Study suggests healing skin without scarring may be possible

Good news!

"... The new study published March 20 in Cell reveals a way to fully regenerate skin by unblocking an embryonic healing mechanism that shuts off after birth. Demonstrated on mice, the strategy may help guide the development of similar therapies for human patients. ...

In mice wounded three days before birth, the skin regenerated diverse cell types and closely resembled unwounded skin.

But when wounded at five days after birth, the site was covered by epithelial cells and became packed with collagen scar tissue and abnormally dense nerve fibers and immune cells. Many other skin cell types failed to regrow. ...

They found that postnatal wound sites became densely packed with nerves. This “hyperinnervation” occurs because fibroblasts in postnatal wounds upregulate the gene Cxcl12, which recruits excessive nerves to the area and impairs the regrowth of other skin-cell types.

When researchers depleted Cxcl12 in wounds in postnatal mice, “hyperinnervation” was curtailed, and the skin regrew diverse cell types. Blocking local nerve signaling with botulinum toxin A (Botox) produced similar effects. ..."

From the highlights and abstract:

"Highlights

• Embryonic skin regenerates diverse cell types after injury, whereas postnatal skin does not

• Postnatal wounds have wound-specific fibroblasts that drive hyperinnervation via CXCL12

• Excessive innervation at the wound site blocks multilineage regeneration

• Reducing hyperinnervation restores multilineage regeneration after postnatal injury

Summary

Some mammalian tissues can replace lost cells within one lineage, but organ-level regeneration—restoring diverse cell types across lineages—remains rare. Here, we show that late embryonic full-thickness skin injuries heal by regenerating epithelial, mesenchymal, neuronal, and vascular tissues with proper connectivity. However, this ability is lost soon after birth, resulting in failure to restore most cell types and hyperinnervation within the wound bed. Single-cell sequencing identified a postnatal wound-specific fibroblast (PWF) population absent after embryonic wounding. Through an in vivo screen, we discovered that three PWF-enriched genes—Timp1, Cxcl12, and Ccl7—inhibit organ-level regeneration and cause hyperinnervation when overexpressed in embryonic wounds. Reducing hyperinnervation in postnatal wounds through the depletion of Cxcl12 in fibroblasts or nerve ablation enables regeneration of diverse lineages after injury. Our study identifies mechanisms that transition an organ from regenerative to non-regenerative, discovers fibroblast-driven hyperinnervation as a key barrier, and demonstrates that removing this barrier unlocks organ-level regeneration.

"

Study suggests healing skin without scarring may be possible — Harvard Gazette "Researchers unblock embryonic regrowth mechanism that shuts down after birth in mice"

Hyperinnervation inhibits organ-level regeneration in mammalian skin (open access)

Graphical abstract

Figure 1 Multilineage regeneration differs between embryonic and postnatal wounding

Unlocking the Skin’s Natural Healing Power

Amazing stuff!

"Key points

• The skin has an amazing ability to regenerate and heal.
• Researchers have uncovered one of the earliest steps in how skin stem cells learn to repair tissue.
• The findings could inform the development of skin healing methods, including for organ repair and skin transplants.

...

discovered that, during the earliest stages of embryonic development, skin stem cells contribute to forming a protective skin layer that accelerates healing as the embryo grows.

Their findings reveal one of the earliest steps in how skin stem cells learn to repair tissue ...

The researchers examined development in zebrafish embryos, the skin organization of which is similar to human embryos. Specifically, they analyzed the thin transparent layer of cells that lines the zebrafish fin folds in the embryo, structures that transition into fins during development in a process that’s similar to limb development in mammals. ...

compared their findings in the embryonic zebrafish fin fold to a bilayer model of the human epidermis. Their modeling revealed that collagen and laminin matrices similarly influence human skin cells. Specifically, they found that laminin inhibited the proteins that drive desmosome junction formation. ..."

From the abstract:

"Epidermal stem cells interact with the extracellular matrix (ECM) to regulate their differentiation and maintain skin architecture.

Here, we demonstrate a role for basal epidermal stem cells (BECs)-ECM interaction in regulating adhesion molecules expressed by the periderm—the superficial epidermal cells (SECs) of the embryonic bilayered skin.

Using the developing zebrafish fin fold, we identify BECs form distinct regions of collagen- versus laminin- enriched basement membranes through integrin-mediated adhesions.

Mechanistically, collagen-associated BECs form desmosomes and adherens junctions (AJs) with SECs while laminin-associated BECs display reduced desmosomes but sustain AJs and actomyosin expression with SECs.

Notably, we show both in vivo and in a bilayered human keratinocyte model, that laminin, compared to collagen, is sufficient to repress desmosome formation while sustaining AJs specifically at the interlayer cell contacts.

In vivo, laminin deficiency enhances desmosome expression across layers and impairs the wound-healing capacity of SECs. This defect was partially rescued by genetic reduction of the desmosome protein Desmoplakin-1a, highlighting the role of ECM-dependent junctional specialization in mediating differences in SEC injury response.

Overall, our findings identify that stem cells, through their matrix, establish specialized junctions in the overlying stratified epithelium, which contribute to skin healing properties."

Unlocking the Skin’s Natural Healing Power < Yale School of Medicine

Epidermal stem cells control periderm injury repair via matrix-driven specialization of intercellular junctions (open access)

Fig. 1: Region-Specific Junctional and Cytoskeletal Organization of BECs in the Fin Fold.

‘Serotonin shield’: The placenta’s critical role in the health of babies

Amazing stuff!

Notice the Yale University still sprads DEI and woke ideology! What is a pregnant parent? This "parent" was almost certainly a woman! Very disturbing and disparaging of mothers!

