was supplemented with 5M Y27632 (TOCRIS, Cat.# 1254), a Rho-associated kinase inhibitor, on the first day of each passage. All cell lines were authenticated by their name, checked their sterrility regularly, and monitored of mycoplasma contamination using by PCR kit (Minerva biolabs, Cat.# 11-9025).

CMs were differentiated from hiPSCs using a previously reported protocol33. Briefly, hiPSCs were seeded into a 12-well growth-factor-reduced (GFR) Matrigel-coated plate, grown for 4days at 37C in 5% CO2 and mTeSR1 medium, and allowed to reach 8090% confluency. On day 0 of differentiation, the medium was changed to differentiation media, which was RPMI containing 2% B27 minus insulin supplement (Gibco, Cat.# A18956-01) and 1012M CHIR99021 (Selleck, Cat.# S2924), a GSK3 inhibitor. After incubation for 24h, the medium was replaced with fresh differentiation medium. On day 3, the medium was replaced with differentiation medium containing 5M IWP-2 (TOCRIS, Cat.# 3533), a Wnt inhibitor. On day 5, the medium was replaced with fresh differentiation medium. On day 7, B27 minus insulin was replaced with a B27 supplement (Gibco, Cat.# 17504044). Differentiated hiPSC-CMs were purified in glucose-depleted lactate medium as described previously34.

C2C12 cells were kindly provided by Dr. Yuji Yamanashi (The Institute of Medical Science, The University of Tokyo)35. The growth medium was DMEM/F12 (Sigma-Aldrich, Cat.# D6421) containing 20% FBS, 2mM glutamine (Gibco, Cat.# 25030081), 100 units/mL penicillin, and 100g/mL streptomycin. Cells were incubated at 37C in a humidified incubator containing 5% CO2. Myoblasts were differentiated into myotubes in DMEM/F12 medium containing 2% horse serum (Gibco, Cat.# 16050122, Lot. 1968945)36,37.

Lenti-CRISPR v2 (Addgene, Cat. # 52961), which contains a puromycin resistance gene, carrying a guide RNA oligonucleotide (5-acctcacccttcagtcacgg-3 for Exon 5 of the Hoil-1l gene or 5-acgcagcaccacggcctcgc-3 for Exon 7 of the Hoil-1l gene) was constructed. HEK293T cells were transfected with the plasmids using Lipofectamine 2000 (Thermo Fisher, Cat.# 11668019). Viruses were harvested at 48h after transfection, and the media were filtered through a 0.45m PES filter. C2C12 cells were transduced with the viruses in medium containing 10g/mL polybrene. At 24h after transduction, puromycin selection was started. The selected cells were collected and KO of Hoil-1l was confirmed by Sanger DNA sequencing.

Myotubes differentiated from C2C12 cells on day 5 of differentiation were fixed in 4% paraformaldehyde (PFA) for 1h at 4C, permeabilized in 0.1% Triton X-100 for 10min at room temperature, and blocked in PBS containing 3% skim milk for 1h. Thereafter, myotubes were stained with an anti-MHC antibody (1:200, mouse monoclonal, R&D Systems, Cat.# MAB4470). The fusion index was calculated by dividing the number of nuclei in myotubes by the total number of nuclei in a field of view36. The MHC density was calculated by dividing the area occupied by MHC-positive myotubes by the total area of the field of view. The fusion index and MHC density were reported as averages of at least three fields of view (>500 total nuclei). Three independent experiments were performed for the calculation. For pluripotency marker analysis, undifferentiated hiPSC colonies were fixed in the same way, and fixed cells were stained with mouse anti-Oct3/4 (1:50, Santa Cruz Biotechnology, Cat.# sc5279) and anti-TRA1-81 (1:100, Millipore, Cat.# MAB4381) antibodies. Cells were then incubated with Alexa Fluor-conjugated secondary antibodies (1:1000) overnight at 4C.Nuclei were stained withHoechst 33342(1:1000, Invitrogen, Cat.#H3570). For immunofluorescence microscopy analysis of hiPSC-CMs, size and multinucleation were analyzed after around 5060days of differentiation and mitosis was analyzed after 20days of differentiation. hiPSC-CMs were replated onto GFR Matrigel-coated 24-well dishes, incubated at 37C in 5% CO2 for 72h, fixed in 4% PFA for 1h at 4C, permeabilized in 0.1% Triton X-100 for 10min at room temperature, and blocked in PBS containing 3% skim milk for 1h. Thereafter, hiPSC-CMs were stained with anti-cTnT (1:100, mouse monoclonal, Thermo Fisher, Cat.# MA5-12960) and anti-phospho-histone H3 (Ser10) (1:1000, rabbit monoclonal, Cell Signaling, Cat.# D7N8E) antibodies. After primary antibody treatment, cells were rinsed three times with PBS for 5min at room temperature and then incubated overnightat 4 with secondary antibodies diluted 1:1000 in PBS. Nuclei were stained with Hoechst 33342. For isotype controls, mouse IgG1 isotype (BD Biosciences, Cat.# 554121) and rabbit IgG isotype (BD Biosciences, Cat.# 550875) were used. All immunofluorescence analyses were performed using a BZ-710X microscope (Keyence). The TUNEL assay was performed using a Cell Death Detection Kit (Roche, Cat.# 11684795910) following the manufacturers protocol.

