A 'reality check' for lab-grown human embryo models or the human embryo reference

Cause for concern? This research is actually only about a new, but important benchmark!

It appears the University of Sydney did not publish any news release yet!

"... University of Sydney researchers have developed a new way to test how closely lab-grown biological models resemble real human embryos, finding that while some models perform well, none yet fully capture the complexity of early human development.

Research on embryo models derived from stem cells, known as blastoids, offers scientists a way to study the biological events that underpin fertility, pregnancy success and early human development without relying on donated human embryos. ...

Researchers at the University of Sydney have developed a computational framework that helps answer that question. Their study systematically evaluated four leading human blastoid-generation methods and found substantial differences in how faithfully they reproduce the cell types and developmental processes seen in natural human embryos. ..."

From the highlights and abstract:

"Highlights

• An integrated human embryo reference resolves lineage- and stage-specific identities

• Complementary metrics assess multiple dimensions of blastoid fidelity

• Blastoid protocols differ in cell identity, timing, and lineage structure

• Different protocols show complementary strengths in modeling human blastocysts

Summary

Recent generation of stem-cell-derived blastoids that recapitulate the architecture and cellular constitution of the human blastocyst offers an experimental model for the elucidation of the biology of early human development.

To evaluate the fidelity of the blastoids for modeling human blastocysts, we first established a reference map of cell identity and lineage differentiation of the human blastocysts through the integration and curation of single-cell transcriptome data of ex vivo blastocysts profiled at a range of developmental time points in culture.

We next used this reference map to assess the coverage and the authenticity of cell lineages and the progression of lineage differentiation of various blastoid models generated with different cellular sources and protocols.

The reference map generated from this study enables the benchmarking of blastoids that may guide the optimization of the protocol for the generation of high-fidelity blastoid models that faithfully recapitulate the natural human blastocyst."

A 'reality check' for lab-grown human embryo models

Systematic transcriptomic evaluation of blastoid models of early human development

Graphical abstract

Figure 1 Generation of the human embryo reference

RNA editing for stem cell health and longer life

Good news! Behind the secrets of aging!

"Intestinal stem cell function declines with age, and dysregulation of these cells is associated with a shortened lifespan. Zhang et al. found that the RNA-editing enzyme adenosine deaminase acting on RNA (ADAR) restrained intestinal stem cell proliferation in fruit flies, and its abundance decreased with aging and after gut injury.

Loss of ADAR in these cells in young flies caused intestinal hyperproliferation and reduced lifespan, whereas ADAR overexpression in aged flies improved gut function and increased lifespan.

Reductions in colonic ADAR2 were associated with aging in humans and with intestinal regeneration in mice, suggesting that ADAR mediated regulation of intestinal stem cells may be conserved."

From the editor's summary and abstract (a very technical abstract):

"Editor’s summary

Intestinal stem cell (ISC) function declines with age, and ISC dysregulation is associated with shortened life span. 

Zhang et al. found that the RNA editing enzyme ADAR restrained ISC proliferation in fruit flies, and its abundance and activity decreased with aging and after gut injury.

ISC-specific loss of ADAR in young flies caused intestinal hyperproliferation and reduced life span, whereas ADAR overexpression in aged flies improved gut function and increased life span. 

ADAR inhibited proliferative MAPK signaling in ISCs because its RNA editing activity generated a translational repressor of MAPK pathway components. Reductions in colonic ADAR2 and a protein that stabilizes it were associated with aging in humans and with intestinal regeneration in mice, suggesting that ADAR-mediated regulation of ISCs may be conserved. ...

Abstract

Aging impairs intestinal stem cell (ISC) function, disrupting epithelial homeostasis and regenerative repair.

Loss of ISC quiescence promotes intestinal dysfunction and contributes to organismal aging.

Here, we report an epitranscriptomic mechanism through which a decrease in adenosine-to-inosine (A-to-I) RNA editing by the adenosine deaminase ADAR in ISCs during aging disrupts a conserved signaling axis that maintains ISC quiescence. 

In Drosophila melanogaster, ISC-specific loss of dADAR triggered hyperproliferation and tissue aging, whereas dADAR overexpression reduced age-related gut dysfunction and extended life span.

Intestinal injury induced a decrease in dADAR, which was necessary for tissue regeneration, and in the zinc finger protein dZn72D, which stabilized dADAR to support intestinal homeostasis during aging. dADAR edited transcripts encoding the RNA binding protein Pumilio (dPUM) to generate an isoform that inhibited translation of two components of the mitogen-activated protein kinase (MAPK), dEGFR and dERK, thereby maintaining ISC quiescence.

The abundance of ADAR2 and of the dZn72D ortholog ZFR decreased in human colonic crypts with aging and in mouse colon after injury, suggesting that attenuation of ADAR activity may play a conserved role in ISC aging and in facilitating colonic regeneration.

Our work identifies a conserved mechanism of epitranscriptomic regulation that safeguards tissues and the decay of ADAR-mediated RNA editing as a form of age-related epigenetic information loss that disrupts ISC homeostasis."

In Science Journals | Science

A reduction in A-to-I RNA editing by ADAR disrupts Pumilio-mediated inhibition of MAPK signaling to drive intestinal stem cell aging (open access)

Fig. 1. A-to-I RNA editing in ISCs declines during aging.

Fig. 2. dADAR inhibits ISC proliferation in a cell-autonomous manner.

Fig. 4. dADAR loss drives gut aging and reduces life span in Drosophila.

Fig. 6. dADAR maintains ISC quiescence by inhibiting the MAPK signaling pathway.

A step toward lab‑grown sperm: Scientists turn stem cells into early sperm cells in a mini‑testis

Good news!

"... In a recent study published in Cell Stem Cell, scientists presented a recipe for transforming human blood-derived cells into immature primate sperm precursor cells in a mini-testis-like environment.