What does the first name Pericles of the current Dean of Yale U Pericles Lewis mean if anything? Pericles, the great Greek statesman, is probably wildly spinning in his grave given this ideology and indoctrination espoused by Yale U!

"... in a new study, ... researchers ... show that the placenta doesn’t produce serotonin but instead regulates its delivery to the embryo and fetus. They found that serotonin comes from the pregnant parent [???], with the placenta acting as a “serotonin shield” that controls how much reaches the embryo and fetus. ...

how a parent’s [???] serotonin levels might affect the development of their baby’s body and brain, the researchers say. ...

Often called a “happiness hormone,” serotonin regulates mood, so it’s often associated with the brain. In reality, less than 5% of serotonin is made in the brain, with 95% of it made in the gut. But serotonin does more than just regulate mood. It’s also a growth hormone. In the gut, it gets taken up by platelets and is delivered to parts of the body that need to grow, including in wound healing. ...

During pregnancy, serotonin also helps with growth: It travels into the placenta through a special protein known as the serotonin transporter (SERT) where it plays a critical role in the development of the embryo and fetus. ...

For the new study, researchers sought to better understand these relationships by using a pure source of placenta cells, unlike in previous studies that looked at either whole animals or isolated mouse placentas. To do so, they first purified human cytotrophoblasts, which are the stem cells that make all the cells of the placenta. They then added serotonin to those cells to see where it would go and discovered it concentrated in the nucleus. Next, they used a selective serotonin reuptake inhibitor (SSRI) that blocked SERT — the antidepressant escitalopram, commonly known by the brand name Lexapro — to show that the normal growth, function, and differentiation of these cells was completely blocked. 

They also used another inhibitor called cystamine to block serotonylation, or the process by which serotonin is added to proteins like histone 3, which turns genes “on” and “off.” Again, that completely blocked the normal growth of the cells. 

Blocking either SERT or serotonylation led to significant changes in gene expression of RNAs in the cytotrophoblasts, they found.

Some genes — including ones involved in making, moving, and growing cells — became downregulated, or less active, when serotonin couldn’t enter the cell. Other genes — including ones that help cells stay alive and protect them — became upregulated, or more active. According to the researchers, these findings show that serotonin is critical for the growth of the cytotrophoblasts, the placenta, and by extension, the fetus. ...

For example, ... this explains why taking SSRIs — which decrease the levels of serotonin into the placenta — leads to smaller babies, and why, conversely, increased levels of serotonin may lead to bigger babies, with bigger brains, who may be at increased risk for developmental disabilities like autism. ..."

From the abstract *unfortunately, a very technical abstract):

"Serotonin (5-hydroxytryptamine; 5-HT) is transported into the human placenta through the serotonin transporter (SERT/SLC6A4) on the surface of the syncytiotrophoblast. During this transit, a significant amount of 5-HT becomes concentrated in the cytotrophoblast nucleus.

We used immunochemistry, inhibitors of SERT and transglutaminase 2, and RNA sequencing to elucidate the mechanism and consequences of this nuclear localization.

Exogenous 5-HT recapitulated the uptake of 5-HT into the trophoblasts and its preferential concentration in cytotrophoblast nuclei we observed in the intact placenta. Cystamine eliminated the staining of the nuclei in placental explants by exogenous 5-HT, suggesting that serotonylation mediated this phenomenon. This was confirmed by Western blots and immunoprecipitation that identified histone 3, and specifically the 5th glutamine residue in histone 3, as a site of serotonylation. Inhibiting SERT with escitalopram or transglutaminase 2 with cystamine blocked cytotrophoblast differentiation in vitro and led to marked changes in RNA expression. Of the 38 524 mRNAs identified in these trophoblasts, cystamine changed the expression of 1986 and escitalopram significantly altered 374. Both treatments altered the expression of 155 mRNAs either positively or negatively. The downregulated genes were involved with cell proliferation, morphogenesis, motility, and growth, whereas genes that were upregulated controlled cell survival and protection pathways.

These findings suggest that maternal 5-HT promotes placental, embryonic/fetal, and organismal development through histone serotonylation and consequent alterations in gene expression. They raise the possibility that alterations in 5-HT flux in the placenta affect placental and fetal growth, as well as organismal somatic, neurologic developmental, and pathological trajectories."

‘Serotonin shield’: The placenta’s critical role in the health of babies | Yale News "In a new study, Yale researchers show that the placenta regulates serotonin delivery to the fetus, contrary to past beliefs that it manufactures the hormone."

Role of Serotonin on Gene Expression and Physiology in Human Cytotrophoblasts and Placenta (open access)

A literal window into how the fallopian tube transports embryos via a leaky peristaltic pump

Amazing stuff! However, you could not repeat this with a pregnant woman!

If only the embryo knew what was going on! 😊

"... most of the oviduct’s [fallopian tube] functions haven’t been observed in their natural environment. ...

Wang and colleagues have used “optical coherence tomography” (OCT) to peer inside the abdomens of female mice.  ...

The team performed surgery on 12 female mice, implanting a small window made of glass and resin to allow them to bypass the skin and muscle and directly visualise the fallopian tubes. ...

Doing this over time allowed the researchers to capture both the oviduct dynamics and the embryo movement within the fallopian tube. ..."

From the abstract:

"The mammalian oviduct (also called the fallopian tube) is an essential organ for natural pregnancy. As one of its major functions, the oviduct transports preimplantation embryos to the uterus for implantation. This is a critical process, and abnormalities are responsible for a range of reproductive disorders, such as tubal ectopic pregnancy and infertility, whose etiologies are unclear.

For transporting embryos, the oviduct is fundamentally a tubular mechanical pump with motile cilia lining the luminal epithelium and smooth muscle surrounding the mucosa wall. Although bidirectional movement of embryos has been observed during the transport process, how the oviduct produces this type of embryo movement remains unknown.