Myotubes at day 5 of differentiation were lysed in M-PER buffer (Thermo Scientific, Cat.# 78501) containing 1protease inhibitor and then incubated on ice. The samples were sonicated on ice for 30s. The lysates were incubated on ice for 10min and then centrifuged at 15,000rpm for 15min. Protein concentrations were determined using the Bradford assay. Thereafter, 30g of protein was loaded onto each lane of 10% SDS-PAGE gels. The membranes were probed with an anti-MHC antibody (1:100, R&D Systems, Cat.# MAB4470) in blocking buffer (5% BSA) at 4C overnight, washed, incubated in secondary antibodies for 1h at room temperature, developed using ECL western blotting substrate (Bio-Rad, Cat.# 1705060), and imaged using the ChemiDoc MP Imaging System (Bio-Rad). The blots were cut prior to hybridization with antibodies, and two replicates were done at the same time for Fig.1B and Supplementary Fig.2C as shown in supplementaryFig.5.

hiPSC-CMs were dissociated on the day of evaluation by incubating them in 0.25% trypsinEDTA for 1015min at 37C. They were fixed in Cytofix/Cytoperm solution (BD Biosciences, Cat.# 554714) for 20min at 4C, washed with BD Perm/Wash buffer (Cat.# 554723), stained with an anti-cTnT antibody (1:200, mouse monoclonal, Thermo Fisher, Cat.# MA5-12960) followed by Alexa Fluor-conjugated secondary antibodies, and analyzed using FACSverse (BD Biosciences). In cell cycle analysis, hiPSC-CMs after 20days of differentiation were gathered. After fixing and washing the hiPSC-CMs as described above, they were stained with an anti-cTnT antibody (1:200) and an anti-Ki67 antibody (1:400, rabbit monoclonal, Cell Signaling Technology, Cat. # 9129) followed by Alexa Fluor-conjugated secondary antibodies, and analyzed using FACSverse. Data were collected from at least 10,000 events. Data with>70% cTnT populations were used for all experimental analyses.

Total RNA was extracted from day 0 to day 7 of myotube differentiation using an RNeasy Mini Kit (Qiagen, Cat.# 74104) according to the manufacturers instructions. qPCR was performed using SYBR Green PCR Master Mix (Takara, Cat.# RR820) on a StepOnePlus system (Thermo Fisher Scientific) with the Ct method. GAPDH was used to standardize gene expression. Total RNA was extracted from hiPSC-CMs at 4560days after differentiation.

Hoil-1l-KO and control mouse embryos were generated as described previously14. Paraffin sections of E10.5 Hoil-1l null/+ and control littermate mouse embryos were deparaffinized and stained with H&E.

RNA was isolated from C2C12 cells using a RNeasy Mini Kit, according to the manufacturers instructions. RNA integrity was measured using an Agilent 2200 TapeStation and RNA Screen Tapes (Agilent Technologies). Sequencing libraries were prepared using a NEBNext Ultra II RNA Library Kit for Illumina (New England Biolabs) with the NEBNext Poly (A) mRNA Magnetic Isolation Module (New England Biolabs), according to the manufacturers protocol. Prepared libraries were run on an Illumina HiSeq X sequencing platform in 150bp paired-end mode. Sequencing reads were aligned to the GRCm38 mouse genome assembly using STAR (c.2.5.3). Mapped reads were counted for each gene using the GenomonExression pipeline (https://github.com/Genomon-Project/GenomonExpression). Normalization of the read counts of RNA seq data and differential expression analysis were performed using the Bioconductor package DESeq2 (version 1.26.0). Differentially expressed genes with a greater than twofold change and a false discovery rate less than 0.1 were filtered and evaluated. RNA seq data have been deposited with links to BioProject accession number PRJDB17426 in the DDBJ BioProject database.

GSEA was performed using software (version 4.0.3) from the Broad Institute. Normalized expression data obtained from RNA seq were assessed using GSEA software and the Molecular Signature Database (http://www.broad.mit.edu/gsea/). c5 ontology gene sets were used, and a false discovery rate less than 0.01 was considered to be statistically significant. Pathway enrichment analysis using g:Profiler and visualization of enrichment results in an enrichment map were performed using Cytoscape software (version 3.7.2) as described previously38.

