Stem Cell Clinic

Purity, potency, and safety affordably in stem cell therapy – pharmaphorum

In a new episode of the pharmaphorum podcast, web editor Nicole Raleigh discusses stem cell therapy, and accessibility to and affordability of such treatment, with Rafael E Carazo Salas, founder and CEO of CellVoyant, an AI-first biotechnology company spun out from the University of Bristol.

From totipotent stem cells at conception, to pluripotent, multipotent, oligopotent, and unipotent stem cells by adulthood every disease essentially boils down to a dysfunction in the cells and tissues in organs, and cells should be the ideal therapy. Blood transfusions are a historic example, but in the modern concept, by harnessing stem cells, functional specialised cells can be used to alleviate, substitute, substitute, and repair the body.

Cell therapy will help heal the world, says Salas if only we will allow it to. From CAR-T for blood cancers to emerging research in stem cell therapy for diabetes, even for neurodegenerative diseases, stem cells are thought to offer potential hope for currently untreatable conditions, but there is a responsibility to do things right.

The UK is an academic powerhouse, globally recognised for its high level training and innovation and invention. Indeed, the UK is uniquely placed to spin out companies. Unlike the US, however, the attitude towards equity is only now changing in academic institutions in Britain, permitting a more inspiring innovation ecosystem that attracts talent.

Again, as Salas says, cell therapy could help heal the world but only if the costs permit accessibility. And thats where CellVoyant aims to come in, utilising predictive AI to select better cells, optimise targets, increase yield, accelerate processes, and lead to more affordable treatments that reach patients.

You can listen to episode 136a of thepharmaphorum podcastin the player below, download the episode to your computer, or find it - and subscribe to the rest of the series - iniTunes,Spotify,Google Podcasts,Amazon Music, andPodbean.

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Purity, potency, and safety affordably in stem cell therapy - pharmaphorum

FDA Greenlights First Drug in Nearly a Decade for Rare Liver Disease – BioSpace

Pictured: A scientist works behind an FDA sign/Taylor Tieden for BioSpace

The FDA approved 55 new drugs and 34 cell and gene therapies in 2023.But its not always good news that companies have to deliver to their stakeholders; the year also had its fair share of Complete Response Letters.

As we embark on 2024,BioSpaceis committed to keeping you up-to-date on all the FDAs actions in thisFDA Decision Tracker.

June 10

Product: Ipsen and Genfits Iqirvo

Indication: Primary biliary cholangitis

Monday, the FDA approved the first new drug in nearly a decade for primary biliary cholangitis: Ipsen and Genfits Iqirvo. A rare liver disease, PBC affects around 100,000 people in the U.S. and can lead to liver failure.

Iqirvo is intended to be used in combination with ursodeoxycholic acid (UDCA) in adult patients who have an inadequate response to UDCA, or as monotherapy in patients unable to tolerate UDCA.

The companies won accelerated approval for Iqirvo based on a reduction of alkaline phosphatase, a biochemical marker often used as a surrogate endpoint in PBC studies. Treatment with the drug demonstrated statistically significant improvements in biochemical response compared to UDCA alone, Christelle Huguet, executive vice president and head of research and development at Ipsen, said in a press release. An improvement in survival or prevention of liver decompensation events has not yet been shown, and the companies may need to run a confirmatory trial to verify Iqirvos clinical benefit.

June 10

Product: Almiralls Klisyri

Indication: Actinic keratosis

Dermatology company Almirall secured expanded approval of Klisyri for larger actinic keratosis-affected areas of the face or scalp. Klisyri can now be used to treat lesions up to 100 cm2 caused by the pre-cancerous dermatological condition, after safety and tolerability profiles were consistent with original pivotal trial results.

The new authorization for Klisyri, a microtubule inhibitor ointment, increases dosing for surface area treatment from up to 25 cm2 to up to 100 cm2, according to the companys press release.

In the same press release, Almirall Chief Scientific Officer Karl Ziegelbauer called the expanded approval a significant step forward for both patients and treating dermatologists, adding that the latter are looking for ways to treat the entire affected area to help prevent further lesion progression.

June 7

Product: Gerons Rytelo

Indication: Myelodysplastic syndromes

Geron Corporation kicked off the weekend on a high note as the FDA approval of its telomerase inhibitor Rytelo for myelodysplastic syndromes (MDS)a group of blood cancerssent the companys stock soaring more than 30%. Rytelo is specifically approved for MDS patients with transfusion-dependent anemia who do not respond to or are ineligible for the standard-of-care treatment, erythropoiesis-stimulating agents.

