Category Archives: Stem Cell Therapy

image:Karla Santos-de-Frutos and Nabil Djouder in the lab. view more

Credit: Antonio Tabernero. CNIO

The intestine is very susceptible and is affected by the harsh conditions caused by DNA-altering agents, such as radiation and chemotherapy, during cancer treatment. For example, many patients with tumours in the gastrointestinal cavity receive radiotherapy, a treatment that often also damages the healthy intestine and affects its regenerative capacity. It is therefore very important to understand how intestinal epithelial regeneration occurs. The cellular and molecular mechanisms involved in this key process are not yet fully understood.

Researchers at the Spanish National Cancer Research Centre (CNIO) have now discovered one of the cellular and molecular mechanisms essential for the regeneration of the intestinal epithelium. This finding lays the foundations for stimulating this process if it fails, and for protecting it against damage caused by radiotherapy and chemotherapy.

According to the study, what prompts intestinal stem cells to regenerate the mucosa depends on the communication between different cell types in the epithelial tissue. The researchers have also found a way to intervene in this communication, and thereby, boost intestinal regeneration.

The paper is published this week in Journal of Experimental Medicine. The research is led by the head of the CNIO's Growth Factors, Nutrients and Cancer Group, Nabil Djouder, and Almudena Chaves-Prez and Karla Santos-de-Frutos are first authors.

The group has spent years researching how to improve the regeneration of various organsparticularly the liver and intestinal mucosaand thus mitigate the effects of radiotherapy. Their findings during this period have been published in high-impact journals.

'Fascinating' four-way cellular communication

"Regeneration of the intestinal epithelium is very important in the proper functioning of the intestine," explains Djouder. "Until now, we knew that it was driven by powerful mitogenic factorsproteinsthat stimulate the proliferation of intestinal stem cells, but we didn't know how these factors were regulated."

This new study suggests thatunexpectedly for the researchers it is the progenitor cells involved in regenerating the epithelial mucosa that modulate the production of mitogenic factors. The process is as follows: when severe damage occurs, injury to the progenitor cells leads to tissue inflammation; this in turn slows down the production of mitogenic factors and thus the proliferation of stem cells and the subsequent regeneration of the mucous membrane.

"For us, this communication between at least four different cell types is new: progenitor cells, which differentiate to form the epithelial mucosa; cells that secrete mitogenic factors; inflammatory cells; and intestinal stem cells themselves," says Djouder. "This communication must be very well controlled, so that the tissue responds appropriately to aggressions."

"That progenitor cells communicate with inflammatory cells and coordinate the proliferation rate of intestinal stem cells is fascinating," he adds.

Djouder places particular emphasis on the new role that progenitor cells have been found to play: "Our study suggests that progenitor cells are not mere bystanders in the process of epithelial regeneration, but play an active and important role in the decisions that intestinal stem cells make in regeneration. Progenitor cells tell intestinal stem cells when and how to divide, and thus control their self-regeneration."

Reducing the side effects of radiotherapy

"This study has allowed us to better understand cell cooperation in order to find new ways to reduce adverse effects in traditional cancer treatments," say Chaves-Prez and Santos-de-Frutos, lead authors of the paper.

The group has also confirmed findings observed in previous work, namely that c-MYC oncogene plays a key role in regeneration. Due to radiation damage and the increase of c-MYC in progenitor cells, inflammation in the intestine increases and mitogenic protein levels are reduced; however, by removing or inhibiting c-MYC, the process is reversed: inflammation is reduced, mitogenic factors increase and intestinal regeneration during severe damage improves.

"Our data show an unexpected role for progenitor cells in the control of inflammatory signalling and mitogenic factor production, essential for maintaining intestinal stem cell proliferation and tissue regeneration," the authors write.

The finding, they say, breaks new ground in research into how to counteract the side effects of radiotherapy in patients with gastrointestinal cancer.

The work has been funded by the Ministry of Science and Innovation, the Carlos III Health Institute, the European Regional Development Fund, the Community of Madrid and the Spanish Association Against Cancer.

