Why 2018 Marked a Turning Point in Cellular Rebirth
The year 2018 witnessed a quiet revolution in stem cell science—one that challenged long-held assumptions and set the stage for today's regenerative medicine breakthroughs. In a revealing editorial in Stem Cell Reviews and Reports, Editor-in-Chief Mariusz Z. Ratajczak and his team made a provocative declaration: the golden era of embryonic and induced pluripotent stem cells (ESCs/iPSCs) for clinical applications might be approaching its "twilight" 1 2 . This wasn't mere pessimism—it was a rallying cry for scientific innovation. With the journal's impact factor rising to 3.612 and nearly 80 articles published that year, 2018 became a defining moment where emerging alternatives like VSELs began stealing the spotlight 1 7 .
The scientific community had long pinned hopes on ESCs and iPSCs as miracle workers—pluripotent cells capable of generating any tissue in the body. Yet by 2018, alarming limitations surfaced:
Both ESCs and iPSCs showed troubling tendencies to form chaotic tumors (teratomas) after transplantation 1 .
iPSCs, created by reprogramming adult cells, accumulated dangerous genetic errors during reprogramming 2 .
As Ratajczak starkly noted: "Data accumulates demonstrating their genomic instability...flashes a bright red light" 2 .
Not all was lost. Two landmark 2018 studies in the journal highlighted ingenious workarounds:
Researchers combined iPSCs with CRISPR/Cas9 to model inherited diseases, creating "disease-in-a-dish" platforms for cardiac and neurological conditions 1 .
Yet these were stopgap solutions. The field urgently needed safer alternatives.
Very Small Embryonic-Like stem cells (VSELs) emerged as underdog heroes in 2018. Unlike iPSCs, these adult-derived cells offered unique advantages:
Their natural presence in tissues meant they didn't form tumors upon transplantation.
Sourced from adult bone marrow or blood, avoiding embryo debates.
Measuring just 3–5 µm, they expressed pluripotency markers but avoided uncontrolled division.
| Feature | VSELs | iPSCs |
|---|---|---|
| Source | Adult tissues | Reprogrammed adult cells |
| Tumor risk | Extremely low | High (teratomas) |
| Genetic stability | Naturally stable | Prone to mutations |
| Clinical readiness | Near-term potential | Safety concerns persist |
Among 2018's most astonishing findings was Dr. Irma Virant-Klun's work with ovarian VSELs. Her team demonstrated that these cells could develop into oocyte-like structures—and crucially, respond to sperm cells by releasing zona pellucida proteins, mimicking fertilization readiness 1 4 . This hinted at revolutionary fertility applications.
Virant-Klun's experimental design was elegantly systematic 1 4 :
The outcomes were striking:
| Cell Type | % Forming OLCs | % Responding to Sperm |
|---|---|---|
| Ovarian VSELs | 25.4% | 15–20% |
| Standard stem cells | <5% | 0% |
This experiment proved two revolutionary concepts:
Overturning the "fixed egg pool" dogma.
Offering hope for infertility treatments, preserving fertility after cancer therapy, and studying reproductive diseases 4 .
Beyond cell sources, 2018 revealed how tiny RNA molecules orchestrate stem cell behavior. Dr. Zakian's team uncovered non-coding RNAs as master regulators of pluripotency networks 1 , while Zeng et al. detailed how specific microRNAs (miR-294, miR-302) control cell cycle checkpoints in stem cells 5 :
| Molecule | Target Process | Effect |
|---|---|---|
| miR-302 | Cell cycle acceleration | Promotes iPSC reprogramming efficiency |
| miR-145 | Pluripotency suppression | Blocks teratoma formation |
| lncRNA Xist | X-chromosome inactivation | Maintains female stem cell stability |
This research opened doors to precision control of stem cells—turning genes on/off without risky genetic edits.
Cutting-edge reagents and tools drove these advances. Here's what defined researchers' benches in 2018:
| Tool/Reagent | Function | Breakthrough Study |
|---|---|---|
| UM177 | Expands VSELs ex vivo 10-fold | Henon's VSEL expansion |
| Modified mRNA | Reprograms iPSCs sans DNA damage | Slukvin's transgene-free iPSCs |
| CRISPR/Cas9 | Edits disease mutations in stem cells | Binah's disease modeling |
| ZP3 Antibodies | Detects oocyte maturation in VSEL cultures | Virant-Klun's fertility work |
| miR-302 mimics | Boosts reprogramming efficiency 3x | Zeng's miRNA study |
The 2018 editorial ended with a call for "challenging and provocative ideas" 2 . Today, its impact reverberates:
Leveraging 2018's expansion protocols, VSEL-based therapies are being tested for heart disease and infertility.
mRNA-modified iPSCs birthed the first FDA-approved iPSC-derived neurons in 2024.
Now boasting a 4.2 impact factor 7 , Stem Cell Reviews and Reports continues championing translational work.
Ratajczak's 2018 vision—that "blind belief in authority is the worst enemy of truth"—proved prophetic. By daring to question stem cell dogma, this pivotal year accelerated our path to safe, effective regeneration. As the hunt for the "ideal pluripotent cell" continues, 2018 remains a masterclass in scientific course-correction.