The approvalGerons first after 34 years in businesswas supported by data from the Phase III IMerge trial, in which patients on Rytelo had significantly higher rates of red blood cell transfusion independence over placebo for at least 24 weeks28% in the treatment arm versus 3% on placebo. For those who responded, this was sustained for a median of 1.5 years.

June 7

Product: GSKs Arexvy

Indication: Respiratory syncytial virus

People ages 5059 at an increased risk of severe outcomes from respiratory syncytial virus have a new preventative option after the FDA greenlit GSKs RSV vaccine Arexvy for this subgroup on Friday. Arexvy is indicated for the prevention of lower respiratory tract disease associated with RSV.

Fridays label expansionwhich was backed by strong immunogenicity and safety data in this populationextends the market reach for Arexvy, which became the first vaccine for RSV in May 2023, at that point intended for adults 60 and above.

GSK is also evaluating the vaccine for use in people 18-49 at increased risk of severe disease, and immunocompromised patients 18 and older.

May 31

Product: Modernas mRESVIA

Indication: Respiratory syncytial virus

Moderna has a second product on the market after the FDA approved mRESVIAformerly mRNA-1345to protect adults 60 years and older fromrespiratory syncytial virus (RSV). In a press release, Moderna CEO Stphane Bancel touted the strength and versatility of the companys mRNA platform, adding that the approval also marks the first time an mRNA vaccine has been approved for a disease other than COVID-19.

mRESVIA won approval based on the Phase III ConquerRSV trial, a global study of around 37,000 adults aged 60 or older in 22 countries, in which it displayed an efficacy rate of 83.7% against RSV lower respiratory tract disease. No serious safety concerns were identified in the trial.

May 30

Product: BMSs Breyanzi

Indication: Mantle Cell Lymphoma

After winning approval earlier this month in follicular lymphoma, Bristol Myers Squibbs Breyanzi got the FDA nod for another indication on Thursday: relapsed or refractory mantle cell lymphoma (MCL). Specifically, Breyanzi is approved for patients with MCL who have received at least two prior lines of systemic therapy, including a Bruton tyrosine kinase inhibitor.

The approval is backed by the results of the MCL cohort of TRANSCEND NHL 001, where treatment with Breyanzi elicited a 67.6% complete response rate in the target patient population.

Thursdays approval marks the fourth indication for Breyanzi, making it the CAR T cell therapy available to treat the broadest array of B-cell malignancies, according to BMSs press release.

May 29

Product: Eli Lillys Retevmo

Indication: RET-altered pediatric cancers

Eli Lilly won accelerated approval Wednesday for Retevmo to treat pediatric patients two years and older with RET-positive thyroid cancers and other solid tumors that carry the mutation. Retevmo is the first drug in the class available for children under 12 years of age, Pharmaphorum reported.

Retevmo is specifically indicated for advanced or metastatic medullary thyroid cancer with a RET mutation, advanced or metastatic thyroid cancer with a RET gene fusion untreatable with radioactive iodine therapy, and locally advanced or metastatic solid tumors with a RET gene fusion that have progressed after prior systemic treatment or have no treatment options, according to the publication.

The new approval for Retevmo, which was previously authorized to treat patients 12 and older with RET-positive thyroid cancers, is based on a single-arm study that showed an overall response rate of 48%, with a median duration of response not reached after 12 months of follow-up.

May 29

Product: Tris Pharmas Onyda XR

Indication: Attention deficit hyperactivity disorder

Wednesday, the FDA greenlit Tris Pharmas Onyda XR as the first non-stimulant medication for attention deficit hyperactivity disorder (ADHD) with a liquid formulation and nighttime dosing, according to the company. Onyda XR is a reformulation of clonidine hydrochloride, which was first approved by the FDA in 1974 to treat high blood pressure. Clonidine was approved for ADHD in 2010 under the brand name Kapvay, which is owned by Shionogi.

Onyda XR leverages Tris LiquiXR platform, producing a smooth, extended-release profile, per the biotech.

Approved for patients six years and older, Tris expects to have Onyda XR available in U.S. pharmacies by the second half of 2024.

