Targeted Mitochondrial Charging of Impaired Cells Using Mesenchymal Stem Cell

A “high-powered” MSC with the capacity of potent mitochondrial biogenesis and facilitated mitochondrial transfer was generated, showing therapeutic potentials to restore the mitochondrial dysfunctional cells by a selective, efficient and sustained “charging” of healthy mitochondria.
Published in Biomedical Research
Targeted Mitochondrial Charging of Impaired Cells Using Mesenchymal Stem Cell
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Mitochondria, a well-known energy battery in eukaryotic cells, have been studied as a critical target for disease treatment. Beyond the energy supply, mitochondria are recently revealed as signaling organelles and actively participate in the self-protection of cells during stress. Such importance of mitochondria in functioning cells has captivated scientists with its pivotal role in disease progress and has inspired the idea of repairing dysfunctional mitochondria for disease intervention1.

However, the restoring of impaired mitochondria is a challenge. A more feasible strategy of using exogenous mitochondria to replenish dysfunctional mitochondria, known as mitochondrial replenishment therapy (MRT), is recently proposed. The idea of this strategy is simple, which is just like replacing faded battery in smart phones to prolong the useful life. Nevertheless, realizing this in cells is much more challenging. We should first lock the dysfunctional cells from millions of cells and “charge” them specifically with healthy mitochondria. This high requirement sets a challenge of directly injecting isolated mitochondria into diseased tissues. In addition, the fast deactivation of isolated mitochondria in extracellular environment is another obstacle for the practice application. An alternative strategy is learned from the self-protection mechanism of our body. Studies had uncovered that mitochondria can be transferred from one cell to the adjacent cell to deal with disease stress2,3. However, a major challenge in this strategy is the poor efficiency of the natural occurred mitochondrial transfer between cells, which hardly satisfies the high demands of reversing mitochondrial dysfunction.

This challenge excited our curiosity to see whether the efficiency of mitochondrial transfer between cells could be improved and be applied to recure impaired cells. As scientists of pharmaceutics, we see mitochondria as a “bioactive drug” and the question for us is to find a suitable carrier, which can not only protect mitochondria during the delivery but also find the mitochondria dysfunctional cell and deliver them with healthy mitochondria efficiently. Based on our research experiences during the past decade, we see mesenchymal stem cell (MSC) as the most promising candidate, not only because of its inherent homing capabilities towards diseased tissues, but also because of its inherent willingness to donate mitochondria to bioenergy desiderated cells. Such willingness is probably owing to its low bioenergetic needs in glycolytic state2,4,5.

Regardless of the benevolent character of MSC, we observed a poor capacity of MSC to deliver the mitochondria in natural state, which is mainly restricted by the limited delivery approaches and the relatively low number of mitochondria in MSC. Connexin 43 (Cx43) contained gap junctions are regarded as one of the main approaches for intercellular mitochondrial delivery. We previously applied iron oxide nanoparticles (IONPs) to successfully trigger the overexpression of Cx43 in MSC and observed a significant Cx43-facilitated mitochondrial transfer from MSC to injured lung cell. We further confirmed that this highly efficient mitochondrial transfer could protect lung epithelial cell to resist the bleomycin caused injury, thereby mitigating the progress of pulmonary fibrosis (PF)6. The dysfunction of mitochondria has been regarded as a major pathogenic mediator of PF7. Our finding indicated that efficient mitochondrial transfer can be a novel strategy for PF intervention.

However, the story of mitochondria transfer is far from over. The low energy demands of MSC in turn restrict its mitochondrial generation capability, thereby limiting the number of mitochondria available for transfer and adversely affecting therapeutic outcomes. We had observed that although the IONPs-engineered MSC (Fe-MSC) showed an efficient intervention for PF, they demonstrated poor therapeutic efficiency against the progressive PF, partly due to the insufficient and quickly exhausted mitochondrial transfer. Therefore, we thought of the possibility to endow an efficient and continued supply of mitochondria by increasing the mitochondrial mass in MSCs, thereby ensuing an effective restoring of mitochondrial bioenergetics in injured lung epithelial cells.