Article reference

Transit-amplifying cells control R-spondins in the mouse crypt to modulate intestinal stem 2 cell proliferation. Almudena Chaves-Prez1, Karla Santos-de-Frutos et al. (Journal of Experimental Medicine).

DOI: 10.1084/jem.20212405

Journal of Experimental Medicine

Experimental study

Transit-amplifying cells control R-spondins in the mouse crypt to modulate intestinal stem 2 cell proliferation

13-Sep-2022

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Link:
Discovered key mechanisms to improve intestinal regeneration and alleviate the side effects of radiotherapy - EurekAlert

According to the latest report by IMARC Group Nerve Repair and Regeneration Market: Global Industry Trends, Share, Size, Growth, Opportunity and Forecast 2021-2026, The globalnerve repair and regeneration marketexhibited strong growth during 2015-2020. Looking forward, IMARC Group expects the market to grow at a CAGR of around 12% during 2021-2026.

Nerve repair and regeneration (NRaR) is performed to support the replacement of injured nervous tissue caused by trauma or neurodegenerative diseases. It promotes the regrowth of new neurons, myelin, axon, synapses, and glial cells to restore normal nerve functionalities. NRaR employs biomaterials, along with neurostimulation and neuromodulation devices, for conducting nerve grafting, direct Neurotherapy, stem cell therapy, transcranial magnetic, and sacral nerve stimulation. As a result, they are extensively applied in cell relocation studies, material sciences, and nanotechnology and bioengineering fields.

Market Trends:

The increasing prevalence of neurological disorders and rising incidents of nervous injuries, especially in the geriatric population, represent the key factors contributing to the global NRaR market growth. In line with this, extensive research and development (R&D) activities in the field of neurology to introduce advanced NRaR products are further catalyzing market growth. Moreover, rising healthcare expenditure and the widespread adoption of effective management and treatment strategies, such as endogenous and exogenous stem cell transplantation, are positively influencing the market growth.

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We are regularly tracking the direct effect of COVID-19 on the market, along with the indirect influence of associated industries. These observations will be integrated into the report.

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The competitive landscape of the market has been studied in the report with the detailed profiles of the key players operating in the market.

Some of these key players include:

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Nerve Repair and Regeneration Market 2021-26: Size, Share, Demand And Forecast - Digital Journal

Intensive first-line treatment with high-dose chemotherapy and autologous stem cell transplant was not associated with higher rates of late effects compared with outcomes from less intensive therapies in patients with mantle cell lymphoma.

Intensive first-line treatment with high-dose chemotherapy and autologous stem cell transplant (ASCT) was not associated with higher rates of late effects compared with outcomes from less intensive therapies in patients with mantle cell lymphoma (MCL), according to findings from a population-based study. The results also showed that patients with MCL had a higher rate of outpatient visits, hospitalizations, and bed days vs healthy comparators.

When compared with matched comparators from the general population, patients with MCL had a rate of outpatient visits during follow-up that was 2 times higher (incidence rate ratio [IRR], 2.0; 95% CI, 1.8-2.2). Furthermore, rates of inpatient visits for those with MCL were 7 times higher (incidence rate ratio for inpatient visits, 7.2 [95% CI, 6.3-8.3] and incidence rate ratio for bed days was 8 times higher, 8.3 [95% CI, 6.8-10.1]) 12 months after MCL diagnosis.

Studies of late effects by different MCL therapies are of interest as new treatments are introduced and the role of [high-dose chemotherapy plus] ASCT is questioned, and may provide a basis for novel treatment strategies and improvements in supportive care and follow-up, lead study author, Sara Ekberg, of the Uppsala University and Uppsala Akademiska Hospital, and colleagues, wrote.

The current standard of care for younger patients with MCL is rituximab (Rituxan) with dose-intensified cyclophosphamide, vincristine, doxorubicin, and prednisone (R-CHOP) and high-dose cytarabine, followed by high-dose chemotherapy and ASCT, also known as the Nordic MCL2 protocol. However, the benefit of chemoimmunotherapy with consolidating high-dose chemotherapy plus ASCT in this era of novel targeted agents is still to be determined.