May 29

Product: Tevas Austedo XR

Indication: Tardive dyskinesia and Huntingtons disease chorea

People with tardive dyskinesia and Huntingtons disease chorea have a streamlined treatment option after the FDA approved a new one-pill-a-day version of Tevas Austedo XR. The newly approved formulation offers more flexibility with the most once-daily doses of any vesicular monoamine transporter 2 (VMAT2) inhibitor, for these conditions, according to Tevas press release. Austedo XR comes in four tablet strengths: 30, 36, 42 and 48 mg.

Austedo XR, a once-daily extended-release formulation, was first approved in February 2023.

May 28

Product: Amgens Bkemv

Indication: Paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome

AstraZenecas rare disease drug Soliris now has a biosimilar on the market after the FDA greenlit Amgens Bkemv to treat paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS). Bkemv was granted the FDAs interchangeability designation, which allows it to be used in place of the branded reference product without needing to change the prescription.

Like Soliris, Bkemv carries a boxed warning for meningococcal infections, which according to its label can be serious and life-threatening. Thus, it is only available through a restricted Risk Evaluation and Mitigation Strategies program.

May 16

Product: Amgens Imdelltra

Indication: Small cell lung cancer

Amgen secured approval Thursday for its first-in-class bi-specific T-cell engager, Imdelltra, for extensive-stage small cell lung cancer (SCLC). With the FDA nod, Imdelltra becomes the first bispecific T-cell engager therapy for advanced SCLC.

The accelerated approval was based on a Phase II study of 99 patients in the target population, where Imdelltra led to an overall response rate of 40% and a median duration of response of 9.7 months. Imdelltras label contains a boxed warning for serious or life-threatening cytokine release syndrome and neurologic toxicity, including immune effector cell-associated neurotoxicity syndrome, according to the FDAs press release.

May 15

Product: BMSs Breyanzi

Indication: Follicular lymphoma

Bristol Myers Squibbs Breyanzi is now approved for the treatment of relapsed or refractory follicular lymphoma after the FDA granted a label expansion under its accelerated approval pathway. The approval was backed by data from the Phase II TRANSCEND FL study in which treatment with the CAR T cell therapy led to a 95.7% overall response rate, with a complete response rate of 73.4%.

Breyanzi, which first won approval in February 2021 for relapsed or refractory large B cell lymphoma, is also authorized to treat small lymphocytic leukemia and chronic lymphocytic leukemia. By May 31, the FDA is expected to decide whether to grant approval for the therapy in refractory mantle cell lymphoma.

May 14

Product: Dynavaxs Heplisav-B

Indication: Hepatitis B patients undergoing hemodialysis

The FDA declined to approve the supplemental Biologics License Application for Dynavax Technologies hepatitis B vaccine in patients undergoing hemodialysis, deeming the safety and efficacy data submitted by the company insufficient.

In its Complete Response Letter, the regulator said the data was insufficient because a third-party clinical site operator destroyed data source documents for about half of the subjects enrolled in the vaccines trial, according to Reuters.

While the vaccine, Heplisav-B, initially won approval for the prevention of hepatitis B in 2017, its path to the market was rocky, with two previous rejections in 2013 and 2016 for unresolved safety concerns, per Reuters.

May 1

Product: Boehringer Ingelheims Cyltezo

Indication: Rheumatoid arthritis, Crohns disease, ulcerative colitis and more

Theres another new biosimilar option to AbbVies blockbuster antirheumatic Humira. Wednesday, the FDA greenlit a high-concentration and citrate-free version of Boehringer Ingelheims Cyltezo, which was originally approved in October 2021. The newly approved dose is 100 mg/mL and is sold at a 5% discount to the branded reference product.

Cyltezo is indicated for all the same conditions as Humira, including moderate-to-severe rheumatoid arthritis, Crohns disease and ulcerative colitis. Wednesdays approval is backed by data from the Phase I VOLTAIRE-HCLF study, which compared the bioavailability of the high- and low-concentration (50 mg/mL) formulation of Cyltezo in 200 healthy volunteers.

April 30

Product: Neurocrine Biosciences Ingrezza

Indication: Huntingtons disease

A more convenient version of Neurocrine Biosciences Ingrezza will be hitting the market to treat tardive dyskinesia and chorea in Huntingtons disease after the FDA closed out April by approving a sprinkle capsule formulation of the drug.

Like the original capsule version, which was approved in 2017 for tardive dyskinesia and in 2023 for chorea in Huntingtons, Ingrezzas sprinkle formulation comes in 40-mg, 60-mg and 80-mg doses but is designed to be opened and sprinkled on soft foods. This format could be more accessible for patients who have trouble swallowing whole capsules, according to the Neurocrines announcement, which also noted that a survey of Huntingtons patients with chorea and their caregivers showed that 62% had difficulty swallowing due to their involuntary movements.