Data are shown as meanSEMs, as indicated in the figure legends. All statistical analyses were performed using Welchs t-test with GraphPad Prism (version 9.00, GraphPad Software). P<0.05 was defined as significant.

Use of patient-derived iPSCs was approved by the Ethics Committee of Kyoto University (R0091 and G0687), and written informed consent obtained from the donor (or their guardians) in accordance with the Declaration of Helsinki.

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HOIL-1L deficiency induces cell cycle alteration which causes immaturity of skeletal muscle and cardiomyocytes ... - Nature.com

SCG CELL THERAPY AND A*STAR LAUNCH JOINT LABS WITH COLLABORATION NEARING S$30 MILLION TO … – PR Newswire

By Induced Pluripotent Stem Cells

SINGAPORE, April 16, 2024 /PRNewswire/ --SCG Cell Therapy (SCG) and the Agency for Science, Technology and Research (A*STAR) announced the launch joint laboratories for cellular immunotherapies. This collaboration, at a combined funding of close to S$30 million supported under Singapore's Research, Innovation and Enterprise 2025 Plan (RIE2025), aims to advance the development of induced pluripotent stem cell (iPSC) technology to produce novel cell therapies that meet Good Manufacturing Practice (GMP) standards. The collaboration will also establish a talent development programme to train the next generation of experts in this field, in accordance with current GMP and regulatory requirements.

The research and application of new technologies are essential for addressing growing healthcare needs and maintaining long-term sustainability. However, turning laboratory innovations into practical clinical solutions poses significant challenges. These often involve developing manufacturing processes, validating analytical methods, and implementing automation and digitalisation to guarantee the stability and scalability of products.

The joint laboratories, established at SCG's GMP facility and A*STAR's research facility, leverage SCG's and A*STAR's proprietary technologies to develop scalable GMP-grade iPSC and therapeutic products. SCG contributes its specialised, automated cell therapy manufacturing technologies, while A*STAR brings its unique monoclonal antibody assets, iPSC banks, and expertise in process scaling and analytics.

This collaboration bridges the expertise between public sector research and development (R&D) and industry, consolidating resources from SCG Cell Therapy and A*STAR's Bioprocessing Technology Institute (BTI) and Institute of Molecular and Cell Biology (IMCB) to advance innovative R&D towards GMP manufacturing. Additionally, it immerses researchers in the rigorously controlled GMP environment, facilitating the progression from research to clinical application.

"Cellular immunotherapies herald a new era of regenerative medicine, offering hope for patients with cancers and other serious illnesses. As a key player in T cell receptor (TCR) T cell therapeutics, SCG has developed in-house cGMP manufacturing capabilities to supply high-quality cell therapy products to patients. Through this first-of-its-kind joint collaboration with A*STAR, we bring together A*STAR's advanced iPSC technology and bioprocessing capabilities with our expertise in GMP cell therapy manufacturing and clinical development, furthering our mission to provide affordable off-the-shelf cell therapy treatment options to patients", said Christy Ma, Chief Strategy Officer of SCG Cell Therapy.

"The discovery of iPSCs has revolutionised regenerative medicine, offering the potential for standardised, off-the-shelf cell therapies. Through this collaboration with SCG Cell Therapy, we aim to accelerate the translation of iPSC research into clinically viable therapies and strengthen Singapore's position as a global leader in cell therapy innovation. By leveraging our complementary expertise and resources, the joint labs will not only advance iPSC technology for scalable, GMP-compliant cell therapy production but also serve as a platform for nurturing the next generation of talent in this transformative field," said Prof Koh Boon Tong, Executive Director, A*STAR's BTI.

About iPSC

Induced pluripotent stem cells (also known as iPS cells or iPSCs) are a type of pluripotent stem cell that can be generated directly from adult cells. The iPSC technology was pioneered by Shinya Yamanaka's lab in Kyoto, Japan, who showed in 2006 that the introduction of four specific genes encoding transcription factors could convert adult cells into pluripotent stem cells. He was awarded the 2012 Nobel Prize along with Sir John Gurdon "for the discovery that mature cells can be reprogrammed to become pluripotent". Pluripotent stem cells hold great promise in the field of regenerative medicine. Because they can propagate indefinitely, as well as give rise to every other cell type in the body (such as neurons, heart, pancreatic and liver cells), they represent a single source of cells that could be used to replace those lost to damage or disease.

About SCG Cell Therapy

SCG is a clinical-stage biotechnology company focusing on the development of novel immunotherapies in infections and its associated cancers. The company targets the most common cancer-causing infections: helicobacter pylori, human papillomavirus, and hepatitis B, and develops a broad and unique pipeline against infections and to prevent and cure its associated cancers. Established and headquartered in Singapore, SCG combines regional advantages in Singapore, China and Germany, covering the entire value chain from innovative drug research and discovery, manufacturing, clinical development and commercialization. For more information about SCG, please visit us at http://www.scgcell.com.

