How Cell Sheets Heal Wounds Without Scarring
A revolutionary healing technology not only closes wounds but regenerates hair and skin glands.
Imagine a treatment that could not only close stubborn wounds but actually regenerate normal skin complete with hair and glands, rather than forming scar tissue. For millions suffering from pressure ulcers—chronic wounds that develop from prolonged pressure on the skin—this possibility represents hope for recovery from a condition that causes significant pain, frequent infections, and even life-threatening complications.
Recent breakthroughs in regenerative medicine have opened exciting new possibilities. Among the most promising advances is the use of mesenchymal stromal cells (MSCs) derived from adipose (fat) tissue. While stem cell injections have shown some promise, a novel approach using "cell sheets" has demonstrated remarkable results in animal studies, not just healing wounds but preventing fibrosis—the process that leads to scarring 1 5 .
Under ideal circumstances, our skin undergoes a carefully orchestrated healing process with three overlapping phases:
Immediate response to injury with clotting and immune cell recruitment
Formation of "granulation tissue" - a provisional structure rich in blood vessels and cells
Resolution of inflammation and tissue maturation 4
Granulation tissue serves as the foundation for repair during the proliferation phase, but its quality and structure determine whether the outcome will be regeneration or scarring 7 .
In chronic wounds like pressure ulcers, this process gets stuck in the inflammatory phase. The wound remains in a state of persistent inflammation that prevents progression to the later stages of healing 4 .
Additionally, conditions such as spinal cord injury or diabetes can involve skin denervation (loss of nerve supply), which further impairs the healing process 4 .
Scar formation represents a biological compromise—a quick way to close wounds that sacrifices form and function. Scars lack the specialized structures of normal skin, such as hair follicles, sweat glands, and the precise organization of collagen fibers. Once a scar forms, it creates a "non-receptive" site that blocks endogenous regeneration, presenting a particular challenge for regenerative medicine approaches 5 .
Mesenchymal stromal cells (MSCs) are multipotent progenitor cells that can be obtained from various tissues, including bone marrow, umbilical cord, and adipose tissue 2 . These cells possess remarkable abilities that make them ideal candidates for regenerative therapies:
Among various sources, adipose-derived MSCs offer distinct advantages:
Abundant tissue availability
Higher yield of cells
Low immunogenicity
Ethical acceptability
These practical advantages make adipose-derived MSCs particularly attractive for widespread clinical application 2 4 6 .
While MSC injections have been used experimentally for various conditions, research has revealed significant limitations with this delivery method. Injecting cells into tissues induces apoptosis (programmed cell death) and rapid clearance from the treatment area 5 .
Cell sheet technology represents a revolutionary alternative. Rather than dissociating cells through enzymatic treatment, researchers culture MSCs until they form a complete, intact layer containing both cells and their native extracellular matrix. This preservation of natural cell-to-cell connections and microenvironment dramatically changes cell behavior and therapeutic potential 5 .
Harvest adipose tissue
Isolate and culture MSCs
Form intact cell sheets
Transplant to wound site
A compelling 2020 study published in the International Journal of Molecular Sciences directly compared three approaches for treating pressure ulcers in mice: MSC injections, MSC secretome (the molecules secreted by cells), and MSC cell sheets 1 5 .
The findings revealed striking differences between the treatment approaches:
| Day | Cell Sheet | MSC Injection | Secretome | Untreated Control |
|---|---|---|---|---|
| Day 3 | No significant difference | No significant difference | No significant difference | No significant difference |
| Day 7 | No significant difference | No significant difference | No significant difference | No significant difference |
| Day 14 | ~33% of original size | ~58% of original size | Similar to control | ~44% of original size |
| Day 21 | Most advanced healing | ~63% of original size | Intermediate healing | ~27% of original size |
| Outcome Measure | Cell Sheet | MSC Injection | Secretome | Untreated Control |
|---|---|---|---|---|
| Wound Closure Rate | Accelerated | Slowed | Intermediate | Baseline |
| Skin Appendages | Present (hair, glands) | Absent | Absent | Absent |
| Fibrosis/Scarring | Significantly Reduced | Similar to control | Similar to control | Baseline scarring |
| Collagen Organization | Healthy skin pattern | Disorganized | Disorganized | Disorganized |
The research team discovered that despite relatively short retention on the ulcer surface (3-7 days), the cell sheets initiated profound changes in granulation tissue structure. The sheets altered the vascularization pattern, resulting in reduced blood vessel density but increased vessel maturity 1 5 .
This shift toward more mature, functional blood vessels represents a crucial advantage, as unstable, immature vessels are common in chronic wounds and contribute to poor healing outcomes.
The most fascinating revelation came from analyzing the molecules secreted by MSC cell sheets compared to traditionally cultured MSCs. The sheets produced:
This represented a very different paracrine signature—the spectrum of healing factors the cells release. The cell sheets essentially shifted their secretions away from simply activating capillary growth toward matrix remodeling and vasculature maturation 1 .
| Factor | Function | Effect in Cell Sheets |
|---|---|---|
| PDGF-BB | Pericyte recruitment, vessel maturation | Increased production |
| HGF | Tissue regeneration, anti-fibrotic | Increased production |
| G-CSF | Immune cell regulation | Increased production |
| VEGF₁₆₅ | Blood vessel sprouting | Unchanged or decreased |
| Fatty Acid Metabolism Enzymes | Negative regulation of vessel sprouting | Upregulated |
Transcriptome analysis using RNA sequencing confirmed this shift, showing upregulation of proteins responsible for collagen binding and granulation tissue maturation, along with fatty acid metabolism enzymes known to be negative regulators of blood vessel sprouting 1 .
The implications of this research extend far beyond pressure ulcers. The ability to prevent fibrosis has significance for many conditions involving abnormal scarring, including:
The development of MSC cell sheets represents a paradigm shift in wound healing—from simply closing defects to genuinely regenerating functional tissue. By harnessing the innate healing capacities of our own cells and presenting them in a more natural, tissue-like organization, scientists have unlocked a powerful approach that addresses the root causes of fibrosis and poor healing.
While more research is needed to standardize protocols and confirm efficacy in human clinical trials, cell sheet technology offers hope for millions suffering from chronic wounds and scarring conditions. The future of regenerative medicine may lie not in injecting isolated cells, but in transplanting intelligent, self-organizing tissues that can guide our bodies toward true healing and restoration.
For further reading on the science behind this breakthrough, the original research article "Cell Sheets from Adipose Tissue MSC Induce Healing of Pressure Ulcer and Prevent Fibrosis via Trigger Effects on Granulation Tissue Growth and Vascularization" is published in the International Journal of Molecular Sciences (2020).