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Mesenchymal Stem Cell-based Combinatorial Treatment Shows Promise for Lung Repair

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Review of “Activation of p70S6 Kinase-1 in Mesenchymal Stem Cells is Essential to Lung Tissue Repair” from STEM CELLS Translational Medicine by Stuart P. Atkinson

Lung transplantation currently represents the primary therapeutic option for diseases such as emphysema that involve severe damage to the pulmonary parenchyma, the portion of the lung involved in gas transfer; however, this option suffers from limitations, including cost-effectiveness and a lack of donor lungs. Studies have suggested alternative treatment options, including immunomodulation by mesenchymal stem cells (MSCs) [1], all‐trans retinoic acid (ATRA) treatment [2], and, potentially, modulation of the mammalian target of rapamycin (mTOR)‐S6 kinase (S6k) signaling pathway [3].

To test a possible synergism between these alternative treatment options, researchers from the laboratory of Katsuyuki Takeda (National Jewish Health, Denver, Colorado, USA) employed an elastase‐induced mouse emphysema model. In their new STEM CELLS Translational Medicine study, the team now report that a combinatorial treatment of ATRA and MSCs in partnership with active signaling from the p70 isoform of S6k1 (p70S6k1) promotes the repair of lung damage [4]. 

The model system employed involved the intratracheal instillation of porcine pancreatic elastase (PPE) to induce emphysematous tissue damage in mice. Damage included a loss in lung elasticity, a worsening in lung structure, and decreased alveolar surface area. Treatment for ten days with MSCs or ATRA both improved the previously mentioned lung parameters; however, the authors discovered that a combinatorial treatment of ATRA and MSCs provided a positive synergistic effect on lung repair.

Interestingly, p70S6k1-null MSCs combined with ATRA only displayed modest effects, while p70S6k1 overexpressing‐MSCs combined with ATRA provided the best lung repair results of all combinations tested, thereby highlighting the general importance of active p70S6k1 signaling to lung repair. To explain this effect, the authors tracked MSCs post-infusion, discovering that MSCs in combination with ATRA treatment accumulated and survived in the lungs of in disease-induced mice, where they may secrete paracrine-acting factors that positively influence lung repair.

The authors hope now to understand how p70S6k1 activation promotes lung repair mediated by the MSC/ATRA combination by analyzing MSC-secreted factors and deducing the lung cell types involved in repair, while also assessing how prolonged retention time of MSCs may serve to reverse established lung disease.

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References

  1. Ortiz LA, Dutreil M, Fattman C, et al., Interleukin 1 receptor antagonist mediates the antiinflammatory and antifibrotic effect of mesenchymal stem cells during lung injury. Proc Natl Acad Sci U S A 2007;104:11002-7.
  2. Massaro GD and Massaro D, Retinoic acid treatment abrogates elastase-induced pulmonary emphysema in rats. Nat Med 1997;3:675-7.
  3. Yoshida T, Mett I, Bhunia AK, et al., Rtp801, a suppressor of mTOR signaling, is an essential mediator of cigarette smoke-induced pulmonary injury and emphysema. Nat Med 2010;16:767-73.
  4. Takeda K, Ning F, Domenico J, et al., Activation of p70S6 Kinase-1 in Mesenchymal Stem Cells Is Essential to Lung Tissue Repair. STEM CELLS Translational Medicine 2018;7:551-558.