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Wharton's Jelly Mesenchymal Stem Cells Protect the Immature Brain in Rats and Modulate Cell Fate
Martin Mueller1,2,3, Byron Oppliger1,2, Marianne Joerger-Messerli1,2
11 Department of Clinical Research, University of Bern , Bern, Switzerland .
Insights
Mesenchymal stem cells from Wharton's Jelly (WJ-MSCs) show protective effects against immature brain injury in mice. WJ-MSCs reduce myelin loss and improve behavior, targeting key cell fate regulators for potential perinatal injury therapies.
Area of Science:
- Neuroscience
- Regenerative Medicine
- Developmental Biology
Background:
- Preterm birth is a leading cause of neonatal death and morbidity, with immature brain injury posing a significant challenge.
- Advances in perinatal care have reduced mortality but not morbidity, highlighting the need for novel therapeutic strategies.
- Mesenchymal stem/stromal cells (MSCs) are a promising cell therapy candidate for various conditions.
Purpose of the Study:
- To investigate the therapeutic potential of Wharton's Jelly-derived MSCs (WJ-MSCs) in a murine model of immature brain injury.
- To elucidate the underlying molecular mechanisms by which WJ-MSCs exert protective effects.
- To identify key signaling pathways and factors involved in WJ-MSC-mediated neuroprotection.
Main Methods:
- Transplantation of WJ-MSCs into a murine animal model of immature brain injury.
- Assessment of neuroprotective effects, including myelin integrity and astroglial activation.
- Evaluation of behavioral outcomes, specifically locomotor function.
- Analysis of key regulators of DNA damage response and cell fate pathways using profiler polymerase chain reaction arrays.
Main Results:
- WJ-MSC transplantation demonstrated significant protective activity, reducing myelin loss and astroglial activation in the injured brain.
- Locomotor behavior was notably improved in WJ-MSC-treated animals.
- WJ-MSCs were found to target pivotal regulators of cell fate, including cyclin-dependent kinase (CDK)/14-3-3/Akt signaling.
- Leukemia inhibitory factor was identified as a potential mediator of WJ-MSC-induced modifications.
Conclusions:
- WJ-MSCs exhibit therapeutic potential for mitigating immature brain injury in a preclinical model.
- The neuroprotective effects of WJ-MSCs involve the modulation of critical cell fate regulatory pathways.
- WJ-MSCs may adapt their response based on the injury type, positioning them as promising candidates for perinatal injury cell therapy.
Abstract:
The development of a mammalian brain is a complex and long-lasting process. Not surprisingly, preterm birth is the leading cause of death in newborns and children. Advances in perinatal care reduced mortality, but morbidity still represents a major burden. New therapeutic approaches are thus desperately needed. Given that mesenchymal stem/stromal cells (MSCs) emerged as a promising candidate for cell therapy, we transplanted MSCs derived from the Wharton's Jelly (WJ-MSCs) to reduce the burden of immature brain injury in a murine animal model. WJ-MSCs transplantation resulted in protective activity characterized by reduced myelin loss and astroglial activation. WJ-MSCs improved locomotor behavior as well. To address the underlying mechanisms, we tested the key regulators of responses to DNA-damaging agents, such as cyclic AMP-dependent protein kinase/calcium-dependent protein kinase (PKA/PKC), cyclin-dependent kinase (CDK), ataxia-telangiectasia-mutated/ATM- and Rad3-related (ATM/ATR) substrates, protein kinase B (Akt), and 14-3-3 binding protein partners. We characterized WJ-MSCs using a specific profiler polymerase chain reaction array. We provide evidence that WJ-MSCs target pivotal regulators of the cell fate such as CDK/14-3-3/Akt signaling. We identified leukemia inhibitory factor as a potential candidate of WJ-MSCs' induced modifications as well. We hypothesize that WJ-MSCs may exert adaptive responses depending on the type of injury they are facing, making them prominent candidates for cell therapy in perinatal injuries.
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