Understanding this pumping mechanism is vital to identifying the functional causes of oviduct-related reproductive disorders, but answering this question requires dynamic imaging of the transport process in its native environment, which is difficult to achieve in mammalian models.

Here, we use optical coherence tomography and apply in vivo dynamic 3D imaging of the mouse oviduct to uncover the oviduct pumping mechanism in transporting preimplantation embryos toward pregnancy.

By inhibiting the oviduct smooth muscle contraction, we first show that the oviduct muscular activity drives the bidirectional embryo movement. We then present a quantitative assessment of the oviduct contraction wave. This analysis, together with the embryo movement information, indicates that the forward movement of embryos is produced by peristalsis, while the backward embryo movement is generated by a suction process driven by the oviduct relaxation at earlier contraction sites, showing a leaky peristaltic pump.

Finally, we reveal how the net displacement of embryos is created under this pumping mechanism, which effectively transports embryos toward the uterus.

This work elucidates, for the first time, the oviduct pumping mechanism in transporting preimplantation embryos, paving the way for understanding the biomechanics of the mammalian oviduct."

A window into how the fallopian tube transports embryos

Researchers use OCT imaging to uncover how the fallopian tube transports embryos "Mouse study lays groundwork for understanding reproductive challenges like infertility and ectopic pregnancy"

In vivo dynamic imaging reveals the oviduct as a leaky peristaltic pump in transporting a preimplantation embryo toward pregnancy (open access)

(A) In vivo imaging setup with a clamp stabilising the window implanted on the right dorsal side of the mouse.

(B) In vivo bright-field image of the oviduct as well as the ovary and a portion of the uterus through the window.

(C) In vivo 3D OCT image of the oviduct showing its 3D morphology and structure through the window. Scale bars are 500 µm.

Fig. 2. In vivo 3D OCT imaging of the preimplantation embryo movement and the oviduct contraction and relaxation. The embryo movement is bidirectional in all regions of the oviduct isthmus and coincides with the oviduct muscular activity shown as contraction and relaxation (Visualization 1). Triangles of the same color point at the same embryo at different time points. Scale bar is 300 µm.

New study reveals how cleft lip and cleft palate can arise from genetic variants

Good news! Can we finally get rid cleft in an embryo!

"In a new study, ... biologists have discovered how a genetic variant often found in people with these facial malformations leads to the development of cleft lip and cleft palate.

Their findings suggest that the variant diminishes cells’ supply of transfer RNA, a molecule that is critical for assembling proteins. When this happens, embryonic face cells are unable to fuse to form the lip and roof of the mouth. ..."

From the abstract:

"Orofacial clefts are the most common form of congenital craniofacial malformation worldwide. The etiology of these birth defects is multifactorial, involving genetic and environmental factors.

However, in most cases, the underlying causes remain unexplained, precluding a molecular understanding of disease mechanisms.

Here, we integrated genome-wide association data, targeted resequencing of case and control cohorts, tissue- and cell-type-specific epigenomic profiling, and genome architecture analyses to molecularly dissect a genomic locus associated with an increased risk of non-syndromic orofacial cleft.

We found that common and rare risk variants associated with orofacial cleft intersect with an enhancer (e2p24.2) that is active in human embryonic craniofacial tissue.

We mapped e2p24.2 long-range interactions to a topologically associated domain harboring MYCN, DDX1, and CYRIA.

We found that MYCN and DDX1, but not CYRIA, are required during craniofacial development in chicken embryos.

We investigated the role of DDX1, a key component of the tRNA splicing complex, in cranial neural crest cells (cNCCs).

The loss of DDX1 in cNCCs resulted in the accumulation of unspliced tRNA fragments, depletion of mature intron-containing tRNAs, and ribosome stalling at codons decoded by these tRNAs. This was accompanied by defects in both global protein synthesis and cNCC migration.

We further showed that the induction of tRNA fragments is sufficient to disrupt craniofacial development.

Together, these results uncovered a molecular mechanism in which impaired tRNA splicing affects cNCCs and craniofacial development and positioned MYCN, DDX1, and tRNA processing defects as risk factors in the pathogenesis of orofacial clefts."

New study reveals how cleft lip and cleft palate can arise | MIT News | Massachusetts Institute of Technology "MIT biologists have found that defects in some transfer RNA molecules can lead to the formation of these common conditions."

A non-syndromic orofacial cleft risk locus links tRNA splicing defects to neural crest cell pathologies

Graphical abstract

How the mother and embryo’s first moments of life shape longevity

Amazing stuff! Maternal obesity during pregnancy has consequences.

"... They conducted a pre-clinical trial and found that cellular processes within the egg at the time of fertilisation determine the telomere length in the offspring. ...

The team conducted the trials using mouse models and found that when mitochondrial activity is disrupted, whether by high oxygen levels, or conditions such as maternal obesity and metabolic syndrome, the embryo fails to properly “reset” its telomere length. This leads to babies being born with shorter telomeres. ..."

"... “Some babies are born with shorter telomeres than others, increasing their lifetime risk of chronic diseases associated with ageing.

“As just one example, shorter telomeres are observed in children of women with obesity or metabolic syndrome. As adults, these individuals are at increased risk of premature mortality from cardiovascular events, like a heart attack or stroke, even when they are not obese themselves. ...

“There are specific types of cellular damage during the very first days of embryo development which cause the defect in the telomeres of the embryo, which causes them to be shorter at the time of birth,”...

“The process is highly responsive to signals from the mother’s body. Our findings show maternal health and environmental conditions at the time of conception can have long-term consequences and can even influence the offspring’s susceptibility versus resilience to ageing-associated diseases in later life. ..."