Promoting mitochondrial biogenesis may be one of the most efficient approaches to enhance the loading capacity of mitochondria in MSC. We tried several potential approaches to active the mitochondrial biogenesis and eventually found pioglitazone, a prescription drug for diabetes, could efficiently activate the mitochondrial biogenesis in MSC and is primarily through the PGC-1α-NRF1-TFAM pathway. We further observed that the promoted mitochondrial biogenesis could enhance the intercellular mitochondrial transfer, but the efficiency was lower than that of Fe-hMSC. Notably, despite the mitochondrial biogenesis showed limited advantages in promoting the mitochondrial transfer, the transfer duration at a high efficiency was significantly prolonged. Thus, we designed a joint-engineering strategy by the sequential treatment of pioglitazone and IONPs with MSC, which showed a high mitochondrial transfer efficiency (> 30%) and a sustained mitochondrial transfer capacity (> 72 h). Due to this powerful capacity of mitochondrial transfer, we term this engineered MSC as “High-powered” MSC. We then showed that this high-powered MSC can be a smart “super battery” with high mitochondrial generation capacity and the ability to recognise and “charge” the mitochondrial dysfunctional cells with healthy mitochondria. By using this high-powered MSC, a prominent therapeutic ability to intervene in PF progression in a mouse model with progressive PF was achieved. Furthermore, the efficient therapeutic potential of the high-powered hMSCs was confirmed in both fibrotic human lung cells and three-dimensional humanised lung spheroids. Interestingly, we further observed the re-activation of inhibited mitophagy in injured lung epithelial cells after the mitochondrial transfer, providing genetic evidence to support the possibility of reversing inhibited mitophagy by the efficient transfer of mitochondria.

We generated “high-powered” MSC as smart “super battery”, showing the ability to selectively “charge” the mitochondrial dysfunctional cells with healthy mitochondria efficiently and sustainably.

In conclusion, the present study provided a pioneering report regarding to a highly efficient and precise restoration of mitochondrial homeostasis in injured cells. In addition, the idea of arming MSC with potent mitochondrial biogenesis and enhanced mitochondrial transfer capacity may provide a potential solution to overcome the major challenges of highly efficient and sustained mitochondrial transfer for workable disease treatment. Our findings may inspire a new era of using mitochondria as drugs to treat various diseases caused by mitochondrial dysfunction.

References

  1. 1. Huang, T., Zhang, T. & Gao, J. Targeted mitochondrial delivery: A therapeutic new era for disease treatment. J Control Release343, 89-106 (2022).
  2. Islam, M.N., et al. Mitochondrial transfer from bone-marrow-derived stromal cells to pulmonary alveoli protects against acute lung injury. Nat Med 18, 759-765 (2012).
  3. Hayakawa, K., et al. Transfer of mitochondria from astrocytes to neurons after stroke. Nature 535, 551-555 (2016).
  4. Piekarska, K., et al. Mesenchymal stem cells transfer mitochondria to allogeneic Tregs in an HLA-dependent manner improving their immunosuppressive activity. Nat Commun 13, 856 (2022).
  5. Chen, C.T., Shih, Y.R., Kuo, T.K., Lee, O.K. & Wei, Y.H. Coordinated changes of mitochondrial biogenesis and antioxidant enzymes during osteogenic differentiation of human mesenchymal stem cells. Stem Cells 26, 960-968 (2008).
  6. Huang, T., et al. Iron oxide nanoparticles augment the intercellular mitochondrial transfer-mediated therapy. Sci Adv 7, eabj0534 (2021).
  7. Yu, G., et al. Thyroid hormone inhibits lung fibrosis in mice by improving epithelial mitochondrial function. Nat Med 24, 39-49 (2018).

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