About the Agency for Science, Technology and Research (A*STAR)

The Agency for Science, Technology and Research (A*STAR) is Singapore's lead public sector R&D agency. Through open innovation, we collaborate with our partners in both the public and private sectors to benefit the economy and society. As a Science and Technology Organisation, A*STAR bridges the gap between academia and industry. Our research creates economic growth and jobs for Singapore, and enhances lives by improving societal outcomes in healthcare, urban living, and sustainability. A*STAR plays a key role in nurturing scientific talent and leaders for the wider research community and industry. A*STAR's R&D activities span biomedical sciences to physical sciences and engineering, with research entities primarily located in Biopolis and Fusionopolis. For ongoing news, visit http://www.a-star.edu.sg.

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SCG CELL THERAPY AND A*STAR LAUNCH JOINT LABS WITH COLLABORATION NEARING S$30 MILLION TO ... - PR Newswire

Man Paralyzed In Surfing Accident Regains Ability to Walk After Stem Cell Treatment – The Inertia

By Stem Cell Treatment

After a surfing accident left Chris Barr paralyzed from the neck down, stem cell treatment got him back on his feet again. Photo: Mayo Clinic

Seven years ago, Chris Barr went surfing at San Franciscos Ocean Beach, the same as hed done every weekend for a decade. It began as a day like any other, but it would end with a life-changing accident. Barr walked into the water that day, but when he fell on a wave, he broke his neck in eight places. He was paralyzed from the neck down. But after a miraculous stem cell trial at the Mayo Clinic, Barr is walking again.

He was so distraught over being paralyzed from the neck down as a result of his injuries, wrote Joel Streed for the Mayo Clinic, that the first thing he mouthed to his wife, Debbie, through the intubation tube when she arrived at his hospital bedside was a plea to take it all away.

Her husband asked the impossible of her. The first words he mouthed to me were Pull the plug, which was so shocking, she said.

Thankfully, Barrs mental state improved with time. A few days later, a friend of Barrs named Chris Whitewho was the one who pulled Barr out of the water on that fateful day came to visit him. Knowing Barr was in a dark place, he had some words of encouragement.

He said, Theres technology, new developments every day, Barr remembered. Why would you throw in the towel? Youve got nothing to lose.'

In the weeks following his injury, Barr underwent a battery of tests, surgeries, and therapies. He improved for the first six months, but then his process flatlined. Thats when a nuerosurgeon from the Mayo Clinic named Mohamad Bydon came to see him and offered him something he couldnt turn down: the chance to participate in a stem cell trial aimed at helping paralyzed people improve their mobility.

Stem cell treatments are still relatively new, but they show enormous promise.

Mesenchymal stem cells taken from the stomach fat of a patient with a spinal cord injury are given time to multiply in a cultured laboratory setting, according to the Mayo Clinic. Then they are injected into the patients lower back. The cells migrate to the site of the patients injury and help augment healing and any initial improvement in motor and sensory function the patient might have experienced after surgery.

Dr. Bydon emphasizes that the six-month wait is an important part of the stem cell recovery process.

We want to intervene when the physical function has plateaued, he said, so that we do not allow the intervention to take credit for early improvements that occur as part of the natural history with many spinal cord injuries.

After a few more months and consultations, Barr entered the Mayo Clinic to be patient number one in a clinical trial, including nine others, each with a variety of different spinal cord injuries. The trial tested the safety, side effects, and dosages of stem cells, and as of this writing, hasnt been approved by the Food and Drug Administration.

But the results were, quite frankly, astonishing. Barr told ABC that the effects were immediate.

I could feel it, he said of the hours after his first stem cell injection. I absolutely felt something in my legs.

From there, Barrs condition only continued to improve. The stem cells worked on repairing his injuries, and in the following months nearly everything got better. His scores on a grip and pinch strength test, a 10-meter walking test, and an ambulation test improved by 50 percent above his waist and 25 percent below.

Still, though, his recovery was and still is a long road, but the improvements Barr was seeing spurred him on. While Barrs response to the treatment were extraordinary, Dr. Bydon knows that it wasnt the norm.

Although some patients like Chris are super-responders, other patients are moderate responders or nonresponders, he said. But this trial will help us advance the field, so we can offer new treatments for patients with spinal cord injury.

Barr still does require a cane and a helping hand now and then to walk and go about his day-to-day business, but considering the fact that he was paralyzed from the neck down, the stem cell treatment was like a miracle.

