The Tiny Challengers

How VSELs Stole the Spotlight in 2018's Stem Cell Revolution

Published: August 8, 2025

Introduction: A Critical Year for Stem Cells

The year 2018 marked a pivotal moment in stem cell science—a field poised between disillusionment and discovery. As Stem Cell Reviews and Reports (SCRR) closed its second year under new leadership, its pages reflected a dramatic shift: scientists were questioning the once-celebrated induced pluripotent stem cells (iPSCs) and turning attention to an underdog candidate—Very Small Embryonic-Like stem cells (VSELs). With the journal's impact factor rising to 3.612 and nearly 80 articles published, 2018 became the year of rigorous debate and daring hypotheses ¹ ² .

"A blind belief in authority is the worst enemy of truth."

Journal Growth

SCRR's impact factor rose to 3.612 in 2018 with nearly 80 articles published, reflecting increased interest in stem cell research.

VSELs Emerge

Very Small Embryonic-Like stem cells gained attention as promising alternatives to traditional stem cell approaches.

The Stem Cell Crisis: ESCs and iPSCs Under Fire

The Promise and Peril of Pluripotency

For years, embryonic stem cells (ESCs) and iPSCs dominated regenerative medicine. Both could differentiate into cells of all three germ layers (mesoderm, endoderm, ectoderm), making them ideal candidates for tissue repair. But by 2018, cracks in this paradigm were widening:

Teratoma Risk

Both ESCs and iPSCs showed a troubling tendency to form teratomas (malignant tumors) post-transplantation ¹ .

Genomic Instability

iPSCs, created by reprogramming adult cells, accumulated DNA errors during genetic modification ² .

Paracrine Effects

Clinical trials revealed iPSCs often aided healing only indirectly—by secreting supportive factors ¹ .

VSELs: The Dark Horse Emerges

Amid this crisis, VSELs gained traction. Discovered in adult tissues, these cells exhibit:

Pluripotency Markers: Expression of genes like Oct4 and Nanog, typically seen in embryonic cells.
Primitive Morphology: Exceptionally small size (3–5 µm), suggesting an early developmental origin ¹ .
Ethical Advantage: Sourced without destroying embryos.

In 2018, SCRR published pivotal studies demonstrating VSELs' potential to regenerate ovarian tissue and blood cells—offering a viable alternative to iPSCs ¹ ² .

Experiment Deep Dive: VSELs and the Quest for Artificial Oocytes

The Groundbreaking Study

Dr. Irma Virant-Klun's 2018 SCRR paper delivered a stunning claim: VSELs from ovarian surface epithelium could develop into oocyte-like cells capable of responding to sperm ⁴ . This hinted at future fertility treatments using a patient's own cells.

Methodology: Step by Step

Cell Isolation

Ovarian surface tissue samples were obtained from consenting patients. VSELs were separated using flow cytometry, exploiting their small size and unique surface markers (e.g., CXCR4+) ¹ .

3D Culture

Isolated VSELs were cultured in a collagen-based matrix supplemented with growth factors (FGF2, BMP4) to mimic the ovarian niche.

Differentiation Induction

Cells were exposed to retinoic acid to trigger germ cell development.

Sperm Interaction Test

Mature oocyte-like cells were co-cultured with human sperm to assess fertilization potential.

This experiment positioned VSELs as viable candidates for next-generation fertility therapies—though clinical use remained years away ⁴ .

Results and Implications

Outcome Measure	Observation	Significance
Oocyte-like cell formation	25–30% of VSELs differentiated	Proves VSELs' germline potential
Zona pellucida release	Detected in 68% of cells post-sperm contact	Shows partial fertilization competence
Embryo development	None observed	Highlights need for protocol refinement

2018's Cutting-Edge Tools: Accelerating VSEL Research

Critical advances in reagents and protocols enabled SCRR's breakthroughs. Two studies exemplified this progress:

Henon's UM177 Cocktail

Dr. Henon's team reported that UM177, a small molecule inhibitor, dramatically boosted VSEL expansion ex vivo. By blocking protein degradation pathways, UM177 extended VSELs' self-renewal capacity—a hurdle for clinical scaling ¹ .

Slukvin's mRNA Engineering

Though focused on iPSCs, Dr. Slukvin's work had cross-field impact. His team optimized synthetic mRNA to reprogram cells without risky DNA integration. This method later aided VSEL differentiation studies ³ .

Key Research Tools in 2018 VSEL Studies

Reagent/Technique	Function	Study Impact
UM177	Enhances VSEL survival and expansion	Enabled large-scale VSEL production
Collagen/Matrigel 3D culture	Mimics ovarian stem cell niche	Critical for germ cell differentiation
Retinoic acid	Induces germline commitment	Triggered oocyte-like cell formation
CRISPR/Cas9 (via Binah)	Gene editing in stem cells	Future tool for modifying VSEL pathways

The Scientist's Toolkit

Reagent	Application	Commercial Source Example
Anti-CXCR4 Antibodies	Isolating VSELs via flow cytometry	Thermo Fisher Scientific
UM177	Expanding VSELs in culture	StemCell Technologies
Retinoic Acid	Inducing germ cell differentiation	Sigma-Aldrich
Synthetic mRNA Mix	Non-viral reprogramming	TriLink BioTechnologies
Oct4/Nanog Reporters	Tracking pluripotency in live cells	Addgene

Beyond 2018: The Lasting Impact

The debates and discoveries of 2018 reshaped stem cell science:

iPSCs Reoriented

Research pivoted toward disease modeling (e.g., using CRISPR-edited iPSCs for cardiac disease) over direct therapy ² .

VSELs Validated

Later studies confirmed VSELs in multiple tissues (bone marrow, brain), though functional mechanisms remain under scrutiny.

Journal Legacy

SCRR's emphasis on "challenging ideas" cemented its role in regenerative medicine, with its impact factor rising to 4.2 by 2024 ⁵ .

As we witness clinical trials using VSEL-derived cells (e.g., for ovarian insufficiency), the daring questions raised in 2018 continue to drive the field beyond the twilight of iPSCs—toward a more nuanced dawn.