Additionally, population-based studies that include patients treated with high-dose chemotherapy and ASCT are necessary to determine the magnitude and panorama of the late effects of MCL outside the context of clinical trials.

This population-based study aimed to describe the late effects experienced by patients with MCL treated with or without high-dose chemotherapy and ASCT.

This study cohort included all patients with MCL recorded in the Swedish Lymphoma Register between the ages of 18 and 69 years who received a diagnosis between 2000 and 2014 (n = 620). A total of 247 patients were treated with high-dose chemotherapy plus ASCT and 373 of whom were not.

Patients in the study cohort were matched 1:10 with healthy comparators (n = 6200) from the general population based on birth year, sex, and lymphoma-free status at the date of the patients MCL diagnosis. The median age was 65 years (range, 22-69) for nonHD-ASCT patients and 58 years (range, 32-69) for HD-ASCT patients. The median age of the comparators was 63 years (range, 22-70).

Patients with MCL were classified as HD-ASCT patients if they had received high-dose chemotherapy and ASCT within 12 months of diagnosis. Patients were classified as nonHD-ASCT if they had not received this therapy within 12 months of diagnosis.

Regarding comorbidity, as measured per the Charlson Comorbidity Index, in the nonHD-ASCT group, 57.1% (n = 213), 13.4% (n = 50), and 29.5% (n = 110) had a comorbidity index of 0, 1, or 2 or greater, respectively. In the HD-ASCT group, 76.9% (n = 190), 8.9% (n = 22), and 14.2% (n = 35) had a comorbidity index of 0, 1, or 2 or greater, respectively. Of the comparators, 75.3 (n = 4669), 11.5% (n = 715), and 13.2% (n = 816) had a comorbidity index of 0, 1, or 2 or greater, respectively.

In general, the HD-ASCT patients received R-maxi-CHOP alternated with rituximab plus cytarabine, as well as consolidative high-dose chemotherapy with carmustine, etoposide, cytarabine, and melphalan (BEAM) or carmustine, etoposide, cytarabine, and cyclophosphamide (BEAC) prior to transplant. The nonHD-ASCT patients mostly received R-CHOP plus cytarabine, R-CHOP, rituximab plus bendamustine, or chlorambucil alone. A total of 14 patients received rituximab maintenance.

Among the HD-ASCT patients, 47% underwent transplant within 6 months of diagnosis, and 83% underwent transplant within 12 months of diagnosis, leading to the selected cutoff date of 12 months for the classification of the HD-ASCT group.

Investigators followed patients and comparators through the Swedish Patient Register and Cause-of-Death-Register from 12 months after diagnosis or matching until death or December 31st, 2017. Patients and comparators who died before the start of follow-up were excluded from the landmark analysis.

HD-ASCT patients had a slightly higher rate of outpatient visits during the first 5 years after diagnosis compared with nonHD-ASCT patients (IRR, 1.3; 95% CI, 1.0-1.6). Additionally, HD-ASCT patients had lower rates of inpatient visits 5 to 10 years after diagnosis compared with nonHD-ASCT patients, with an IRR of 0.6 (95% CI, 0.4-0.9). The total rates of bed days were similar between the 2 groups, at 1.1 (95% CI, 0.7-1.6) and 1.0 in the HD-ASCT and nonHD-ASCT groups, respectively.

After 10 years of follow-up, the rates of outpatient visits and hospitalizations were similar between HD-ASCT and nonHD-ASCT patients. Regarding outpatient visits, the IRR were 0.7 (95% CI, 0.5-1.1) and 1.0 for the HD-ASCT and nonHD-ASCT groups, respectively.