I cant say it enough times that the stem-cell regimen and protocol offers hope, he said. The hopelessness of paralysis is just unlike anything you can imagine. And this is the hope.

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Man Paralyzed In Surfing Accident Regains Ability to Walk After Stem Cell Treatment - The Inertia

Rejuvenating the immune system by depleting certain stem cells – National Institutes of Health (NIH) (.gov)

By Stem Cell Treatment

At a Glance

The risk for serious infections rises with age, as peoples immune systems lose the ability to respond to novel infections. Part of the reason for this is that the types of hematopoietic stem cells (HSCs), which make the various types of blood cells, change with age.

Some HSCs, called myeloid-biased HSCs (my-HSCs) produce mostly myeloid cells, which include red blood cells, platelets, and most cells of the innate immune system. Others, called balanced HSCs (bal-HSCs), produce a healthy mix of myeloid and lymphoid cells, which include the T and B cells that make up the adaptive immune system.

The proportion of my-HSCs increases with age. Thisleads to more myeloid cells and fewer lymphoid cells. More myeloid cellsincreaseinflammation and bring an increased risk of atherosclerosis and myeloid-related diseases such as leukemia. Fewer lymphoid cellsreduces theability to fight infections. A research team led by Drs. Kim Hasenkrug and Lara Myers at NIH and Drs. Irving Weissman and Jason Ross at Stanford University School of Medicine explored whether reducing my-HSCs could restore a more youthful immune system in aged mice. The results appeared in Nature on March 27, 2024.

The team began by identifying proteins on the surface of mouse HSCs that are unique to my-HSCs. They then created antibodies against these proteins and used them to deplete my-HSCs in aged mice.

Depletingmy-HSCs reduced the effects of aging on the mouse immune system.Itincreased lymphoid progenitor cells, which give rise to T and B cells, in the bone marrow. Consequently, treated mice had more nave T cells and B cells in their blood than untreated mice. These cells allow the immune system to learn to recognize novel infections. Thetreatmentalsolowered levels of exhausted T cells and age-associated B cells, along with certain inflammatory markers.

When the researchers vaccinated aged mice with a live, weakened virus, those with depleted my-HSCs had a stronger T cell response than untreated mice. The treated mice also gained better protection against infection from the vaccination.

These findings could explain why older people are more vulnerable to infections such as SARS-CoV-2. Weakened adaptive immunity from fewer lymphoid cells makes it harder for them to fight off the infection. At the same time, increased myeloid cells cause harmful inflammation. The researchers noted that the genes that characterize my-HSCs in mice are also found in aged human HSCs. This suggests that my-HSC depletion might be used in humans to relieve certain age-associated health problems.

During the start of the COVID-19 pandemic, it quickly became clear that older people were dying in larger numbers than younger people, Weissman says. This trend continued even after vaccinations became available. If we can revitalize the aging human immune system like we did in mice, it could be lifesaving when the next global pathogen arises.

by Brian Doctrow, Ph.D.

Funding:NIHs National Institute of Allergy and Infectious Diseases (NIAID), National Cancer Institute (NCI), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), and National Institute of General Medical Sciences (NIGMS); Virginia and D.K. Ludwig Fund for Cancer Research; Stanford University; Radiological Society of North America; Stanford Cancer Institute.

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Rejuvenating the immune system by depleting certain stem cells - National Institutes of Health (NIH) (.gov)

Antiviral cellular therapy for enhancing T-cell reconstitution before or after hematopoietic stem cell transplantation … – Nature.com

By Stem Cell Treatment

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Antiviral cellular therapy for enhancing T-cell reconstitution before or after hematopoietic stem cell transplantation ... - Nature.com

Somite Raises $5.3M As Five Leading Scientists Join Forces To Incorporate AI In Stem Cell Therapy – PR Newswire

By Stem Cell Treatment

[[To comply with academic institution guidelines, the founders' academic affiliations and roles are listed only at the end of the statement.]]

BOSTON and AUSTIN, Texas, April 16, 2024 /PRNewswire/ --Somite, a venture-backed company aiming to become the OpenAI of stem cell biology, announces that it has raised $5.3M in pre-seed funding. The round was led by Israel's preeminent Venture fund TechAviv, and joined by renowned Austin-based VCs Next Coast Ventures, Trust Ventures and Texas Venture Partners as well as NY-based Lerer Hippeau and others. The funds will be used to continue development of Somite's proprietary AlphaStem AI platform, building Somite labs and bringing the first therapeutic asset to phase 1 clinical trials.

Founded in October 2023, Somite is building AI foundation models to produce human tissue at scale for cell therapies. These therapies have the potential to cure a wide range of diseases that involve the loss or deficiency of cell populations, such as Diabetes, Obesity, and Muscular Dystrophies.