The researchers started with induced pluripotent stem cells (iPSCs) from humans and rhesus macaques, which are blank-slate cells that can be programmed to become almost any cell type. By exposing them to specific chemical signals, the researchers transformed them into primordial germ cell-like cells (PGCLCs), which are lab-grown versions of the earliest embryonic cells that eventually develop into germline cells, in this case sperm cells. ..."

From the highlights and abstract:

"Highlights

• Human and macaque iPSCs generate spermatogonia after testis reconstitution

• Induced germ cells form xenogeneic reconstituted testes with mouse somatic cells

• Differentiated germ cells recapitulate in vivo phenotypes and transcriptomes

• iPSC-derived spermatogonia express prepachytene piRNAs

Summary

Failures in germline development drive male infertility, but the lack of model systems that recapitulate human spermatogenesis hampers therapeutic development.

Here, we develop a system to differentiate human-induced pluripotent stem cells (iPSCs) into primordial germ cell-like cells that self-organize with mouse fetal testicular cells into seminiferous tubule-like structures within a xenogeneic reconstituted testis (xrTestis).

Subsequent transplantation of xrTestes into immunodeficient mice results in efficient generation of male germ cells up to meiotic onset, including spermatogonia with evidence of prepachytene PIWI-interacting RNA (piRNA) biogenesis, as well as differentiating spermatogonia and rare preleptotene spermatocytes exhibiting transcriptomic and phenotypic similarities to their in vivo counterparts.

As future clinical applications will require testing in non-human primates, we apply a similar strategy to differentiate rhesus iPSCs through fetal germ cell stages into spermatogonia and differentiating spermatogonia.

Together, these platforms provide a foundation for studying primate germ cell lineages and represent a step toward in vitro gametogenesis."

A step toward lab‑grown sperm: Scientists turn stem cells into early sperm cells in a mini‑testis

Generation of spermatogonia from human and non-human primate pluripotent stem cells (open access)

Graphical abstract

Lab-grown retinal cells show promise for new eye therapies

Good news! This could be a breakthrough! Make the blind see again!

"Biomedical engineers ... have used induced pluripotent stem cells (iPSCs) to grow specialized blood vessel cells critical to retinal health for the first time. When injected into mouse models of retinal disease, these "retinal endothelial cells" integrated into the damaged tissue to regenerate blood vessels and restore retinal function. Researchers also demonstrated the cells' ability to form functional retinal vascular tissue in a lab-grown environment, providing a pathway to model and research various eye diseases. ..."

From the abstract:

"Retinal microvascular diseases involve a compromised inner blood–retina barrier (iBRB), which remains poorly understood. A renewable source of human iBRB endothelium is thus vital for advancing eye research and treatment development.

Here we differentiated human induced pluripotent stem cells into retinal endothelial cells (iRECs) via the Wnt–β-catenin pathway, namely Norrin–Frizzled4 signalling.

These iRECs show genetic, protein and functional fidelity as well as unique retinal features.

When injected into oxygen-induced retinopathy mice, iRECs integrated into the host vascular network and revascularized the ischaemic eye, rescuing the tissue.

In microphysiological models, iRECs form perfusable microvascular networks that recapitulate iBRB morphology and phenotype in both healthy and diabetic states while also physiologically organizing and interacting with induced pluripotent stem cell-derived retinal pericytes.

Our study establishes functional human iRECs and microphysiological iBRB models that facilitate mechanistic studies aimed at identifying therapeutic targets and promoting the revascularization of injured retinas, thereby supporting treatment advancement."

Lab-grown retinal cells show promise for new eye therapies

Lab-Grown Retinal Cells Show Promise for New Eye Therapies (original news release) "Critical cells that line retinal blood vessels grown from stem cells restore retinal function in mouse models and form retinal tissue in a lab for future disease studies."

Derivation of functional retinal endothelial cells from human pluripotent stem cells for therapeutics and modelling (open access)

This image depicts a mouse’s retina suffering from conditions similar to diabetic retinopathy both before (right) and after (left) being treated with human lab-grown retinal endothelial cells.

The green in the left image shows the human lab-grown retinal endothelial cells integrating into the damaged mouse retina, demonstrating their potential use to treat early stages of the disease.

Fig. 1: Derivation of retinal endothelial cells from human induced pluripotent stem cells via the Norrin–Fz4 axis.

Fig. 4: iRECs revascularize the ischaemic eye.

Unprecedented view inside live stem cells reveals aging process and loss of regenerative capacity

Amazing stuff!

"Scientists have developed a powerful new technique that allows them to observe how individual cells manufacture proteins during aging, offering an unprecedented glimpse into the hidden molecular activity of stem cells in living tissue. ...

What scientists saw was the intricate choreography within stem cells and how those molecular dance steps slow and change with age. The team of Swiss scientists has concluded that the process of aging reshapes how skin stem cells manufacture proteins. ..."

From the highlights and abstract:

"Highlights

• In vivo single-cell ribosome profiling monitors tissue-wide translational landscapes

• RNase I-generated footprints reveal robust triplet periodicity in vivo

• Tissue-wide mapping of translational efficiencies across epidermal cell types

• Aging drives selective translational induction of AP-1 subunits in stem cells

Summary

Somatic stem cells are characterized by their low overall protein-synthesis rates, a feature implicated in driving their stemness. However, how aging reshapes the translational landscape of stem cells remains poorly understood.

Here, we present an in vivo single-cell ribosome profiling strategy to monitor tissue-wide translational landscapes of the epidermis during aging.

By implementing ribosomal elongation-inhibited cell isolation and switching to RNase I, we expand the applicability of single-cell ribosome profiling to in vivo systems and facilitate the evaluation of triplet periodicity, a hallmark of high-quality data.

Leveraging this strategy, we document the in vivo translational landscapes of the major epidermal cell types, outline cell-type-specific translational efficiencies, and identify a pronounced translational reprogramming of AP-1 subunits specifically in aged epidermal stem cells. Our study illustrates the power of in vivo single-cell ribosome profiling to map cell-type-specific translational programs and offers a scalable strategy for tissue-wide interrogation of translational landscapes."