From the abstract:

"The initial setting of telomere length during early life in each individual has a major influence on lifetime risk of aging-associated diseases; however there is limited knowledge of biological signals that regulate inheritance of telomere length, and whether it is modifiable is not known.

We now show that when mitochondrial activity is disrupted in mouse zygotes, via exposure to 20% O2 or rotenone, telomere elongation between the 8-cell and blastocyst stage is impaired, with shorter telomeres apparent in the pluripotent Inner Cell Mass (ICM) and persisting after organogenesis.

Identical defects of elevated mtROS in zygotes followed by impaired telomere elongation, occurred with maternal obesity or advanced age. We further demonstrate that telomere elongation during ICM formation is controlled by mitochondrial-nuclear communication at fertilization.

Using mitochondrially-targeted therapeutics (BGP-15, MitoQ, SS-31, metformin) we demonstrate that it is possible to modulate the preimplantation telomere resetting process and restore deficiencies in neonatal telomere length."

How embryo’s first moments of life shape longevity

Embryo development holds key to healthy lifestyles (original new release)

Telomere length in offspring is determined by mitochondrial-nuclear communication at fertilization (open access) "Researchers from the University of Adelaide have discovered that the earliest days of embryo development have a measurable impact on a person’s future health and ageing."

Fig. 1: Telomere elongation during pre-implantation embryogenesis is impaired by oxidative stress.

Tunneling nanotube–like structures regulate distant cellular interactions during heart formation

Amazing stuff!

From the perspective abstract:

"The heart is the first organ to become functional during embryonic development in vertebrates. The process begins with the formation of the heart tube, which consists of an inner endothelial lining (endocardium) and a layer of muscle cells (myocardium), separated by a thick extracellular matrix called the cardiac jelly. Subsequent development of the heart ventricles involves the formation of trabeculae—muscular ridges lined by the endocardium. How signals pass between the endocardium and myocardium across the cardiac jelly to ensure normal development is not fully understood. ...

report that, in mice, the myocardium and endocardium of the early heart tube communicate directly through tiny membrane-enclosed projections called tunneling nanotube–like structures (TNTLs). Loss of TNTLs disrupts trabecular formation and thus ventricular development and embryonic viability."

From the editor's summary and abstract:

"Editor’s summary

During cardiac development, heart muscle cells (the myocardium) and inner lining cells (the endocardium) are separated by a space filled with cardiac jelly. ... discovered that despite this physical separation, the two cell types communicate with each other through tiny structures called tunneling nanotube-like microstructures (TNTLs) ... TNTLs extend across the cardiac jelly, allowing direct cell-cell contact, signal transduction, and selective protein transfer. Disrupting TNTLs leads to abnormal heart wall formation, highlighting the importance of TNTLs in cardiac development. ...

Structured Abstract

INTRODUCTION

Heart development is a highly orchestrated process dependent on dynamic interactions between the myocardium and the endocardium. The two layers are separated by a noncellular matrix called cardiac jelly and communicate through signaling pathways involving membrane-bound receptors and ligands. However, the mechanisms enabling such signaling interaction over physical distances remain poorly understood.

In this work, we characterized tunneling nanotube–like structures (TNTLs), which we found physically connecting cardiomyocytes (CMs) in the myocardium to endocardial cells (ECs) in the endocardium. These structures likely help to facilitate long-distance intercellular communication essential for heart formation.

RATIONALE

Heart formation relies on precise signaling interactions between the myocardium and endocardium, particularly during trabecular development. Signaling pathways, such as Notch1, Vegf, and Nrg1, have ligands and receptors segregated across these two cardiac layers. The mechanisms enabling these long-distance interactions across the intervening cardiac jelly are unclear.

We hypothesized that TNTL structures exist between the cardiac layers and could mediate intercellular long-distance communication in the developing heart, allowing for the transport of signaling molecules and cytoplasmic proteins between them.

RESULTS

We used genetic labeling, contact-tracing techniques, and advanced imaging to demonstrate the existence of TNTLs in mouse embryonic hearts. These TNTLs extended from CMs to ECs across the cardiac jelly, establishing direct connections that enable signal transduction and cytoplasmic protein transfer.

The TNTLs were identified in the heart through the genetic labeling of cellular protrusions. During mouse development TNTLs were shown to form between CMs and ECs as early as embryonic day 8.0. The filamentous structures inside TNTL were characterized by three-dimensional imaging and the reconstruction of the electron microscopy (EM) and cryo-EM images.

The TNTLs contained actin filaments, and TNTL formation depended on actin polymerization. The presence of actin filaments in TNTLs was confirmed in a transgenic mouse line that could label actin filaments with a fluorescent marker. Inhibiting actin polymerization chemically or by ablating the small guanosine triphosphatase, Cdc42, eliminated TNTLs.

The TNTLs were involved in regulating Notch1 signaling and other signaling pathways. TNTLs were sufficient to activate Notch1 signaling in ECs, with ligands from CMs transported through these microstructures to ECs.

Loss of TNTLs resulted in reduced Notch signaling and other signaling pathways. TNTLs were able to transport signaling molecules, cytoplasmic proteins, and trafficking vesicles, underscoring their role as conduits for intercellular communication.

The TNTLs were essential in cardiac morphogenesis. Disruption of TNTLs in embryonic hearts resulted in impaired ventricular wall morphogenesis, evidenced by loss of trabeculae and defective myocardial growth.

CONCLUSION

In this work, we identified TNTLs as a critical mechanism for long-distance intercellular communication during heart development. These actin-rich structures physically bridge the myocardium and endocardium, allowing for the efficient exchange of signaling molecules necessary for trabecular formation and ventricular wall morphogenesis.

