Improving Mesenchymal Stem Cell Migration to the Damaged Lung Boosts Therapeutic Effects

Review of "Genetic Modification of Mesenchymal Stem Cells Overexpressing Angiotensin II Type 2 Receptor Increases Cell Migration to Injured Lung in LPS-induced Acute Lung Injury Mice" from STEM CELLS Translational Medicine by Stuart P. Atkinson

Mesenchymal stem cell (MSC) therapy for the treatment of acute lung injury (ALI) and acute respiratory distress syndrome [1] exhibits enormous potential but suffers from low-level therapeutic effects due to relatively poor homing of MSCs to the injured lung. Lung injury results in the increased production of the pro-inflammatory mediator Angiotensin II (Ang II) [2, 3] and this can promote the migration of MSCs in vitro through interactions with the Angiotensin II type 2 receptor (AT2R) [4].

As receptor expression in vitro expanded MSCs decreases with time, researchers led by Hai-bo Qiua (Southeast University, Nanjing, China) sought to modify MSCs to overexpress AT2R as a strategy to improve migration in vivo. Reporting in STEM CELLS Translational Medicine, Xu et al. now demonstrate that this strategy promotes the therapeutic effect of MSCs in ALI model mice by permitting the increased accumulation of administered MSCs in the injured lung [5].

Initial in vitro testing established that enhanced AT2R expression in human bone marrow MSCs, via the introduction of an AT2R expressing lentiviral vector, significantly improved Ang II-enhanced human bone marrow MSC migration. When systemically administered into a lipopolysaccharide-induced mouse model of ALI, AT2R-overexpressing MSCs migrated in greater numbers towards the damaged lung tissue at both 24 and 72 hours, when compared to unmodified MSCs.

The enhanced migrational capabilities of MSCs and the associated increase in lung residence time led to significantly reduced pulmonary vascular permeability, improved lung histopathology, and mediated potent anti-inflammatory effects. Of note, MSCs engineered to express a short hairpin RNA against AT2R displayed less lung retention time, highlighting the overall importance of the Ang II-AT2R interaction in the therapeutic effects of MSCs in ALI treatment.

The authors hope to confirm the enhanced therapeutic effect of AT2R-overexpressing MSCs in ALI mice by conducting longer-term studies and, additionally, to study the potential impact of A2TR overexpression on MSC differentiation and paracrine factor secretion and to assess the distribution of MSCs in other organs and tissues.

For more on stem cell migration and new advanced therapies for ALI, stay tuned to the Stem Cells Portal!

References

1. Johnson CL, Soeder Y, and Dahlke MH, Concise Review: Mesenchymal Stromal Cell-Based Approaches for the Treatment of Acute Respiratory Distress and Sepsis Syndromes. Stem Cells Transl Med 2017;6:1141-1151.
2. Imai Y, Kuba K, Rao S, et al., Angiotensin-converting enzyme 2 protects from severe acute lung failure. Nature 2005;436:112-6.
3. He H, Liu L, Chen Q, et al., Mesenchymal Stem Cells Overexpressing Angiotensin-Converting Enzyme 2 Rescue Lipopolysaccharide-Induced Lung Injury. Cell Transplant 2015;24:1699-715.
4. Xu X-p, He H-l, Hu S-l, et al., Ang II-AT2R increases mesenchymal stem cell migration by signaling through the FAK and RhoA/Cdc42 pathways in vitro. Stem Cell Research & Therapy 2017;8:164.
5. Xu X-P, Huang L-L, Hu S-L, et al., Genetic Modification of Mesenchymal Stem Cells Overexpressing Angiotensin II Type 2 Receptor Increases Cell Migration to Injured Lung in LPS-Induced Acute Lung Injury Mice. STEM CELLS Translational Medicine 2018;7:721-730.