Unprecedented view inside live stem cells reveals aging process and loss of regenerative capacity

In vivo single-cell ribosome profiling reveals cell-type-specific translational programs during aging (open access)

Graphical abstract

Celebrate the twenty-year anniversary of an influential paper on induced pluripotent stem cells

Something to celebrate indeed!

"Induced pluripotent stem cells turn twenty

Nobel laureate Shinya Yamanaka has spent over twenty years researching induced pluripotent stem cells (iPSCs). In 2006, Yamanaka co-authored a paper on how to make iPSCs in a Petri dish.

This year, he is celebrating the approval of the first two iPSC-derived therapeutics in Japan."

Nature Briefing: Translational Research

How do mutations of mitochondrial DNA affect your health? A new embryonic stem (ES) cell–based platform may allow better investigations

Good news!

"Highlights

• Salk scientists have created a platform to study mitochondrial DNA mutations that lead or contribute to human disease
• They generated a library of 155 mitochondrial DNA mutant cells, nearly the human level of mitochondrial DNA mutant diversity
• The platform and library will accelerate innovation in the mitochondrial disease therapeutic space

...

“Mitochondrial DNA accumulates mutations at a high rate, and more than 260 inherited disease-causing mtDNA mutations have been identified in humans,” ..."

From the significance and abstract:

"Significance

Mitochondrial DNA (mtDNA) accumulates mutations at a high rate, and more than 260 pathogenic germline mtDNA mutations have been identified in humans, producing diverse and often tissue-specific disorders.

In addition, numerous population-specific mtDNA variants have arisen through evolution and may influence adaptation and disease susceptibility.

However, the lack of animal models representing this diversity has limited mechanistic insight and therapeutic development.

Our scalable embryonic stem (ES) cell–based platform enables efficient generation of mouse models carrying functional mtDNA mutations across a broad spectrum of physiological effects. This resource will facilitate systematic investigation of mtDNA variation in health, disease, and evolution, and accelerate efforts to develop treatments for mitochondrial disorders.

Abstract

Mitochondria are central to energy metabolism and cellular signaling, and mutations in mitochondrial DNA (mtDNA) can disrupt these processes and contribute to human disease.

However, progress in defining how mtDNA variation influences adaptation, pathophysiology, and disease susceptibility has been limited by the lack of suitable animal models. Although recent base-editing approaches enable direct mtDNA modification, their low efficiency restricts the generation of diverse models reflecting human mtDNA variation.

Here, we develop a scalable embryonic stem (ES) cell–based platform for efficient production of mtDNA mutant mice. Random mutagenesis using an error-prone mtDNA polymerase generates a broad spectrum of mtDNA mutations, which are transferred into ES cells via a multiplexed cybrid fusion strategy coupled with sensitive mutation detection.

Optimized ES cell–embryo aggregation enables robust contribution of mtDNA mutant ES cells to host embryos, producing chimeric mice with germline transmission.

Using this platform, we generate a library of 155 donor fibroblast lines carrying distinct homoplasmic single-nucleotide mtDNA mutations that produce diverse mitochondrial phenotypes, including impaired oxidative phosphorylation, increased reactive oxygen species, and altered mitochondrial membrane potential. We further generate 34 female C57BL/6 ES cell lines harboring 18 mtDNA mutations across a range of heteroplasmy levels, yielding multiple chimeric mice and achieving germline transmission for one mutation.

These data reveal a strong correlation between mitochondrial function and early embryonic development, suggesting a minimal energetic threshold required for normal development. This scalable resource enables systematic investigation of mtDNA variation in physiology, adaptation, disease mechanisms, and therapeutic development."

How does mitochondrial DNA affect your health? - Salk Institute for Biological Studies "Salk Institute researchers establish new platform for studying mitochondrial DNA in human physiology, adaptation, disease mechanisms, and therapeutic development"

A scalable embryonic stem cell–based platform for efficient generation of mitochondrial DNA mutant mice (no public access)

Can This 3d printed, personalized “Living Knee” Revolutionize Joint Replacement due to osteoarhthrits?

Good news! This seems to be a promising approach! A company was already formed to commercialize this new orthopedic joint. It uses patient stem cells to build new cartilage.

"... to create a new biological knee joint that can last a lifetime, expand joint surgery to younger patients, and provide a better joint for all patients.

Two years into the project, ARPA-H has now given the team the green light to move into the second phase of development and begin preclinical testing of their “living knee” implant, called NOVAKnee. ...

“Our decades of research studying cartilage have shown that no other material has the same joint lubrication or load-bearing properties of articular cartilage. Based on this, we decided that we needed a strategy to regenerate a living knee, rather than simply replacing it,” ...

The Columbia design for this new joint looks like current metal and plastic replacement joints and will be surgically implanted with the same procedures. But NOVAKnee is a living, 3D-printed human organ, created with a biodegradable scaffolding material infused with stem cells. After implantation, the cells will regenerate the joint’s natural cartilage and bone tissues as the scaffold disappears. 

The team identified new biomaterials and used them to design an implant that can sustain the loading of the human knee. The implant contains combinations of biomaterials to make femoral- and tibial-shaped implants, sized to the patient’s knee. Then it gets seeded with cartilage and bone cells, derived from stem cells either from the patient’s own body (lipoaspirate from the abdomen) or from adult inducible pluripotent stem cells. ...

To accelerate this breakthrough technology's path to patients, NOVAJoint Orthopedics ... has been established as an independent company committed to commercializing the NOVAKnee implant and extending the technology across orthopedic applications. ..."

Can This “Living Knee” Revolutionize Joint Replacement? | Columbia University Irving Medical Center

NOVAJoint Orthopedics

Japan set to OK iPS treatments for heart, Parkinson's patients

Good news! Recommendable!