Disruption of TNTLs compromises these interactions, highlighting their essential role in heart patterning. This work provides insights into mechanisms of cellular communication and suggests that TNTL formation might help cells to regulate long-distance cell-cell communication and modulate tissue patterning in mammalian systems. ..."

Tunneling through cardiac jelly (no public access) "Membrane projections from muscle cells enable signaling in the developing mouse heart"

Tunneling nanotube–like structures regulate distant cellular interactions during heart formation | Science (no public access)

Microstructure regulates signaling interaction and cytoplasmic proteins transfer between CMs and ECs.

Ancient unicellular organism indicates embryonic development might have existed prior to animals' evolution

Amazing stuff! What was first, the egg or the chicken? Or did evolution develop the same thing twice independently?

"Chromosphaera perkinsii is a single-celled species discovered in 2017 in marine sediments around Hawaii. The first signs of its presence on Earth have been dated at over a billion years, well before the appearance of the first animals. ...

this species forms multicellular structures that bear striking similarities to animal embryos. These observations suggest that the genetic programs responsible for embryonic development were already present before the emergence of animal life, or that C. perkinsii evolved independently to develop similar processes. ...

By observing C. perkinsii, the scientists discovered that these cells, once they have reached their maximum size, divide without growing any further, forming multicellular colonies resembling the early stages of animal embryonic development. Unprecedentedly, these colonies persist for around a third of their life cycle and comprise at least two distinct cell types, a surprising phenomenon for this type of organism. ..."

From the abstract:

"All animals develop from a single-celled zygote into a complex multicellular organism through a series of precisely orchestrated processes. Despite the remarkable conservation of early embryogenesis across animals, the evolutionary origins of how and when this process first emerged remain elusive. Here, by combining time-resolved imaging and transcriptomic profiling, we show that single cells of the ichthyosporean Chromosphaera perkinsii—a close relative that diverged from animals about 1 billion years ago—undergo symmetry breaking and develop through cleavage divisions to produce a prolonged multicellular colony with distinct co-existing cell types. Our findings about the autonomous and palintomic developmental program of C. perkinsii hint that such multicellular development either is much older than previously thought or evolved convergently in ichthyosporeans."

Ancient unicellular organism indicates embryonic development might have existed prior to animals' evolution

The egg or the chicken? An ancient unicellular says egg! "A cell division resembling that of an animal embryo has been observed in a prehistoric unicellular organism, suggesting that embryonic development might have existed prior to the evolution of animals."

A multicellular developmental program in a close animal relative (no public access)

A cell of the ichthyosporean C. perkinsii showing distinct signs of polarity, with clear cortical localization of the nucleus before the first cleavage. Microtubules are shown in magenta, DNA in blue, and the nuclear envelope in yellow.

Fetal Cells Can Be Traced Back to the First Day of Embryonic Development

Amazing stuff! Wonders of life!

"... a new study ... demonstrates that when human embryos are composed of two cells, at just 1 day old, only one of these cells will create most of the fetal body cells in addition to placental cells, while the other will only create placental cells. The research changes the long-standing paradigm that the two cells at this stage both contribute equally to all parts of the developing embryo, suggesting that "specification"—the phenomenon of cells having specific individual roles—happens much earlier in development than previously believed. ..."

From the highlights and abstract:

"Highlights

• Lineage tracing of human embryos from the 2-cell to the blastocyst stage

• The majority of the epiblast is derived from only one 2-cell stage blastomere

• Early asymmetric divisions are a bottleneck controlling the embryo’s clonal composition

• First-dividing 2-cell blastomere generates more asymmetric divisions at 8-cell stage

Summary

Retrospective lineage reconstruction of humans predicts that dramatic clonal imbalances in the body can be traced to the 2-cell stage embryo. However, whether and how such clonal asymmetries arise in the embryo is unclear. Here, we performed prospective lineage tracing of human embryos using live imaging, non-invasive cell labeling, and computational predictions to determine the contribution of each 2-cell stage blastomere to the epiblast (body), hypoblast (yolk sac), and trophectoderm (placenta). We show that the majority of epiblast cells originate from only one blastomere of the 2-cell stage embryo. We observe that only one to three cells become internalized at the 8-to-16-cell stage transition. Moreover, these internalized cells are more frequently derived from the first cell to divide at the 2-cell stage. We propose that cell division dynamics and a cell internalization bottleneck in the early embryo establish asymmetry in the clonal composition of the future human body."

Fetal Cells Can Be Traced Back to the First Day of Embryonic Development - www.caltech.edu Though over 8 million babies have been born through in vitro fertilization (IVF), 70 percent of IVF implantations fail. As IVF is becoming a more common route to pregnancy in cases of infertility, there is a need for better understanding of embryonic development at this early stage.

The first two blastomeres contribute unequally to the human embryo (open access)

Graphical abstract

A human blastocyst expressing GFP in some cells (green), and stained to reveal the cell membranes (orange) and nuclei (blue). Labelling with GFP allowed the authors to reveal that only one 2-cell stage blastomere contributes most of the cells to the future body.

Alabama Top Court Rules Frozen Embryos Are "Children". Will it Affect IVF? with Palki Sharma

Lot's of hysteria and alarmism about this court ruling! To reduce this issue exclusively to IVF (In vitro fertilization) is regrettable! When does human life begin? At conception?

We've Finally Seen in Exquisite Detail How Human Fingers And Toes Grow

Amazing stuff!

""We identified 67 distinct cell clusters from 125,955 captured single cells, and spatially mapped them across four first trimester timepoints to shed new light on limb development," ..."

"Human fingers and toes do not grow outward; instead, they form from within a larger foundational bud, as intervening cells recede to reveal the digits beneath. This is among many processes captured for the first time as scientists unveil a spatial cell atlas of the entire developing human limb, resolved in space and time. ... an atlas characterising the cellular landscape of the early human limb, pinpointing the exact location of cells."