Somite Raises $5.3M in Pre-seed Round to Transform Cell Therapy with Al

The founding team comprises five distinguished experts in their respective fields: Dr. Micha Breakstone, a seasoned AI entrepreneur who successfully sold Chorus.ai for $575 million, serves as the CEO. Joining him are the CTO,Dr. Jonathan Rosenfeld, who pioneered AI scaling laws at MIT,along with Boston-based scientistsDr. Olivier Pourquie, Dr. Allon Klein, and Dr. Cliff Tabin, who bring expertise in developmental biology, stem cells and computational biology.

Cell therapy, a revolutionary approach to treating medical conditions, involves replacing missing, damaged, or diseased cells. While recent strides in stem cell research have opened new avenues for producing various human cell types, challenges persist in terms of efficiency, scalability, and robustness across existing protocols. Somite.ai stands out as the premier company excelling in the efficient production of cells derived from somites, crucial embryonic structures giving rise to musculoskeletal cells. These include muscle, brown adipose, cartilage, bone, tendon, and dermis. Leveraging its expertise, Somite is pioneering the development of a digital twin of the embryoa computational model mirroring real embryo development and behavior. Drawing from data-rich sources such as scRNA-Seq, scATAC-seq, and gene expression databases, the digital twin empowers Artificial Intelligence to swiftly uncover innovative protocols, identify regulators of cell differentiation, and conduct rapid optimization cycles.

Somite's proprietary digital twin not only surfaces actionable insights but also expedites protocol iterations. Somite also builds on work performed in the Pourquie laboratory where production of somite-derived lineages such as human satellite and brown adipose cellsin vitro was optimized using computational analysis and AI, allowing a critical increase in purity without the need for sorting procedures.

Since its inception, Somite has rapidly achieved noteworthy milestones, including gaining acceptance to the esteemed Blavatnik Harvard Life Labs and securing intellectual property for groundbreaking patents.

"The future of medicine lies at the intersection of AI and biology," says Micha Breakstone, CEO and Co-Founder of Somite. "With Somite's AlphaStem platform we have the unique opportunity to both unlock the governing principles of cell differentiation and introduce therapies to cure tens of millions of people. This funding round is only one of many first steps in our exciting journey."

"We are proud to partner with Somite and have high conviction in the exceptional team and transformative solution for stem cell therapy," says Yaron Samid, Founder and Managing Partner at TechAviv. "I am captivated by Somite's potential to redefine the boundaries of medical innovation. They are committed to advancing their groundbreaking stem cell therapy technology and have the power to transform the lives of millions of people by leveraging AI to produce human tissue for cell therapies."

About SomiteSomite.aiis a venture-backed company aiming to become the OpenAI of stem cell biology, developing AI foundation models to produce human tissue for cell therapies at scale for diseases such as diabetes, obesity, and muscular dystrophies. Somite's AI platform, AlphaStem, fuels a virtuous cycle: It enables new cell therapies, generating massive data that further improve the platform, empowering even faster therapy creation with broader applications.

Incorporated in Oct. 2023, Somite.ai has raised $5.3m to date.

Somite Management Team:

Scientific Co-founders:

Media Contact: [emailprotected]

SOURCE Somite Therapeutics

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Somite Raises $5.3M As Five Leading Scientists Join Forces To Incorporate AI In Stem Cell Therapy - PR Newswire

Cell Therapies Now Beat Back Once Untreatable Blood Cancers. Scientists Are Making Them Even Deadlier. – Singularity Hub

By Stem Cell Treatment

Dubbed living drugs, CAR T cells are bioengineered from a patients own immune cells to make them better able to hunt and destroy cancer.

The treatment is successfully tackling previously untreatable blood cancers. Six therapies are already approved by the FDA. Over a thousand clinical trials are underway. These arent limited to cancerthey cover a range of difficult medical problems such as autoimmune diseases, heart conditions, and viral infections including HIV. They may even slow down the biological processes that contribute to aging.

But CAR T has an Achilles heel.

Once injected into the body, the cells often slowly dwindle. Called exhaustion, this process erodes therapeutic effect over time and has dire medical consequences. According to Dr. Evan Weber at the University of Pennsylvania, more than 50 percent of people who respond to CAR T therapies eventually relapse. This may also be why CAR T cells have struggled to fight off solid tumors in breast, pancreatic, or deadly brain cancers.

This month, two teams found a potential solutionmake CAR T cells more like stem cells. Known for their regenerative abilities, stem cells easily repopulate the body. Both teams identified the same protein master switch to make engineered cells resemble stem cells.

One study, led by Weber, found that adding the protein, called FOXO1, revved up metabolism and health in CAR T cells in mice. Another study from a team at the Peter MacCallum Cancer Center in Australia found FOXO1-boosted cells appeared genetically similar to immune stem cells and were better able to fend off solid tumors.