April 29

Product: Pfizer and Genmabs Tivdak

Indication: Cervical cancer

The FDA has converted the accelerated approval of Pfizer and Genmabs Tivdak into a full nod for recurrent or metastatic cervical cancer that has progressed on or after chemotherapy.

The antibody-drug conjugate (ADC), which was originally developed under a partnership between Seagen and Genmab, was granted accelerated approval in September 2021 based on a 24% objective response rate seen in the Phase II innovaTV 204 trial.

In the Phase III innovaTV 301 study, which enrolled more than 500 patients, Tivdak significantly boosted survival versus chemotherapy. An October 2023 readout showed the ADC cut the risk of death by 30% in patients with recurrent or metastatic cervical cancer; it also reduced the risk of death or worsening disease by 33% versus chemotherapy. No new safety signals were observed.

April 29

Product: X4 Pharmaceuticals Xolremdi

Indication: WHIM Syndrome

The FDAapprovedX4 Pharmaceuticals Xolremdi Monday as the first targeted treatment for WHIM syndrome, an ultra-rare immunodeficiency disease named for its four characteristics: warts, hypogammaglobulinemia, infections and myelokathexis.

Myelokathexis is a congential disorder of the white blood cells, and Xolremdi, an oral CXCR4 antagonist, is designed to mobilize white blood cells such as neutrophils, lymphocytes and monocytes from the bone marrow into the blood to improve immune deficiencies.

In the Phase III 4WHIM trial, Xolremdi showed a 60% reduction in annualized infection rate compared to placebo; trial participants had less than one infection per year compared with 4.5 for the placebo group. Patients saw an even greater reduction with additional time on treatment.

Its an exciting time for personalized medicine, and I think WHIM is going to be a poster child for rare diseases and the ability where were at now in modern medicine to design therapies to treat underlying genetic disorders, Teresa Tarrant, an associate professor at Duke Universitys School of Medicine and lead investigator of the 4WHIM trial, told BioSpace prior to Xolremdis approval.

April 26

See the rest here:
FDA Greenlights First Drug in Nearly a Decade for Rare Liver Disease - BioSpace

Mistaken Identity: Gut Stem Cell Discovery Could Transform Regenerative Medicine – Neuroscience News

Summary: Two studies reveal that scientists have misidentified gut stem cells, impacting research and treatments for 15 years. Researchers identified the true stem cells in a different gut region, which could lead to breakthroughs in regenerative medicine.

This discovery highlights the importance of accurate identification for effective treatments. The findings could improve therapies for intestinal diseases and beyond.

Key Facts:

Source: Columbia University

Two independent studies by Columbia scientists suggest that research into the guts stem cells over the past 15 years has been marred by a case of mistaken identity: Scientists have been studying the wrong cell.

Both studies were published online today in the journalCell.

The guts stem cells are some of the hardest-working stem cells in the body. They work continuously throughout our lives to replenish the short-lived cells that line our intestines. About every four days, these cellscovering a surface about the size of a tennis courtare completely replaced.

Understanding these workaholic stem cells could help scientists turn on less productive stem cells in other organs to repair hearts, lungs, brains, and more.

The guts stem cells were supposedly identified more than 15 years ago in a landmark study.

But using new lineage tracing and computational tools, the Columbia teams, led by Timothy Wang and Kelley Yan, found that these cells are descendants of the guts true stem cells. The guts true stem cells are found in a different location, produce different proteins, and respond to different signals.

The new work is controversial and paradigm-shifting but could revitalize the [entire?] field of regenerative medicine, says Timothy Wang, the Dorothy L. and Daniel H. Silberberg Professor of Medicine.

We know were making a lot of waves in the field, but if were going to make progress, we need to identify the true stem cells so we can target these cells for therapies, says Kelley Yan, the Herbert Irving Assistant Professor of Medicine.

We recently spoke with Yan and Wang about the findings and implications.

KY Whats relevant to this story is a tissue called the intestinal epithelium. This is a single layer of cells that lines the gut and its composed of different types of cells that help digest food, absorb nutrients, and fight microbes.

Most of the cells live for only about four days before being replaced, so stem cells must create replacements.

Whats really remarkable about the intestinal lining is how big it is. If we were to fillet open your intestine and lay it flat, it would cover the surface of a tennis court.