From the abstract:

"Human limbs emerge during the fourth post-conception week as mesenchymal buds, which develop into fully formed limbs over the subsequent months. This process is orchestrated by numerous temporally and spatially restricted gene expression programmes, making congenital alterations in phenotype common. Decades of work with model organisms have defined the fundamental mechanisms underlying vertebrate limb development, but an in-depth characterization of this process in humans has yet to be performed. Here we detail human embryonic limb development across space and time using single-cell and spatial transcriptomics. We demonstrate extensive diversification of cells from a few multipotent progenitors to myriad differentiated cell states, including several novel cell populations. We uncover two waves of human muscle development, each characterized by different cell states regulated by separate gene expression programmes, and identify musculin (MSC) as a key transcriptional repressor maintaining muscle stem cell identity. Through assembly of multiple anatomically continuous spatial transcriptomic samples using VisiumStitcher, we map cells across a sagittal section of a whole fetal hindlimb. We reveal a clear anatomical segregation between genes linked to brachydactyly and polysyndactyly, and uncover transcriptionally and spatially distinct populations of the mesenchyme in the autopod. Finally, we perform single-cell RNA sequencing on mouse embryonic limbs to facilitate cross-species developmental comparison, finding substantial homology between the two species."

We've Finally Seen in Exquisite Detail How Human Fingers And Toes Grow : ScienceAlert

First map of human limb development reveals unexpected growth processes and explains syndromes found at birth Scientists reveal unprecedented insights into human limb development, including the many intricate processes that govern their formation.

A human embryonic limb cell atlas resolved in space and time (open access)

Fig. 1: A single-cell temporal–spatial atlas of the human embryonic limb.

Showing gene expression patterns

IVF study sheds new light on early stages of embryo development

Amazing stuff! Looks like we still have to learn a lot more about the early stages of embryos. Still a long way to an artificial womb.

"By genetically testing nearly 1,000 embryos, scientists have provided the most-detailed analysis of embryo fate following human in vitro fertilization.

Nearly half the embryos studied underwent developmental arrest because of genetic mishaps in early development—a revealing insight that suggests more IVF babies could come to term with changes in the fertility treatment process. The unique combination of data from arrested embryos also sheds new light on the still largely mysterious earliest stages of pregnancy through natural means. ..."

From the abstract:

Background

The high incidence of aneuploidy in early human development, arising either from errors in meiosis or postzygotic mitosis, is the primary cause of pregnancy loss, miscarriage, and stillbirth following natural conception as well as in vitro fertilization (IVF). Preimplantation genetic testing for aneuploidy (PGT-A) has confirmed the prevalence of meiotic and mitotic aneuploidies among blastocyst-stage IVF embryos that are candidates for transfer. However, only about half of normally fertilized embryos develop to the blastocyst stage in vitro, while the others arrest at cleavage to late morula or early blastocyst stages.

Methods

To achieve a more complete view of the impacts of aneuploidy, we applied low-coverage sequencing-based PGT-A to a large series (n = 909) of arrested embryos and trophectoderm biopsies. We then correlated observed aneuploidies with abnormalities of the first two cleavage divisions using time-lapse imaging (n = 843).

Results

The combined incidence of meiotic and mitotic aneuploidies was strongly associated with blastocyst morphological grading, with the proportion ranging from 20 to 90% for the highest to lowest grades, respectively. In contrast, the incidence of aneuploidy among arrested embryos was exceptionally high (94%), dominated by mitotic aneuploidies affecting multiple chromosomes. In turn, these mitotic aneuploidies were strongly associated with abnormal cleavage divisions, such that 51% of abnormally dividing embryos possessed mitotic aneuploidies compared to only 23% of normally dividing embryos.

Conclusions

We conclude that the combination of meiotic and mitotic aneuploidies drives arrest of human embryos in vitro, as development increasingly relies on embryonic gene expression at the blastocyst stage.

IVF study sheds new light on early stages of embryo development | Hub

Meiotic and mitotic aneuploidies drive arrest of in vitro fertilized human preimplantation embryos (open access)

Fig. 1 Developmental outcomes of 1232 normally fertilized (2PN) embryos and their associated PGT-A results. 

Scientists grow whole model of human embryo, without sperm or egg

Amazing stuff!

Developing human embryos less than 5 days old live imaged in real time at highest-ever resolution

Amazing stuff! Seeing the wonders of life at the very beginning!

"Researchers have captured the most-detailed images yet of human embryos developing in real time, using two common laboratory tools — fluorescent dyes and laser microscopes.

The technique ... allows researchers to study crucial events in the first few days of development without genetically altering the embryos, which has previously restricted the use of some imaging techniques in human embryos, owing to ethical concerns. ...
“This is the first time we can actually image an early human embryo at the very early stages of development with cellular resolution,” says Nicolas Plachta, a cell biologist at University of Pennsylvania in Philadelphia and a co-author of the paper. “We can see single cells and how they interact with each other as they form the pre-implantation embryo.” ...
the imaging technique could lead to the development of ways to non-invasively screen embryos conceived through in vitro fertilization (IVF). ...

The researchers were also able to compare key events in human embryos and mouse ones — which are often used as models to study embryonic development. They observed some important differences. For example, a process called compaction, which involves alterations in cell shape, starts at the 12-cell stage in human embryos compared with the 8-cell stage in mice; the process is also more asynchronous in human embryos, leading to variations in inner- and outer-cell formation. ..."