(151) Japan set to OK iPS treatments for heart, Parkinson's patientsーNHK WORLD-JAPAN NEWS - YouTube

Researchers have created a human iPS-cell-derived 3D model of the blood-brain barrier

 Good news!

"Researchers have created a 3D model of the blood-brain barrier — a membrane that protects the brain from pathogens — entirely from human induced pluripotent stem cells. The model provides an alternative to rodent and in vitro models which fall short on translatability and hinder drug discovery. Stem cells are induced to become endothelial cells, astrocytes and pericytes or smooth muscle cells, which then develop into vessel-like tubes (pictured) mimicking the blood-brain barrier. Malfunctions of the barrier can cause neurodegenerative disorders and other health problems."

From the abstract:
"Blood–brain barrier (BBB) integrity is critical for brain homeostasis, with malfunctions contributing to neurovascular and neurodegenerative disorders. Mechanistic studies on BBB function have been mostly conducted in rodent and in vitro models, which recapitulate some disease features, but have limited translatability to humans and pose challenges for drug discovery.
Here we report on a fully human induced pluripotent stem (iPS)-cell-derived, microfluidic three-dimensional (3D) BBB model consisting of endothelial cells (ECs), mural cells and astrocytes. Our model expresses typical fate markers, forms a barrier in vessel-like tubes and enables perfusion, including with human blood. Deletion of FOXF2 in ECs, a major risk gene for cerebral small vessel disease, induced key features of BBB dysfunction, including compromised cell junction integrity and enhanced caveolae formation.
Proteomic analysis revealed dysregulated endocytosis and cell junction pathways. Disease features phenocopied those seen in mice with EC-specific Foxf2 deficiency. Moreover, lipid-nanoparticle-based treatment with Foxf2 mRNA rescued BBB deficits, demonstrating the potential for drug development."

Nature Briefing: Translational Research

A fully iPS-cell-derived 3D model of the human blood–brain barrier for exploring neurovascular disease mechanisms and therapeutic interventions (open access)

Fig. 2: Generation and characterization of a fully iPS-cell-derived human 3D BBB model to investigate neurovascular disorders. [what a busy figure]

First breathing lung-on-chip developed using genetically identical cells

Amazing stuff!

"Researchers at the Francis Crick Institute and AlveoliX have developed the first human lung-on-chip model using stem cells taken from only one person. These chips simulate breathing motions and lung disease in an individual, holding promise for testing treatments for infections like tuberculosis (TB) and delivering personalized medicine. ...

Until now, these lung-on-chip devices have been made of a mixture of patient-derived and commercially available cells, meaning they can't fully replicate the lung function or disease progression of a single individual.

In the study, the team ... developed a new lung-on-chip model that contains only genetically identical cells derived from stem cells from a single donor. ...

To further simulate the human lung, AlveoliX has designed specialized machines to impose rhythmic three-dimensional stretching forces on the recreated air sac barrier, mimicking the motion of breathing. This stimulates the formation of microvilli, a key feature of alveolar epithelial cells, to increase surface area for lung functions ..."

"... Tuberculosis (TB) is a very slow-progressing disease in humans, taking months for a person to develop symptoms after being infected with the bacteria Mycobacterium tuberculosis. ... this highlights an increasing need to understand what’s happening in the early stages, when TB bacteria first encounter the body’s defences in the air sacs in the lungs. ..."

From the abstract (emphasis added):

"Immunocompetent and experimentally accessible alveolar systems to study human respiratory diseases are lacking.

Here, we developed a single-donor human induced pluripotent stem cell-derived lung-on-chip (iLoC) containing type II and I alveolar epithelial cells, vascular endothelial cells, and macrophages in a microfluidic device that mimic lung three-dimensional mechanical stretching and air-liquid interface.

Imaging and single-cell RNA sequencing analysis revealed that the iLoC recapitulated cellular profiles present in the human distal lung.
Infection of the iLoC with the human pathogen Mycobacterium tuberculosis (Mtb) showed that both macrophages and epithelial cells were infected but not permissive to bacterial replication. Stochastically, large macrophage clusters containing necrotic macrophages supporting Mtb replication were observed. A genetically engineered autophagy-deficient iLoC revealed that after Mtb infection, macrophage necrosis was higher upon ATG14 deficiency without bacterial replication. Together, we report an autologous, genetically tractable human alveolar model to study lung diseases and therapies."

First breathing 'lung-on-chip' developed using genetically identical cells

Built to breathe: mini ‘lungs’ recreate individual response to infection (original news release) "Lung-on-chip device exposes earliest stages of tuberculosis infection, and opens doors to investigate diversity in disease progression and personalised treatment. "

Autologous human iPSC–derived alveolus-on-chip reveals early pathological events of Mycobacterium tuberculosis infection (open access)

Image of the lung-on-chip, with cell nuclei in blue, macrophage in magenta, endothelial cells in yellow and tight junctions between epithelial and endothelial cells in white.

Image of a lung-on-chip infected by Mycobacterium tuberculosis, with cell nuclei in blue, dead macrophage in magenta, tight junctions between epithelial and endothelial cells in yellow and TB bacteria in white.

Fig. 1. iPSC-derived iAT2 and iAT1s are differentiated in a lung-on-chip microfluidic device.

Fig. 5. The iLoC mimic early stages of infection with Mtb.

Researchers build bone marrow model entirely from human cells

Good news!

"Scientists have successfully engineered the first entirely human-made bone marrow system in a lab, a key development for advanced blood research."

"... Now, researchers have succeeded for the first time in recreating this cellular complexity in the laboratory using only human cells. The novel system could reduce the need for animal experiments for many applications ...

Typically, bone marrow research relies heavily on animal models and oversimplified cell cultures in the laboratory. Now, researchers from the Department of Biomedicine at the University of Basel and University Hospital Basel have developed a realistic model of the bone marrow engineered entirely from human cells. ..."