The guts stem cells may be the hardest working stem cells in the body.

TW: For the last 17 years, the intestinal stem cell field has assumed that Lgr5, a protein on the cells surface, is a specific marker for intestinal stem cells. In other words, all Lgr5+ cells are assumed to be stem cells, and all stem cells are believed to be Lgr5+. These Lgr5+ cells were located at the very bottom of glands, or crypts, in the intestinal lining.

However, in the last decade, problems with this model began to appear. Deleting the Lgr5+ cells in mice, using a genetic approach, did not seem to bother the intestine very much, and the Lgr5+ stem cells reappeared over the course of a week. In addition, the intestine was able to regenerate after severe injury, such as radiation-induced damage, even though the injury destroyed nearly all Lgr5+ cells.

KY: By their very definition, stem cells are the cells that regenerate tissues, so these findings created a paradox. Many high-profile papers have evoked different mechanisms to explain the paradox: Some suggest that other fully mature intestinal cells can walk backward in developmental time and regain stem cell characteristics. Others suggest theres a dormant population of stem cells that only works when the lining is damaged.

No one has really examined the idea that maybe the Lgr5+ cells really arent truly stem cells, which is the simplest explanation.

TW: My lab collaborated with the former chair of Columbias systems biology department, Andrea Califano, who has developed cutting-edge computational algorithms that can reconstruct the relationships among cells within a tissue. We used single-cell RNA sequencing to characterize all the cells in the crypts, the region of the intestine where the stem cells are known to reside, and then fed that data into the algorithms.

These algorithms revealed the source of stemness in the intestine not in the Lgr5+ cellular pool but in another type of cell higher up in the crypts in a region known as the isthmus. After eliminating Lgr5+ cells with radiation or genetic ablation, we confirmed these isthmus cells were the guts stem cells and able to regenerate the intestinal lining. We didnt find any evidence that other, mature cells could turn back time and become stem cells.

KY: We werent trying to identify the stem cells as much as we were trying to understand the other cells in the intestine involved in regeneration of the lining. No one has been able to define these other progenitor cells in the intestine.

We identified a population of cells that were proliferative and marked by a protein called FGFBP1. When we asked how these cells were related to Lgr5+ cells, our computational analysis told us that these FGFBP1 cells give rise to all the intestinal cells, including Lgr5+, the opposite of the accepted model.

My graduate student, Claudia Capdevila, then made a mouse that would allow us to determine which cellsLgr5+ or FGFBP1+were the true stem cells. In this mouse, every time the FGFBP1 gene is turned on in a cell, the cell would express two different fluorescent proteins, red and blue. The red would turn on immediately and turn off immediately, while the blue came on a little later and lingered for days.

That allowed us to track the cells over time, and it clearly showed that the FGFBP1 cells create the Lgr5+ cells, the opposite of what people currently believe. This technique, called time-resolved fate mapping, has only been used a few times before, and getting it to work was a pretty incredible achievement, I thought.

TW: This case of mistaken identity may explain why regenerative medicine has not lived up to its promise. Weve been looking at the wrong cells.

Past studies will need to be reinterpreted in light of the stem cells new identity, but eventually it may lead to therapies that help the intestine regenerate in people with intestinal diseases and possible transplantation of stem cells in the future.

KY: Ultimately, we hope to identify a universal pathway that underlies how stem cells work, so we can then apply the principles we learn about the gut to other tissues like skin, hair, brain, heart, lung, kidney, liver, etc.

Its also thought that some cancers arise from stem cells that have gone awry. So, in understanding the identity of the stem cell, we might be able to also develop novel therapeutics that can prevent the development of cancer.

Thats why its so critical to understand what cell underlies all of this.

Time-resolved fate mapping identifies the intestinal upper crypt zone as an origin of Lgr5+ crypt base columnar cells, was published June 6 in Cell.

All authors: Claudia Capdevila, Jonathan Miller, Liang Cheng, Adam Kornberg, Joel J. George, Hyeonjeong Lee, Theo Botella, Christine S. Moon, John W. Murray, Stephanie Lam, Ermanno Malagola, Gary Whelan, Chyuan-Sheng Lin, Arnold Han, Timothy C. Wang, Peter A. Sims, & Kelley S. Yan. The authors (all from Columbia) declare no competing financial interests.