The short-term complications, defined as those that occurred within 60 days after transplant in HD-ASCT patients, included blood and blood-forming organ diseases (27.5%), infectious diseases (26.3%), circulatory system diseases (14.2%), and digestive system diseases (9.3%). Other common complications included respiratory system diseases (6.1%), skin and subcutaneous tissue diseases (5.7%), endocrine diseases (4.9%), and genitourinary system issues (4.0%). Musculoskeletal system diseases and mental complications were rare, occurring in 2.4% and 0.8% of patients, respectively. The median duration of hospitalization after high-dose chemotherapy plus ASCT was 22 days; 2 patients (0.8%) in this group died within 60 days after transplant.

The long-term complications investigated among all patients and comparators included the first specialist outpatient visit, hospitalization, or death at least 12 months after diagnosis within any of the 15 mutually exclusive disease groups defined by the investigators. Additionally, investigators quantified all specialist outpatient visits, bed days, and hospitalizations starting from 1 year after diagnosis to illustrate the total health care burden.

When compared with the matched comparators, the patients with MCL had higher relative risks and health care burdens for blood and blood-forming organ diseases (comparators, HR, 1.00 vs nonHD-ASCT, HR, 9.84 [95% CI, 6.91-14.00]; HD-ASCT, HR, 5.80 [95% CI, 3.42-9.84]), respiratory system diseases (comparators, HR, 1.00; nonHD-ASCT, HR, 4.38 [95% CI, 3.53-5.42]; HD-ASCT, HR, 5.26 [95% CI, 4.08-6.77]), and infectious diseases (comparators, HR, 1.00; nonHD-ASCT, HR, 4.66 [95% CI, 3.62-5.99]; HD-ASCT, HR, 5.62 [95% CI, 4.20-7.52]). These rates were seen irrespective of high-dose chemotherapy and ASCT treatment status. These patterns were also observed in the sensitivity analysis at 9, 18, and 24 months after diagnosis.

The most common respiratory disorders included influenza, upper respiratory infections, and pneumonia. The most common infectious diseases were bacterial infections, although HD-ASCT patients had a higher incidence of viral infections than nonHD-ASCT patients. The most common blood and blood-forming organ diseases were anemia, immunodeficiency, idiopathic thrombocyte platelet deficiency, and other diseases.

The rates of secondary malignancies, including melanoma, neoplasms of the skin, prostate cancer, and malignant neoplasm in the urinary tract, were comparable between HD-ASCT and nonHD-ASCT patients.

Deaths from causes other than MCL occuring at least 12 months after diagnosis were rare in both MCL patient groups. The 5-year cumulative probabilities of MCL-specific death were 23% (95% CI, 18%-30%) and 32% (95% CI, 26%-38%) in HD-ASCT and nonHD-ASCT patients, respectively. A standardized analysis showed no evidence of difference in cumulative probabilities of MCL-specific death between the 2 groups when subgroup differences were eliminated.

Avoiding efficient MCL treatment because it is more demanding and possibly causes late effects may seem reasonable in the short term, but our results indicate that the vast majority of long-term healthcare needs in patients up to 70 years is related to the lymphoma. This calls for continued efforts to improve treatment efficacy in MCL, the study authors concluded.

Ekberg S, Smedby KE, Albertsson-Lindblad A, et al. Late effects in mantle cell lymphoma patients treated with or without autologous stem cell transplantation. Blood Adv. Published online August 16, 2022. doi:10.1182/bloodadvances.2022007241

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Late Effects Arise Irrespective of High-Dose Chemotherapy and ASCT Status in MCL - OncLive

Nowadays, most people face teeth-related issues, expecting to retain their natural teeth or want functional teeth replacement with modern techniques. Modern techniques for missing tooth replacement include complete dentures, cast partial dentures, Implants, and prosthetic crowns. But these are not as equivalent to functional teeth and natural teeth. Recent research is ongoing on boosting tooth regeneration by inducing positive stress.

The study published online in the Journal of Dental Research by Dr. Waruna Dissanayaka, an Assistant Professor in Oral Biosciences, has overcome adaptive mechanisms in tooth stem cells preconditioning stress that boost tooth pulp tissue generation. This positive stress can have good changes in tooth stem cells by making them more resistant to disease and injury. So, in the future, this can help to improve implant cell survival and pulp tissue regeneration.