From the highlights and abstract:

"Highlights

• eVON model recapitulates molecular and cellular features of native BM endosteal niches

• Endosteal vasculature enhances human myelopoiesis in the eVON

• eVON preserves HSPC multilineage repopulating capacity

• VEGF-A, CXCL12, and SCF signaling are active and could be perturbed in the eVON

Summary

Endosteal bone marrow (BM) niches are crucial to sustain non-steady-state hematopoiesis but are challenging to be modeled in their cellular and molecular complexity in standardized, human settings.

We report a developmentally guided approach to generate a macro-scale organotypic model of BM endosteal niches (engineered vascularized osteoblastic niche [eVON]) based on human induced pluripotent stem cells and porous hydroxyapatite scaffolds. The eVON contains long-lasting vascular networks covered by pericytes and neural fibers within an osteogenic matrix.

Key niche signals (CXCL12, KITLG, and vascular endothelial growth factor A [VEGFA]) are expressed in human-specific patterns.

The system supports hematopoiesis in vitro and preserves hematopoietic stem and progenitor cell (HSPC) multilineage repopulation capacity in vivo.

eVON perturbations at cellular (removing vasculature) and molecular (deregulating VEGF-A and CXCL12 signaling) levels enabled the investigation of the contribution of endosteal vasculature to myelopoiesis.

The eVON faithfully captures phenotypic, structural, and functional features of human endosteal BM, enabling the study of pathophysiological interactions with hematopoietic cells."

Researchers build bone marrow model entirely from human cells | University of Basel

Macro-scale, scaffold-assisted model of the human bone marrow endosteal niche using hiPSC-vascularized osteoblastic organoids (open access)

Credits: The Flyover

Graphical abstract

Scientists made human egg cells from skin cells

Amazing stuff! This could be a breakthrough since cloning of Dolly the sheep in 1996. 

When will the first human baby be born from an artificial womb outside a woman's body? I bet it could happen within the next 10-20 years.

The Oregon based researchers could not resist to mention "... this method would allow for the possibility of same-sex couples to have a child genetically related to both partners ..."

"Creating human eggs from adult cells just got one step closer to reality.

A technique used in cloning combined with fertilization and a bit of chemical coaxing caused human skin cells to produce eggs able to give rise to early human embryos ...

The effort is the latest attempt to make eggs and sperm from human cells. Researchers have already succeeded in making these important cell types from many types of animals, including pandas. But producing human eggs and sperm has proven elusive. ..."

From the abstract:

"Somatic cell nuclear transfer (SCNT) enables the direct reprogramming of somatic cells into functional oocytes, albeit with a diploid genome.

To address ploidy reduction, we investigated an experimental reductive cell division process, termed mitomeiosis, wherein non-replicated (2n2c) somatic genomes are prematurely forced to divide following transplantation into the metaphase cytoplasm of enucleated human oocytes.

However, despite fertilization with sperm, SCNT oocytes remained arrested at the metaphase stage, indicating activation failure.

Artificial activation using a selective cyclin-dependent kinase inhibitor successfully bypassed this arrest, inducing the segregation of somatic chromosomes into a zygotic pronucleus and a polar body.

Comprehensive chromosome tracing via sequencing revealed that homologous chromosome segregation occurred randomly and without crossover recombination. Nonetheless, an average of 23 somatic chromosomes were retained within the zygote, demonstrating the feasibility of experimentally halving the diploid chromosome set.

Fertilized human SCNT oocytes progressed through normal embryonic cell divisions, ultimately developing into embryos with integrated somatic and sperm-derived chromosomes. While our study demonstrates the potential of mitomeiosis for in vitro gametogenesis, at this stage it remains just a proof of concept and further research is required to ensure efficacy and safety before future clinical applications."

Scientists made human egg cells from skin cells

OHSU researchers develop functional eggs from human skin cells (original news release)

Induction of experimental cell division to generate cells with reduced chromosome ploidy (open access)

Fig. 1: Ploidy reduction by mitomeiosis.

Researchers find how epilepsy genes disrupt different brain regions using stem cell models

Good news!

"Key takeaways

• ... researchers used patient-derived stem cells to model how gene variants that cause developmental and epileptic encephalopathy type 13, a rare genetic childhood epilepsy, affect different regions of the brain.
• ​​​​​​The team discovered that the same variants drive seizure-like hyperactivity in the cortex but disrupt memory-related neural rhythms in the hippocampus by depleting inhibitory neurons — offering insight into why seizure medications alone may not address the full scope of symptoms.
• By reproducing abnormal brain activity observed in patients, the study establishes the first hippocampal assembloid model, creating a new platform for studying epilepsy, autism, Alzheimer’s disease and other brain disorders.

...

Using patient-derived induced pluripotent stem cells, the researchers generated advanced models known as 3D assembloids of two key brain areas:

the cortex, which is essential for movement and higher-order thinking, and

the hippocampus, which supports learning and memory. The results revealed strikingly different effects depending on the brain region.

In cortical models, the SCN8A variants made neurons hyperactive, mimicking seizure activity.

In hippocampal models, however, the variants disrupted the brain rhythms associated with learning and memory. This disruption stemmed from a selective loss of specific hippocampal inhibitory neurons — the brain’s traffic cops that regulate neural activity. 

These findings may help explain why patients with epilepsy often struggle with symptoms beyond seizures. ..."

From the highlights and abstract:

"Highlights

• Cortical assembloids with SCN8A mutations exhibit marked network hyperexcitability

• Hippocampal assembloids show theta-gamma coupling deficits, mirroring patient recordings

• Computational modeling predicts selective O-LM interneuron loss in the hippocampus

• scRNAseq and IHC reveal region-specific neuronal identity changes in DEE-13 assembloids

Summary

Neurodevelopmental disorders often impair multiple cognitive domains. For instance, a genetic epilepsy syndrome might cause seizures due to cortical hyperexcitability and present with memory impairments arising from hippocampal dysfunction.