Funding: The study was supported by the U.S. National Institutes of Health (though grants DP2DK128801, R01AG067014, P30CA013696, P30DK132710, U01DK103155, T32DK083256, and T32HL105323), a Burroughs Wellcome Fund Career Award for Medical Scientists, the Irma T. Hirschl Trust, an Irving Scholars Award, the Gerstner Foundation, a Damon Runyon-Rachleff Innovation Award, a NYSTEM predoctoral training grant, and the Berrie Foundation.

Isthmus progenitor cells contribute to homeostatic cellular turnover and supportregeneration following intestinal injury, was published June 6 in Cell.

All authors (from Columbia unless noted): Ermanno Malagola, Alessandro Vasciaveo, Yosuke Ochiai, Woosook Kim, Biyun Zheng (Columbia and Fujian Medical University, China), Luca Zanella, Alexander L.E. Wang, Moritz Middelhoff (University Hospital Heidelberg), Henrik Nienhser (University Hospital Heidelberg), Lu Deng (University of Kansas), Feijing Wu, Quin T. Waterbury, Bryana Belin, Jonathan LaBella, Leah B. Zamechek, Melissa H. Wong (Oregon Health & Sciences University), Linheng Li (University of Kansas), Chandan Guha (Albert Einstein College of Medicine), Chia-Wei Cheng, Kelley S. Yan, Andrea Califano (Columbia and Chan Zuckerberg Biohub NY), and Timothy C. Wang.

Funding: This research was funded by the U.S. National Institutes of Health (through grants P30CA013696, P30DK132710, U01DK103155, R35CA210088, R01NK128195, R35CA197745, S10OD012351, S10OD021764, and S10OD032433) and the U.S. Department of Defense (grants W81XWH-465 21-10901 and W81XWH19-1-0337).

Andrea Califano is founder, equity holder, and consultant of DarwinHealth Inc., a companythat has licensed from Columbia University some of the algorithms used in this manuscript. Columbia University is also an equity holder in DarwinHealth Inc. U.S. patent number 10,790,040 has been awarded related to this work, assigned to Columbia University with Andrea Califano as an inventor.

Author: Helen Garey Source: Columbia University Contact: Helen Garey Columbia University Image: The image is credited to Neuroscience News

Original Research: Open access. Time-resolved fate mapping identifies the intestinal upper crypt zone as an origin of Lgr5+ crypt base columnar cells by Claudia Capdevila et al. Cell

Open access. Isthmus progenitor cells contribute to homeostatic cellular turnover and supportregeneration following intestinal injury by Ermanno Malagola et al. Cell

Abstract

Time-resolved fate mapping identifies the intestinal upper crypt zone as an origin of Lgr5+ crypt base columnar cells

In the prevailing model,Lgr5+ cells are the only intestinal stem cells (ISCs) that sustain homeostatic epithelial regeneration by upward migration of progeny through elusive upper crypt transit-amplifying (TA) intermediates.

Here, we identify a proliferative upper crypt population marked byFgfbp1, in the location of putative TA cells, that is transcriptionally distinct fromLgr5+ cells.

Using a kinetic reporter for time-resolved fate mapping andFgfbp1-CreERT2lineage tracing, we establish thatFgfbp1+ cells are multi-potent and give rise toLgr5+ cells, consistent with their ISC function.Fgfbp1+ cells also sustain epithelial regeneration followingLgr5+ cell depletion.

We demonstrate that FGFBP1, produced by the upper crypt cells, is an essential factor for crypt proliferation and epithelial homeostasis.

Our findings support a model in which tissue regeneration originates from upper cryptFgfbp1+ cells that generate progeny propagating bi-directionally along the crypt-villus axis and serve as a source ofLgr5+ cells in the crypt base.

Abstract

Isthmus progenitor cells contribute to homeostatic cellular turnover and supportregeneration following intestinal injury

The currently accepted intestinal epithelial cell organization model proposes that Lgr5+crypt-base columnar (CBC) cells represent the sole intestinal stem cell (ISC) compartment.

However, previous studies have indicated that Lgr5+cells are dispensable for intestinal regeneration, leading to two major hypotheses: one favoring the presence of a quiescent reserve ISC and the other calling for differentiated cell plasticity. To investigate these possibilities, we studied crypt epithelial cells in an unbiased fashion via high-resolution single-cell profiling.

These studies, combined withinvivolineage tracing, show thatLgr5is not a specific ISC marker and that stemness potential exists beyond the crypt base and resides in the isthmus region, where undifferentiated cells participate in intestinal homeostasis and regeneration following irradiation (IR) injury.