While still early, these findings may help improve the design of CAR T cell therapies and potentially benefit a wider range of patients, said Weber in a press release.

Heres how CAR T cell therapy usually works.

The approach focuses on T cells, a particular type of immune cell that naturally hunts downs and eliminates infections and cancers inside the body. Enemy cells are dotted with a specific set of proteins, a kind of cellular fingerprint, that T cells recognize and latch onto.

Tumors also have a unique signature. But they can be sneaky, with some eventually developing ways to evade immune surveillance. In solid cancers, for example, they can pump out chemicals that fight off immune cell defenders, allowing the cancer to grow and spread.

CAR T cells are designed to override these barriers.

To make them, medical practitioners remove T cells from the body and genetically engineer them to produce tailormade protein hooks targeting a particular protein on tumor cells. The supercharged T cells are then grown in petri dishes and transfused back into the body.

In the beginning, CAR T was a last-resort blood cancer treatment, but now its a first-line therapy. Keeping the engineered cells around inside the body, however, has been a struggle. With time, the cells stop dividing and become dysfunctional, potentially allowing the cancer to relapse.

To tackle cell exhaustion, Webers team found inspiration in the body itself.

Our immune system has a cellular ledger tracking previous infections. The cells making up this ledger are called memory T cells. Theyre a formidable military reserve, a portion of which resemble stem cells. When the immune system detects an invader its seen beforea virus, bacteria, or cancer cellthese reserve cells rapidly proliferate to fend off the attack.

CAR T cells dont usually have this ability. Inside multiple cancers, they eventually die offallowing cancers to return. Why?

In 2012, Dr. Crystal Mackall at Stanford University found several changes in gene expression that lead to CAR T cell exhaustion. In the new study, together with Weber, the team discovered a protein, FOXO1, that could lengthen CAR Ts effects.

In one test, a drug that inhibited FOXO1 caused CAR T cells to rapidly fail and eventually die in petri dishes. Erasing genes encoding FOXO1 also hindered the cells and increased signs of CAR T exhaustion. When infused into mice with leukemia, CAR T cells without FOXO1 couldnt treat the cancer. By contrast, increasing levels of FOXO1 helped the cells readily fight it off.

Analyzing genes related to FOXO1, the team found they were mostly connected to immune cell memory. Its likely that adding the gene encoding FOXO1 to CAR T cells promotes a stable memory for the cells, so they can easily recognize potential harmbe it cancer or pathogenlong after the initial infection.

When treating mice with leukemia, a single dose of the FOXO1-enhanced cells decreased cancer growth and increased survival up to five-fold compared to standard CAR T therapy. The enhanced treatment also tackled a type of bone cancer in mice, which is often hard to treat without surgery and chemotherapy.

Meanwhile, the Australian team also zeroed in on FOXO1. Led by Drs. Junyun Lai, Paul Beavis, and Phillip Darcy, the team was looking for protein candidates to enhance CAR T longevity.

The idea was, like their natural counterparts, engineered CAR T cells also need a healthy metabolism to thrive and divide.

They started by analyzing a protein previously shown to enhance CAR T metabolism, potentially lowering the chances of exhaustion. Mapping the epigenome and transcriptome in CAR T cellsboth of which tell us how genes are expressedthey also discovered FOXO1 regulating CAR T cell longevity.

As a proof of concept, the team induced exhaustion in the engineered cells by increasingly restricting their ability to divide.

In mice with cancer, cells supercharged with FOXO1 lasted longer by months than those that hadnt been boosted. The critters liver and kidney functions remained normal, and they didnt lose weight during the treatment, a marker of overall health. The FOXO1 boost also changed how genes were expressed in the cellsthey looked younger, as if in a stem cell-like state.

The new recipe also worked in T cells donated by six people with cancer who had undergone standard CAR T therapy. Adding a dose of FOXO1 to these cells increased their metabolism.

Multiple CAR T clinical trials are ongoing. But the effects of such cells are transient and do not provide long-term protection against exhaustion, wrote Darcy and team. In other words, durability is key for CAR T cells to live up to their full potential.

A FOXO1 boost offers a wayalthough it may not be the only way.

By studying factors that drive memory in T cells, like FOXO1, we can enhance our understanding of why CAR T cells persist and work more effectively in some patients compared to others, said Weber.

Image Credit: Gerardo Sotillo, Stanford Medicine

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Cell Therapies Now Beat Back Once Untreatable Blood Cancers. Scientists Are Making Them Even Deadlier. - Singularity Hub

Stem Cell Treatment Helped A Man Who Was Paralyzed From The Neck Down To Stand On His Own – Bored Panda

By Stem Cell Treatment

Long gone are the days of people being fearful of innovation and writing off any medical advance as witchcraft. However, it is hard not to believe in magic and science when doctors and scientists are making incredible discoveries that help patients improve their life quality and even make miraculous recoveries. Chris Barr is one of those lucky people who, thanks to science, is able to walk again after a severe spinal cord injury.