This study examines how a single disorder differentially affects distinct brain regions using induced pluripotent stem cell (iPSC)-derived cortical- and hippocampal-ganglionic eminence assembloids to model developmental and epileptic encephalopathy 13, a condition arising from gain-of-function mutations in the SCN8A gene encoding the sodium channel Nav1.6.

While cortical assembloids showed network hyperexcitability akin to epileptogenic tissue, 

hippocampal assembloids did not, and instead displayed network dysregulation patterns similar to in vivo hippocampal recordings from epilepsy patients. Predictive computational modeling, immunohistochemistry, and single-nucleus RNA sequencing revealed changes in excitatory and inhibitory neuron organization that were specific to hippocampal assembloids.

These findings highlight the unique impacts of a single pathogenic variant across brain regions and establish hippocampal assembloids as a platform for studying neurodevelopmental disorders."

UCLA researchers find how epilepsy genes disrupt different brain regions using stem cell models | UCLA

Cortical versus hippocampal network dysfunction in a human brain assembloid model of epilepsy and intellectual disability (open access)

Graphical abstract

Recapitulating egg and sperm development in the dish for the first time

Amazing stuff!

"... For the first time, they were able to get these cells to start the complex process of meiosis – which is key to creating eggs and sperm – outside the human body.

This breakthrough, published in Science Advances, could one day lead to treatments to fight infertility. ...

However, replicating meiosis outside the human body, which could eventually allow fertility specialists to create healthy gametes for disadvantaged parents, has been extremely challenging.

Now, researchers ... have developed an in vitro method that enables the differentiation of induced pluripotent stem cells (iPSCs) along the path of meiosis. By introducing a cocktail of genes into iPSCs that turn on meiosis-specific gene expression programs, as well as drugs that alter the processing of signals in cells, the team is the first to observe live human cells initiating meiosis outside of the body. ..."

From the abstract:

"Meiotic failure is a major cause of infertility, but the lack of an in vitro model of human meiosis is a barrier to understanding its mechanism.

Here, we establish a method to initiate meiosis directly from male or female human-induced pluripotent stem cells (iPSCs).

DNMT1 inhibition, retinoid signaling activation, and overexpression of regulatory factors (antiapoptotic BCL2 and promeiotic HOXB5, BOLL, or MEIOC) rapidly activates meiosis over a 15-day protocol.

Our protocol bypasses the primordial germ cell stage and directly generates cells expressing genes similar to meiotic oogonia, including oogonia markers, all synaptonemal complex components, and meiotic recombination machinery. DNMT1 inhibition rapidly erases DNA methylation, including at imprinting control regions and promoters of meiotic genes.

Microscopy shows key aspects of meiosis, including chromosome axis formation and synapsis in live human cells. Our model of human meiosis provides opportunities for studying this critical reproductive process under chemically defined conditions in vitro."

Recapitulating egg and sperm development in the dish "New stem cell differentiation method is first to induce meiosis, a critical step in egg and sperm cell development, with potential for drug development and future fertility treatments"

Initiation of meiosis from human iPSCs under defined conditions through identification of regulatory factors (open access)

Fig. 4. Time course scRNA-seq analysis of meiosis induction.

Natural killer cells could reset immune system to fight autoimmune diseases

Good news!

"Immune cells called ‘natural killer’ (NK) cells could be supercharged to attack cells that fuel autoimmune diseases such as lupus and systemic sclerosis. Two small clinical trials suggest that researchers can genetically engineer NK cells to assassinate the renegade cells that produce antibodies against the body’s own tissues. NK cells can be taken from donor blood, making the treatment potentially much cheaper than another, similar approach called CAR-T-cell therapy, which must be manufactured from a person’s own T cells."

From the highlights and abstract:

"Highlights

• QN-139b is an iPSC-derived CD19/BCMA dual-targeting CAR-NK product

• QN-139b showed minimal toxicity in a patient with severe refractory systemic sclerosis

• QN-139b reversed fibrosis and restored skin and vascular structure in the patient

• QN-139b reduced autoantibodies, depleted pathogenic B cells, and induced immune rest

Summary

This study reports the first-in-human application of iPSC-derived CD19/BCMA dual-targeting chimeric antigen receptor-natural killer (CAR-NK) cells (QN-139b) in a patient with severe, diffuse cutaneous systemic sclerosis. The allogeneic product was genetically edited for reduced alloreactivity and improved in vivo performance, with no structural chromosomal abnormalities detected. The treatment led to significant B cell depletion with minimal toxicity, similar to CAR T cell therapy.

The patient showed marked clinical improvements during the 6-month follow-up, including reduced autoantibodies and reversed fibrosis, which are resistant to conventional treatments.

Single-cell analysis of peripheral blood revealed that the treatment shifted B cells toward more naive phenotypes and eliminated pathogenic B cells.

Proteomic studies demonstrated suppression of inflammation and fibrosis, enhanced tissue regeneration, and improved angiogenesis.

Pathological evaluation confirmed the elimination of infiltrated lymphocytes from affected skin along with restored skin and microvascular structure.

These findings suggest QN-139b is a promising immune-modulatory treatment for severe autoimmune diseases."

Nature Briefing: Translational Research

Turbocharged ‘killer’ cells show promise for autoimmune disease "Experimental treatment could offer a safer, cheaper alternative to CAR-T-cell therapies for disorders such as lupus."

An iPSC-derived CD19/BCMA CAR-NK therapy in a patient with systemic sclerosis

Graphical abstract

10 patients With Severe Diabetes Are Cured in Small clinical Trial of a New Drug

Good news! This could be a breakthrough!

Two deaths occurred among the 14 selected patients, but these death were apparently unrelated to the treatment.

"A single infusion of a stem cell-based treatment may have cured 10 out of 12 people with the most severe form of type 1 diabetes. One year later, these 10 patients no longer need insulin. The other two patients need much lower doses.