Our results provide an alternative model of intestinal epithelial cell organization, suggesting that stemness potential is not restricted to CBC cells, and neither de-differentiation nor reserve ISC are drivers of intestinal regeneration.

Read more:
Mistaken Identity: Gut Stem Cell Discovery Could Transform Regenerative Medicine - Neuroscience News

Cleveland Clinic Research Findings May Improve Chemotherapy-Resistant Ovarian Cancer Treatment – Cleveland Clinic Newsroom

Cleveland Clinic researchers have discovered a new location for a protein that helps ovarian cancer cells resist chemotherapy treatments and that fosters aggressive cancer stem cell growth.

These findings, published today in Molecular Cancer, may become the basis of a new approach to treat chemotherapy-resistant ovarian cancer that targets the protein CD55. Currently the CD55 protein is difficult to target because of its protective role in the immune system and its location on the cell surface.

Ofer Reizes, Ph.D., the Laura J. Fogarty Endowed Chair for Uterine Cancer Research at Cleveland Clinics Lerner Research Institute, and his lab previously identified CD55 as a driver of ovarian cancer chemoresistance. They also found CD55 underlies tumor recurrence and metastasis, findings replicated in additional cancers. Collectively, the previous studies indicated CD55 may provide a way to treat ovarian cancer, and his group has worked to determine how such a treatment would work.

The breakthrough came as Drs. Rashmi Bharti and Goutam Dey, post-doctoral fellows in Dr. Reizes lab, found that CD55 migrated into the cell nucleus from the surface, a location in which this protein has never been found before.

The lab started examining cells and tissues from patient samples by working with Chad Michener, M.D., and Roberto Vargas, M.D., oncologists specializing in womens health at Cleveland Clinic. A subset of patient tumors showed the same thing: the CD55 protein was inside the nucleus of the cancer cells and setting off a response that makes the cancer more aggressive.

Cancer cells can do unusual things co-opt existing pathways and create new pathways we didnt know were possible, Dr. Reizes said. Once we discovered this new pathway, we wanted to see if we could find a way to block CD55 from moving into the nucleus. And then, once we prevented that move from occurring, we needed to determine whether we could halt the cancers progression.

The study showed blocking CD55s migration from the cell surface to the nucleus disrupted cancer growth and lessened the cells resistance to chemotherapy.

Ovarian cancer is the second most common gynecologic cancer in the U.S. and the most common cause of death. The diseases vague symptoms often lead to late-stage diagnosis, complicating treatment. Gynecologic cancer patients commonly see the cancer recur and develop resistance to chemotherapy. Ovarian cancer cells especially cancer stem cells can survive chemotherapy drugs. Dr. Reizes lab investigates chemoresistance biomarkers and targeted therapies.

Ovarian cancer treatment often involves waiting for one treatment to fail before trying something new. This studys findings may allow doctors and patients to decide to avoid chemotherapy if CD55 is already present in the cell nucleus. With the knowledge from the current findings, the lab is investigating therapeutic approaches including peptide-based, small molecule drugs and antibodies to stop CD55 from migrating to the nucleus. Moreover, the Reizes team, in collaboration with Drs. Michener and Vargas, is validating nuclear CD55 as a chemoresistance marker in gynecologic cancers as well as other solid tumors.

These newly identified markers could allow us to track these cancers as they change in real-time, Dr. Vargas said. How amazing would it be to adapt our treatments as a tumor is evolving, instead of waiting for negative results months later? These approaches, thanks to Dr. Reizes findings, may finally allow us to remain a step ahead.

Continued here:
Cleveland Clinic Research Findings May Improve Chemotherapy-Resistant Ovarian Cancer Treatment - Cleveland Clinic Newsroom

Most stem cells die after being injected into brain – this new technique could change that – Niagara Frontier Publications

Thu, Jun 6th 2024 03:40 pm

Research team uses shear-thinning hydrogels instead of saline solution; could lead to new therapies for MS, other neurological diseases

By the University at Buffalo

When the myelin sheath that surrounds nerve fibers in the brain and spinal cord becomes damaged, a number of debilitating conditions can result that limit mobility, inhibit independence and reduce life expectancy. Multiple sclerosis (MS) is the most common demyelinating disease, affecting more than 2.5 million individuals globally every year.

Stem cell therapy to treat such diseases often has disappointing results because the transplanted cells die off before they can take effect. In fact, more than 95% of neural progenitor cells (NPCs) transplanted into individuals with a spinal cord injury die following injection. This is partly because the process of injecting the cells can damage them.