How positive stress can boost tooth regeneration:

When the tooth is injured or decayed, the vital tissue inside the tooth is exposed to harmful bacteria, which is susceptible to infection. If the tooth pulp is infected, the recent approach is to remove it and fill it with artificial material; when the pulp-less tooth is filled with inert material, the tooth dries, which makes the tooth brittle and more prone to crack and reinfection.

The only way is to replace the tooth with a prosthesis or extraction, but stem cell therapy can help in dental pulp regeneration, as per a recent study. Stem cells of human exfoliated deciduous teeth (SHED) preconditioned to a hypoxic condition by hypoxia-inducible factor 1 (HIF-1) stabilization via knockdown of prolyl hydroxylase domain-containing protein 2 (PHD2) using lentiviral short hairpin RNA. HIF-1 was inserted in Pura Matrix hydrogel, which was injected in the root canal of a human tooth fragment and implanted in immunodeficient mice. Then within 28 days, dental pulp-like tissue formation was seen with a higher level of vascularization, which helps enlist host blood vessels.

Dr. Waruna Disasanayaka and his team focus on developing the lost tooth pulp, which revitalizes the tooth and functions like a normal tooth. The tooth root canal is surrounded by hard dental tissue with less blood supply creating a harsh environment for cells of low oxygen and nutrients. So, the research team develops a preconditioning protocol that helps cells in low oxygen conditions to activate the protein.

Dr. Yuanyuan Han, a co-investigator of the team, pointed out: As this protein was reported to activate several key adaptive mechanisms, we wondered whether this phenomenon can be applied to improve cell survival following transplantation until a sufficient blood supply is achieved.

He also explained, In our study, we found that these cells activate a metabolic mechanism to produce energy under low oxygen conditions and scavenge harmful metabolites produced in stress conditions.

Dr. Dissanayaka says, Interestingly, we also found that preconditioned cells significantly enhanced the dental hard tissue formation within the regenerated pulp tissue. Former research has revealed that our cells possess number of adaptive mechanisms for stress, which are regulated by several key genes encoded in our DNA that are normally inactive.

If we can activate these genes, downstream expression of specific proteins can prime less vulnerable to injury, Dr. Dissanyaka said. He also said, Our aim is to find ways to take advantage of this capacity and use positive stress to help regenerate the dental tissues.

He aims to find new strategies to enhance the therapeutic potential of tooth stem cells.

This stem cell therapy helps to regenerate tooth tissue pulp which can help to retain natural tooth functioning. In the future, it will help to overcome teeth-related problems by avoiding the replacement of teeth by various means.

Journal Reference

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Positive stress can boost tooth regeneration - Tech Explorist

The University of Colorado Department of Ophthalmologys ocular stem cell and regeneration research program, CellSight, was awarded two prizes in the National Eye Institutes 3D Retinal Organoid Challenge (NEI 3D ROC).

The NEI, part of the National Institutes of Health, launched the three-phase challenge in 2017 to stimulate research using retina organoids. These organoids are similar to human retinas but aregrown in a lab from stem cells, enabling researchers to study eye diseases and treatments noninvasively.

CellSightDirectorValeria Canto-Soler, PhD, Doni Solich Family Chair in Ocular Stem Cell Research, led the team that won the NEI 3D ROCs disease modeling category, earning $500,000.Natalia Vergara, PhD, director ofCellSightsOcular Development and Translational Technologies Laboratory, led the research group that won the drug-screening category, earning $250,000.

According to a University of Colorado news release, Canto-Solers research group created a three-dimensional retinal model that recreates pathological features of age-related macular degeneration, with the ultimate goal of discovering new treatments for this blinding disease.

Its a privilege that we were able to participate in this endeavorand bring it to fruition, Canto-Soler, who is also an associate professor of ophthalmology at th CU School of Medicine, said in the universiys news release. This challenge is directed to what we all are trying to accomplish: move this field forward to be able to offer patients a therapy that helps them regain vision.