The experimental treatment, called zimislecel and made by Vertex Pharmaceuticals of Boston, involves stem cells that scientists prodded to turn into pancreatic islet cells, which regulate blood glucose levels. The new islet cells were infused and reached the liver, where they took up residence. ..."

"... – All 12 patients with at least one year of follow-up who received a full dose of zimislecel as a single infusion achieved ADA-recommended target HbA1c levels <7% and >70% time-in-range (70-180 mg/dL), and 10/12 patients were insulin free – ..."

From the abstract:

"Background

Zimislecel is an allogeneic stem cell–derived islet-cell therapy. Data on the safety and efficacy of zimislecel in persons with type 1 diabetes are needed.

Methods

We conducted a phase 1–2 study of zimislecel in persons with type 1 diabetes.

In part A, participants received a half dose of zimislecel (0.4×109 cells) as a single infusion into the portal vein, with an option for a second half dose within 2 years. In parts B and C, participants received a full dose of zimislecel (0.8×109 cells) as a single infusion.

All the participants also received glucocorticoid-free immunosuppressive therapy.

The primary end point in part A was safety. The primary end point in part C was freedom from severe hypoglycemic events during days 90 through 365, with a glycated hemoglobin level of less than 7% or a decrease of at least 1 percentage point from baseline in the glycated hemoglobin level at one or more time points between days 180 and 365.

Secondary end points in part C included safety and insulin independence between days 180 and 365.

Assessment of the primary and secondary end points in part C involved the participants who received the full dose of zimislecel as a single infusion in part B or C. 

Detection of serum C-peptide during a 4-hour mixed-meal tolerance test was used to assess engraftment and islet function. All the analyses were interim and not prespecified.

Results

A total of 14 participants (2 in part A and 12 in parts B and C) completed at least 12 months of follow-up and were included in the analyses.

C-peptide was undetectable at baseline in all 14 participants.

After zimislecel infusion, all the participants had engraftment and islet function, as evidenced by the detection of C-peptide.

Neutropenia was the most common serious adverse event, occurring in 3 participants.

Two deaths occurred — one caused by cryptococcal meningitis and one by severe dementia with agitation owing to the progression of preexisting neurocognitive impairment.

All 12 participants in parts B and C were free of severe hypoglycemic events and had a glycated hemoglobin level of less than 7%; these participants spent more than 70% of the time in the target glucose range (70 to 180 mg per deciliter).

Ten of the 12 participants (83%) had insulin independence and were not using exogenous insulin at day 365.

Conclusions

The results of this small, short-term study involving persons with type 1 diabetes support the hypothesis that zimislecel can restore physiologic islet function, warranting further clinical investigation. ..."

People With Severe Diabetes Are Cured in Small Trial of New Drug - The New York Times

Vertex Presents Positive Data for Zimislecel in Type 1 Diabetes at the American Diabetes Association 85th Scientific Sessions (original news release)

Stem Cell–Derived, Fully Differentiated Islets for Type 1 Diabetes (no public access)

Regenerative stem cell therapy trial offers hope for spinal cord injuries

Good news! Approved for trial simultaneously by the US and China!

"... A paradigm shift in the way we treat spinal injuries is now in sight, with the world's first regenerative cell therapy being granted approval for a registrational Phase I clinical trial. ...

This week, the US Food and Drug Administration (FDA) and China’s National Medical Products Administration (NMPA) approved the global clinical trial to treat spinal cord injury (SCI), which is estimated to affect more than 15 million people worldwide. ...

Now, Chinese biotechnology company XellSmart has the potential to change this forever, as its allogeneic induced pluripotent stem cells (iPSC) regenerative therapy has been given the green light by both US and Chinese health administrations to enter a clinical trial. ... The treatment aims to not just repair the injury but provide the foundation to regrow all the cells needed to return function to the damaged region. ...

The SCI trial is being conducted in partnership with Sun Yat-sen University's Third Affiliated Hospital in China, a specialist in treating and researching these complex spinal injuries. ..."

Apparently, China has a several years long history of approving such or similar therapies, possibly well ahead of Western countries:

"... In 2023, China's first iPSC-derived cell therapy (XS228 injection), developed by XellSmart, received FDA approval and was granted global orphan drug designation (ODD).

In 2024, China's first national-level registered clinical study of iPSC-derived cell therapy for neurological diseases was approved to treat Parkinson's disease patients—including China's first case. More than 12 months of follow-up demonstrated good safety and significant improvements in "off" time, MDS-UPDRS scores, and multiple non-motor symptoms.

In 2024, the world's first national-level registered clinical study of iPSC-derived cells (XS228 injection) for amyotrophic lateral sclerosis (ALS) was approved. Multiple ALS patients including the world's first case were treated safely, with preliminary data showing effective slowing of disease progression.

In 2025, China's first allogeneic off-the-shelf iPSC-derived dopaminergic neural progenitor cell (XS411 injection) registrational Phase I clinical trial was launched, led by the National Neurological Disease Medical Center at Beijing Tiantan Hospital, targeting Parkinson's disease — the world's second most common neurodegenerative disorder.

In 2025, China's first randomized, double-blind controlled registrational Phase I/II clinical trial was launched, led by Huashan Hospital affiliated with Fudan University (also a National Neurological Disease Medical Center), targeting early-onset Parkinson's disease (EOPD).

In 2025, the world's first registrational Phase I/II clinical trial of an allogeneic off-the-shelf iPSC-derived subtype-specific neural progenitor cell therapy (XS228 injection) was launched by Peking University Third Hospital, targeting amyotrophic lateral sclerosis (ALS), one of the world's four major incurable diseases. ..."

Regenerative cell therapy trial offers hope for spinal cord injuries

World’s First -- XellSmart’s Allogeneic iPSC-derived Regenerative Cell Therapy for Spinal Cord Injury Officially Approved by the U.S. FDA for a Registrational Phase I Clinical Trial

Invisibility cloak helps transplanted brain cells evade immune system and reverse Parkinson's disease symptoms

Good news!