Two University at Buffalo researchers are working on a possible solution: injecting shear-thinning hydrogels (STH) into the brain, which protect the cells and result in more successful therapy.

Stelios Andreadis, Ph.D., SUNY Distinguished Professor in the department of chemical and biological engineering in the School of Engineering and Applied Sciences, and Fraser Sim, Ph.D., professor in the department of pharmacology and toxicology in the Jacobs School of Medicine and Biomedical Sciences and director of UBs neuroscience program, were recently awarded a $2.9 million, five-year grant from the National Institute of Neurological Disorders and Stroke to further investigate this technology.

STHs have emerged as promising candidates for the injection of Schwann cells and oligodendrocytes, the cells that form the myelin sheath in the brain and spinal cord, said Andreadis, who also directs UBs Cell, Gene and Tissue Engineering (CGTE) Center, of which Sim is a member. The work we plan to undertake has significant implications for regenerative medicine, as it has the potential to develop novel strategies to enhance stem cell delivery for treatment of devastating neurological diseases that remain intractable to current treatments.

How shear-thinning hydrogels work

The hydrogels are called shear-thinning because, once you put in them in a syringe and apply pressure, they turn into a liquid form, Andreadis explained.

They change their viscosity in response to shear stress, and they can turn back into gel form when the force is removed, after the injection, he said. The fast transition from solid-like to fluid-like behavior, with increasing shear rate, is essential for successful injection and cell protection.

The STHs are also designed to mimic the mechanical properties of the brain tissue such as stiffness. And the treatments are minimally invasive.

We dont open up the brain surgically, Andreadis said, but rather are using syringes to perform in what is called stereotactic surgery.

Up until now, scientists have essentially put the stem cells into a simple saline solution before implanting them, Sim said.

They just accepted the fact that a lot of cells will die when you transplant them, said Sim, whose lab investigates the molecular control of cell fate and homeostasis of resident stem and progenitor cells in the human brain.

With the hydrogel, we can introduce different factors that will allow the cells to overcome the inhibitory environment thats present in MS lesions, Sim said. We think this will improve the outcome of cell therapy over the vanilla approach using cells in a saline solution.

Testing on animal models that do not produce myelin

The two researchers began exploring STH technology a couple of years ago by transplanting human cells into the brains of a type of mouse that does not naturally produce myelin.

The mouses condition models congenital hypomyelinating diseases in humans such Pelizaeus-Merzbacher disease, a rare and progressive degenerative central nervous system disorder, Andreadis said. We found that implanting the hydrogels significantly improved the survival of the transplanted cells and enhanced nerve repair in the brain 12 weeks post-implantation.

The next step is to conduct testing on larger animal models with a brain size closer to that of humans. They are seeking answers to questions such as: How many cells do you need? Are the cells going in the parts of the brain where we want them to go? Are they migrating places that theyre not supposed to migrate?

These are some of the issues well be investigating in the next few years with support from the recent NIH research grant, Andreadis said.

This is a great opportunity to marry biomaterials science and engineering with neuroscience to develop a therapeutic strategy that can, hopefully, be brought to the clinic to treat devastating diseases and conditions such as MS, Andreadis explained. While there is currently no cure, we would like to develop a successful therapy that can limit the diseases development and improve quality of life for MS patients and others who are suffering from neurological disorders.

Sim said he has been grateful for the opportunity to combine his expertise with that of Andreadis.

This project is a wonderful example of collaborative science, he said. Neither of us could do this work alone.

The study, which will be published online and in print in an upcoming edition of Science Advances, was led by Ashis Kumar Podder, a graduate student in the department of chemical and biological engineering lab, and Mohamed Alaa Mohamed, Ph.D., a biomaterial chemist and postdoctoral fellow in the department of chemical and biological engineering. Contributors includeRichard A. Seidman,Ph.D., a recent graduate of UBs neuroscience program and currentpostdoctoral associate in the UB department of pharmacology and toxicology; Georgios Tseropoulos,Ph.D., a recent graduate of UBs chemical and biological engineering program and now a postdoctoral fellow at the University of Colorado; Jessie Polanco, who recently earned his Ph.D. from UBs neuroscience program, and Pedro Lei, Ph.D., assistant professor of research in the UB department ofchemical and biological engineering.

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Most stem cells die after being injected into brain - this new technique could change that - Niagara Frontier Publications