Vergara and her team continued their work in the third phase of the NEIs competition with their organoid model, having won phase II of the challenge in 2021.For phase III, they expanded their work to evaluate the effects of drug toxicities on the retina and developed a first-of-its-kind organoid model of Alzheimers disease retinopathy.

We are very excited because these awards are recognition of the work weve been doing for several years to bring these organoid technologies to the next level. We knew that there were certain challenges that needed to be overcome, mainly to provide a system that was robust enough that could be used for quantitative applications, Vergara explains. I think this project was successful because we were able to capitalize on a very diverse set of expertise to make something that will be really helpful for the scientific community and that will help us bring treatments to patients sooner.

This really shows how science has changed in the past several decades and how team science is the way to go now, she continues. When we work as a team, we can accomplish so much more than what any of us could accomplish on their own.

NEI Director Michael Chiang, MD, echoed the importance of team efforts behind the research.

All three of the teams exemplified this, Chiang says. I really love the spirit of all of you. The reason that were doing this is to cure blindness, eliminate vision loss, and improve quality of life.

The awards are a recognition ofCellSights contribution to the scientific community since its creation five years ago.

I want to congratulate Dr. Canto-Soler and Dr. Vergara on their well-deserved prizes in the NEIs 3D Retinal Organoid Challenge. I would also like to recognize the philanthropic supporters of theCellSightprogram, without whom we could not have assembled these great teams and fueled this pioneering work,Naresh Mandava, MD, chair of the CU Department of Ophthalmology and Sue Anschutz-Rodgers Endowed Chair in Retinal Diseases., said in the university news release. It is a testament to their tireless dedication to developing the science needed to find solutions for blinding retinal diseases. On behalf of my colleagues at the University of Colorado, we are so proud to see what we have already known as amazing science recognized in this fashion.

Vergara and Canto-Soler describe their research in videos, titled Improved Fluorescent Reporter Quantification-Based 3D Retinal Organoid Paradigms for Drug Screening" and 3D Human Model of AMD in a Dish. The projects are a collaboration with other research teams in the Department of Ophthalmology, theUniversity of Colorado Alzheimers and Cognition Center, NanoScope Technologies, LLC, and researchers at Miami University.

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University of Colorado's ocular stem cell and regenerative research program recognized - Ophthalmology Times

Photo/Laverock Therapeutics

Laverock Therapeutics Ltd has been founded to develop a gene silencing platform for the creation of programmable, allogeneic cell therapies.

Having recently completed a seed funding round, the U.K. company has opened dedicated labs in the Stevenage Bioscience Catalyst, employing six new team members on top of its senior management team.

Laverock Therapeutics started out in February as Skylark Therapeutics Ltd.

The companys mission is to utilize gene editing induced gene silencing (GEiGS) technology, and its associated computational platform, to engineer induced pluripotent stem cell (iPSC) derived cell therapies with improved efficacy, safety, and accessibility.

Laverock Therapeutics said earlier this year, it demonstrated its technology, exclusively licensed from Tropic Biosciences, would translate from plants to humans. The company has now created GEiGS engineered iPSCs, which it said further de-risks its platform technology and lays the foundation for its approach.

Experiments are under way to demonstrate cell type and condition specific programmability, generating data to support allogeneic programs in type 1 diabetes and solid tumor directed immune therapy.

CTO Tim Allsopp said: As the promise of iPSC-derived therapies continues to grow, so does our understanding of the limitations of existing approaches. Our novel technology has the potential to transform the sector via the creation of programmable, allogeneic cell therapies.

CEO David Venables added: We are thrilled to bring together such an experienced and knowledgeable team of scientific innovators and business leaders to drive forward Laverocks development. Id like to thank all our initial investors and supporters who have helped us reach this stage and look forward to bringing you news of further exciting developments as Laverock progresses.

Originally posted here:
Laverock Therapeutics created to develop programmable cell therapies - Labiotech.eu