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Seven years ago, Chris Barr was having a regular day, just like a hundred other days gone by. The avid surfer was catching waves at a local beach until something went terribly wrong. One wave was particularly dangerous and threw Chris off the board. Soon, he realized that he was injured and the solemn expression on his doctors faces told him the news was going to be hard to swallow.

At the hospital, Chris learned about his life altering diagnosis he was paralyzed from the neck down. But Chris was determined to fight and believed that one day he will be able to regain some control of his body. However, even in his wildest dreams, he never imagined just how advanced his recovery will be and that he will be walking again thanks to an innovative stem cell treatment.

I never dreamed I would have a recovery like this, Chris shared his delight. I can feed myself. I can walk around. I can do day-to-day independent activities.

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Chris was the first patient in the Mayo Clinic study. It consisted of collecting stem cells from his own stomach fat and expanding them in the laboratory to 100 million cells. After that, the cells were injected into Chris lumbar spine. The treatment continued for over five years during which Chris saw a significant improvement in his quality of life, gaining more and more independence with each injection.

Mr. Barrs recovery story was published in the Nature Communications journal, as part of the research on the effects of stem cells in spinal cord injuries. The study claims that out of ten patients participating in the trial, seven saw positive effects in recovery from their injuries. The patients expressed that they have noticed increased strength in muscle motor groups and increased sensation to pinpricks and light touch. Each patient moved at least one level on the American Spinal Injury Association (ASIA) Impairment Scale. The scale has five levels detailing a patients ability to function. The other three patients, sadly, showed no improvement but they did not get worse.

These findings give us hope for the future, Dr. Mohamad Bydon, a neurosurgeon and the lead author of the study shared. The doctor, who is the director of The Christopher Reeve foundation, has dedicated his lifes work to curing spinal cord injuries, and is very hopeful of this trials future.

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The participants ranged from 18 to 65, all spinal injuries were either from the neck or back down. They all had their stem cells harvested from the stomach. Patient 1, Chris, had the most remarkable recovery of them all.

At the beginning of the study, Chris was on a ventilator, completely immobile. As the study progressed, he started using a harness and then even started taking some steps on his own. Besides stem cell treatment, Chris was doing hard work with his physiotherapist.

We waited, we didnt intervene right away, as many studies in this space do, the doctor noted. The earliest we treated anyone was seven months after their injury and the latest was 22 months. The researchers wanted to give the body time to try and recover on its own.

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Despite the incredible findings, the road to this new treatment being approved is still a long way away, as there needs to be more research done so doctors could understand how stem cells operate. To us, it might seem like magic or a miracle but for doctors, it means long years of trial and error, hoping that in their lifetime they will be able to help those in need.

Patients are always looking for a cure. Were not there today, but we have to continue this research in order to get there, Dr. Bydon pondered.

The second part of the study, involving more patients, is now underway, giving hope to those who have heard the horrible words, Youll never walk again. Hopefully, in a few years, those people will take their first steps yet again and say, Take that, bad luck!

As for Chris, he is delighted that he was able to be a part of this groundbreaking study. He might never surf again but at least he is able to take longer and longer walks without any assistance.

Im just thrilled that there are people taking bold steps to try and do research to cure this. Its been a wild ride and its not over yet.

What do you think of this? Do you think stem cell therapy is the future or does this sound like science fiction to you?

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Stem Cell Treatment Helped A Man Who Was Paralyzed From The Neck Down To Stand On His Own - Bored Panda

Anemia: Symptoms, Causes & Treatment – Cleveland Clinic

By Stem Cell Treatment

How do I take care of myself?

While some types of anemia are short-term and mild, others can last a lifetime. Regardless, there are several things you can do to help manage symptoms. Here are some suggestions:

If you have anemia, you should check with your provider if your symptoms get worse despite treatment or if you notice changes in your body that may be new symptoms.

Anemia may increase your risk of a heart attack. Call 911 if you have the following symptoms:

Anemia may affect your body in many ways. It may happen for many different reasons. If you have anemia, here are some questions you may want to ask your healthcare provider:

A note from Cleveland Clinic

Anemia happens when you dont have enough red blood cells or your red blood cells arent working as well as they could. Some people are born with forms of anemia, but most people who have anemia develop the condition over time. Thats why its important to keep track of changes in your body. For example, we all have days when we feel worn out. But if youre feeling very tired for several days despite getting rest, consider talking to your healthcare provider.

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Anemia: Symptoms, Causes & Treatment - Cleveland Clinic

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