From the highlights and abstract:

"Highlights

• Fluorescent dyes enable live imaging of human embryos without genetic manipulation

• Live imaging reveals differences between human and mouse embryo morphogenesis

• Blastocyst expansion causes trophectoderm cell nuclear budding and DNA shedding

• Mechanical stress from blastocyst expansion or biopsy triggers nuclear DNA loss

Summary

Proper preimplantation development is essential to assemble a blastocyst capable of implantation. Live imaging has uncovered major events driving early development in mouse embryos; yet, studies in humans have been limited by restrictions on genetic manipulation and lack of imaging approaches. We have overcome this barrier by combining fluorescent dyes with live imaging to reveal the dynamics of chromosome segregation, compaction, polarization, blastocyst formation, and hatching in the human embryo. We also show that blastocyst expansion mechanically constrains trophectoderm cells, causing nuclear budding and DNA shedding into the cytoplasm. Furthermore, cells with lower perinuclear keratin levels are more prone to undergo DNA loss. Moreover, applying trophectoderm biopsy, a mechanical procedure performed clinically for genetic testing, increases DNA shedding. Thus, our work reveals distinct processes underlying human development compared with mouse and suggests that aneuploidies in human embryos may not only originate from chromosome segregation errors during mitosis but also from nuclear DNA shedding."

Developing human embryos imaged at highest-ever resolution Non-invasive imaging approach could lead to innovations in embryo screening.

Human embryo live imaging reveals nuclear DNA shedding during blastocyst expansion and biopsy (no public access)

Graphical abstract

New Model Provides Unprecedented Window Into Human Embryonic Development

Amazing stuff!

"Two to three weeks after conception, an embryo faces a critical point in its development. In the stage known as gastrulation, the transformation of embryonic cells into specialized cells begins. ... Studying this process in the human-specific context has posed significant challenges to biologists, but new research offers an unprecedented window into this point in time in human development. ...
A groundbreaking model that includes both embryonic and extraembryonic components will allow researchers to study how these two parts interact around gastrulation stages—providing a unique look at the molecular and cellular processes that occur, and offering potential new insights into why pregnancies can fail as well as the origins of congenital disorders. ...
The ethical questions are profound, including whether these models have the potential to develop into human beings. ... the principal investigator of the study, emphasizes that they do not. ...

The majority of previous embryo models of developmental stages around gastrulation were single-tissue models that only contained the embryonic component. ...
While researchers have learned a great deal from embryos of other species such as mice, the lack of accessibility to human embryos has left significant knowledge gaps about our development. ..."

From the abstract:
"Investigating human development is a significant scientific challenge due to the technical and ethical limitations of working with embryonic samples. In the face of these difficulties, stem cells have provided an alternative to experimentally model inaccessible stages of human development in vitro. Here, we show that human pluripotent stem cells can be triggered to self-organise into three-dimensional structures that recapitulate some key spatiotemporal events of early human post-implantation embryonic development. Importantly, our system reproducibly captures spontaneous differentiation and co-development of embryonic epiblast and extra-embryonic hypoblast-like lineages, establishes key signalling hubs with secreted modulators, and can undergo symmetry breaking-like events. Single-cell transcriptomics confirms differentiation into diverse cell states of the peri-gastrulating human embryo without establishing placental cell types, including signatures of post-implantation epiblast, amniotic ectoderm, primitive streak, mesoderm, early extra-embryonic endoderm, as well as initial yolk sac induction. Collectively, our system captures key features of human embryonic development spanning from Carnegie-stage16 (CS) 4 to CS7, offering a reproducible, tractable, and scalable experimental platform to understand the basic cellular and molecular mechanisms that underlie human development, including new opportunities to dissect congenital pathologies with high throughput."

New Model Provides Unprecedented Window Into Human Embryonic Development < Yale School of Medicine

Self-patterning of human stem cells into post-implantation lineages (no public access)

Researchers create embryo-like structures from monkey embryonic stem cells

Amazing stuff! Potentially, a break through!

"The investigators started with macaque embryonic stem cells, which they exposed to a number of growth factors in cell culture. These factors induced the stem cells to form embryo-like structures for the first time using non-human primate cells.

... also called blastoids, were found to have similar morphology to natural blastocysts. As they further developed in vitro, they formed arrangements that looked like the amnion and yolk sac. The blastoids also started to form the types of cells that eventually make up the three germ layers of the body. Single-cell RNA sequencing revealed that the different types of cells found within the structures had similar gene expression patterns to cells found in natural blastocysts or post-implantation embryos.

The blastoids were then transferred into the uteruses of 8 female monkeys; in 3 of the 8, the structures implanted. This implantation resulted in the release of progesterone and chorionic gonadotropin, hormones normally associated with pregnancy. The blastoids also formed early gestation sacs, fluid-filled structures that develop early in pregnancy to enclose an embryo and amniotic fluid. However, they did not form fetuses and the structures disappeared after about a week. ..."

From the highlights and absract:

"Highlights

• Generation of cynomolgus monkey blastoids using naive ESCs [embryonic stem cells]  and optimized protocol

• Monkey blastoids showed similar morphology and lineage composition to blastocysts

• In vitro cultured monkey blastoids recapitulate gastrulation to three germ layers

• In vivo transplantation of monkey blastoids triggers pregnancy with gestation sacs

Summary

Human stem cell-derived blastoids display similar morphology and cell lineages to normal blastocysts. However, the ability to investigate their developmental potential is limited. Here, we construct cynomolgus monkey blastoids resembling blastocysts in morphology and transcriptomics using naive ESCs. These blastoids develop to embryonic disk with the structures of yolk sac, chorionic cavity, amnion cavity, primitive streak, and connecting stalk along the rostral-caudal axis through prolonged in vitro culture (IVC). Primordial germ cells, gastrulating cells, visceral endoderm/yolk sac endoderm, three germ layers, and hemato-endothelial progenitors in IVC cynomolgus monkey blastoids were observed by single-cell transcriptomics or immunostaining. Moreover, transferring cynomolgus monkey blastoids to surrogates achieves pregnancies, as indicated by progesterone levels and presence of early gestation sacs. Our results reveal the capacity of in vitro gastrulation and in vivo early pregnancy of cynomolgus monkey blastoids, providing a useful system to dissect primate embryonic development without the same ethical concerns and access challenges in human embryo study."