"Researchers have successfully developed nerve grafts, currently being trialed as a treatment for Parkinson’s disease, that are invisible to the body’s immune system, according to a new study. It could mean risky post-transplant anti-rejection drugs are soon a thing of the past. ...

In stem-cell-derived neural grafting, human pluripotent stem cells (hPSCs), adult cells such as skin cells reprogrammed to act like stem cells again, are guided to develop into dopamine-producing (dopaminergic) neurons. These are the kinds of neurons that are destroyed in Parkinson’s disease. The dopaminergic neurons are grown in a lab and then transplanted into the brain. ...

For the present study, the researchers engineered hPSCs to “overexpress 8 immunomodulatory transgenes.” ... Overexpression just means making lots of something. "Immunomodulatory' is something that calms or adjusts the immune system. And transgenes are genes scientists have inserted into a cell that weren’t there originally. ...

This is the next generation of neurological treatment, and it could be used as a safe, off-the-shelf product suitable for treating diseases for which cell-based therapies are a viable option, such as stroke, Huntington’s disease, heart disease and diabetes.” ..."

"... Neural grafts are a realistic future treatment for many neurological disorders and for Parkinson’s disease patients this is coming close to reality, with at least 3 major clinical trials in progress. ...

said the neurons also had an ‘off’ switch [suicide gene?] so that they can be activated if desired, to eliminate the risk of tumours developing from grafts. ..."

From the highlights and abstract:

"Highlights

• Cloaked human neural grafts evade immune detection in humanized mouse model

• Cloaked human neural grafts reverse motor symptoms in Parkinsonian rats

• Suicide gene incorporation into cloaked donor stem cells ensures safety

Summary

Human pluripotent stem cell (hPSC)-derived therapies are a realistic possibility for numerous disorders, including Parkinson’s disease.

While generating replacement neurons is achievable, immunosuppressive drug challenges, to prevent rejection, remain.

Here we adopted a hPSC line (termed H1-FS-8IM), engineered to overexpress 8 immunomodulatory transgenes, to enable transplant immune evasion.

In co-cultures, H1-FS-8IM PSC-derived midbrain neurons evaded rejection by T lymphocytes, natural killer cells, macrophages, and dendritic cells.

In humanized mice, allogeneic H1-FS-8IM neural grafts evaded rejection, while control hPSC-derived neural grafts evoked activation of human immune cells, elevated inflammatory cytokines in blood and cerebrospinal fluid, and caused spleen and lymph node enlargement.

H1-FS-8IM neural grafts retained functionality, reversing motor deficits in Parkinsonian rats. 

Additional incorporation of a suicide gene into the H1-FS-8IM hPSC line enabled proliferative cell elimination within grafts. Findings demonstrate feasibility of generating a population-wide applicable, safe, off-the-shelf cell product, suitable for treating diseases for which cell-based therapies are a viable option."

Invisibility cloak helps transplanted brain cells evade immune system

Parkinson’s disease researchers develop cellular ‘invisibility cloak’ to protect neural grafts (original news release)

A cloaked human stem-cell-derived neural graft capable of functional integration and immune evasion in rodent models

Graphical abstract

Neural stem cells outside the brain: Discovery opens new paths for regenerative medicine

Amazing stuff!

"For decades, scientists assumed that neural stem cells (NSCs) only occur in the brain and spinal cord. A new international study ... has now refuted this assumption and discovered a new type of neural stem cell outside the central nervous system (CNS) that opens up enormous possibilities for the development of therapies for neurological diseases. ...

However, to the surprise ... they were able to use the STAP method to obtain a rare cell population from the periphery of the central nervous system that exhibits the properties of neural stem cells (NSCs). These NSCs, called peripheral neural stem cells (pNSCs), were found in several tissues of the mouse, including the lung and tail. Once the NSC population had been identified, it became clear that treatment with low pH was not necessary to cultivate them.

A team of researchers from more than ten laboratories in Europe, Asia and North America then examined these newly identified pNSCs in great detail: pNSCs share important molecular and functional characteristics with NSCs of the brain. pNSCs have the same cell morphology, self-renewal and differentiation capacity as NSCs of the brain.

They express several NSC-specific markers and have genome-wide transcriptional and epigenetic profiles that are consistent with those of NSCs in the brain. Furthermore, many pNSCs that migrate out of the neural tube can differentiate into mature neurons and, to a limited extent, glial cells during embryonic and postnatal development. ..."

From the abstract:

"Conventional understanding dictates that mammalian neural stem cells (NSCs) exist only in the central nervous system.

Here, we report that peripheral NSCs (pNSCs) exist outside the central nervous system and can be isolated from mouse embryonic limb, postnatal lung, tail, dorsal root ganglia and adult lung tissues.

Derived pNSCs are distinct from neural crest stem cells, express multiple NSC-specific markers and exhibit cell morphology, self-renewing and differentiation capacity, genome-wide transcriptional profile and epigenetic features similar to control brain NSCs.

pNSCs are composed of Sox1+ cells originating from neuroepithelial cells. pNSCs in situ have similar molecular features to NSCs in the brain.

Furthermore, many pNSCs that migrate out of the neural tube can differentiate into mature neurons and limited glial cells during embryonic and postnatal development.

Our discovery of pNSCs provides previously unidentified insight into the mammalian nervous system development and presents an alternative potential strategy for neural regenerative therapy."

Neural stem cells outside the brain: Discovery opens new paths for regenerative medicine

Detection of neural stem cells outside the brain (original news release) "A breakthrough for regenerative medicine"

Multipotent neural stem cells originating from neuroepithelium exist outside the mouse central nervous system (open access)

Identification of peripheral neural stem cells (pNSCs) in the mouse lung. 

Fig. 3: Derivation of pNSCs without low-pH treatment.