Researchers create embryo-like structures from monkey embryonic stem cells -- ScienceDaily

Cynomolgus monkey embryo model captures gastrulation and early pregnancy (open acces)

Graphical abstract

Pot, pregnancy, and nursing

Partially recommendable! The author presents a conservative viewpoint stressing alarmism! However, the health and mental risks for the unborn and infant exposed to the Cannabis use of their mother should not be dismissed! More public education and awareness is probably needed and recommended!

With the legalization and greater availability of Cannabis more problems arise! 

Presumably, occasional consumption in small or moderate doses is perhaps fairly harmless. But how about frequent consumption and higher doses while pregnant or nursing?

"... A survey published in 2018 found that employees at 69% of cannabis dispensaries in Colorado recommended treating morning sickness with pot. ...
The same survey reported that about 20% of pregnant women 24 years old or younger tested positive for marijuana in a drug screening. ...
While studies of maternal cannabis use have not proved direct causal relationships with negative outcomes for the child, they certainly have found an association with outcomes like low birth weight and premature birth, which can result in serious health problems for the baby. Cannabis use might also increase the chances of having a stillbirth. ...
what cannabis might do to fetal brain development. One study found that there are “significant molecular modifications,” meaning that cannabis interferes with the brain’s development, which results in “neurotypical and behavioral abnormalities.” ..."

2 ‘Ps’ That Don’t Belong in the Same Pod: Pot and Pregnancy

Artificial embryos: the hidden steps in forming a spine

Amazing stuff! Fascinating images!

World-first stem cell therapy trial treats spina bifida before birth in the womb

Good news! Amazing stuff!

"In a world-first clinical trial, three babies have been born after receiving stem cell treatment for spina bifida. The treatment involves administering a stem cell patch to the fetus’ spine while still developing in the womb, and early results are promising one year on. ...
Cellular Therapy for In Utero Repair of Myelomeningocele (CuRe) trial, conducted at UC Davis Health. ...
Patients enrolled in the trial undergo surgery midway through pregnancy, where a patch containing mesenchymal stem cells is carefully applied to the affected area of the fetus’ spine in utero. ...
So far, three babies have been born out of the eventual 35 that will be enrolled in the CuRe trial. The first received the treatment in July 2021 at 25 and a half weeks gestation ... Over a year later and things seem to still be going well, but the team remains cautious about jumping to conclusions. The scientists will monitor the babies until they’re six years old, and there’s a particular milestone at 30 months of age to check how well they’re walking and toilet training."

"... Spina bifida, also known as myelomeningocele, occurs when spinal tissue fails to fuse properly during the early stages of pregnancy. The birth defect can lead to a range of lifelong cognitive, mobility, urinary and bowel disabilities. It affects 1,500 to 2,000 children in the U.S. every year. It is often diagnosed through ultrasound. ..."

World-first stem cell therapy trial treats spina bifida before birth

Cellular Therapy for In Utero Repair of Myelomeningocele - The CuRe Trial (CuRe)

World’s first stem cell treatment for spina bifida delivered during fetal surgery Groundbreaking trial aims to reverse the paralysis and other abnormal functions of spina bifida before birth

Embryos with mitochondrial replacement therapy develop normally in first safety study

Good news!

"When the first baby to be conceived using a technique that mixes genetic material from three people was born, in 2016, scientists worried that the procedure had not been studied to show it was safe. Now, scientists in China have conducted the first comprehensive study of the technique in early-stage human embryos, and report that it does not seem to affect their development.

Techniques for using genetic material from three people to make embryos are designed to prevent mothers with defects in their mitochondria ... from passing them on to their children. Mitochondria contain their own DNA, and children inherit all of their mitochondria from their mother.

“Mitochondrial replacement therapy is a controversial field,” ...
... studied the safety of one of three main types of mitochondrial replacement therapy, called spindle transfer, which was used to make the first baby with genetic material from three people, who was born in Mexico in 2016. In this method, the nuclear DNA from the egg of a woman with faulty mitochondria is transferred to a donor egg with healthy mitochondria that has had its nuclear DNA removed. The egg is then fertilized with the father’s sperm in a test tube. The resulting embryo contains genes from both parents in addition to mitochondrial genes from the donor. ..."

From the abstract:

"Mitochondrial DNA (mtDNA) mutations are often associated with incurable diseases and lead to detectable pathogenic variants in 1 out of 200 babies. Uncoupling of the inheritance of mtDNA and the nuclear genome by spindle transfer (ST) can potentially prevent the transmission of mtDNA mutations from mother to offspring. However, no well-established studies have critically assessed the safety of this technique. Here, using single-cell triple omics sequencing method, we systematically analyzed the genome (copy number variation), DNA methylome, and transcriptome of ST and control blastocysts. The results showed that, compared to that in control embryos, the percentage of aneuploid cells in ST embryos did not significantly change. The epiblast, primitive endoderm, and trophectoderm (TE) of ST blastocysts presented RNA expression profiles that were comparable to those of control blastocysts. However, the DNA demethylation process in TE cells of ST blastocysts was slightly slower than that in the control blastocysts. Collectively, our results suggest that ST seems generally safe for embryonic development, with a relatively minor delay in the DNA demethylation process at the blastocyst stage."

Embryos with DNA from three people develop normally in first safety study

Single-cell multiomics analyses of spindle-transferred human embryos suggest a mostly normal embryonic development (open access)