Mitochondrial transfer in WJ-MSCs

Mitochondria are frequently described as the “powerhouse of the cell” to help students remember the energy-producing role of these organelles. In fact, the term has reached parody status for how ubiquitous it is across the learning experience worldwide.

Mitochondria are more than just cellular powerhouses. As well as being the sites of production of the chemical energy that fuels all biological processes, they also play roles in cell signaling, cell cycle, apoptosis, and differentiation. Their dysfunction is a hallmark of aging and is associated with a variety of diseases. Additionally, mutations in mitochondrial DNA can lead to inherited mitochondrial disease (1).

The therapeutic potential of mesenchymal stem cells (MSCs) is currently being explored in the treatment of mitochondrial dysfunction, an early and important event in the progression of many diseases. MSCs can directly transfer their healthy mitochondria to the defective cells, restoring some of their function. This mitochondrial transfer occurs through tunneling nanotubes, which are long, thin, cell membrane protrusions that facilitate intercellular connections. These connections enable the transfer of materials, such as some ions, proteins, organelles, and vesicles, between adjacent cells.

Wharton’s Jelly MSCs (WJ-MSCs) represent a valuable tool for mitochondrial transfer, as they avoid many of the ethical and practical concerns of other regenerative cell therapies. Their clinical value has been demonstrated in several preclinical studies, where they have been shown to have tissue repair and regenerative potential (1).

Mitochondrial transfer by UC-MSCs is an emerging cell therapy.

Therapeutic Applications of Mitochondrial Transfer

Mitochondrial transfer by MSCs has been shown to reduce inflammation in an in vitro model of acute respiratory distress syndrome (ARDS) (2) and a mouse model of asthma (3), suggesting it could be a potential therapy in the treatment of respiratory illnesses.

Mitochondrial transfer from MSCs to neuronal stem cells also appears to offer protection against the neurotoxic effects of cisplatin (4), hypoxia-induced brain injuries (5,6), and enhance wound-healing in corneal cells in response to oxidative damage (7). It also promotes tissue repair in cardiac cells damaged by the cardiotoxic effects of anthracycline, another chemotherapy drug (8).

Most studies into the clinical applications of MSCs have used mouse models, or MSCs derived from induced pluripotent stem cells (iPSCs) or bone marrow. However, recent studies have confirmed that WJ-MSCs can participate in mitochondrial transfer. These MSCs also do not require the use of invasive collection procedures and represent a much more accessible cell therapy.

One study showed that WJ-MSCs could successfully transfer mitochondria to ρ0 cells, which are entirely devoid of mitochondrial DNA. Importantly, the transplanted mitochondria were able to rescue the normal physiological functions associated with mitochondrial activity (9). It was later shown, in a clinically relevant model, that WJ-MSCs could restore mitochondrial function to fibroblasts from patients with Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes (MELAS), a group of inherited mitochondrial diseases (10).

Future Directions

Despite the abundance of encouraging preclinical data, there are some potential concerns regarding the therapeutic use of mitochondrial transfer. Namely, mitochondrial transfer can promote the growth of tumor cells by increasing intracellular ATP levels, sustaining their high metabolic activity (1).

Many research studies support the use of WJ-MSCs in the treatment of diseases linked to mitochondrial dysfunction, particularly inherited mitochondrial diseases, and those associated with inflammation and oxidative stress. However, more in vivo and clinical research is required to determine the scope and feasibility of these cell therapies and how they can be practically incorporated into treatment regimes.

By Katy McLaughlin

References

1. Li, C. et al. Mesenchymal stem cells and their mitochondrial transfer: A double-edged sword. Bioscience Reports vol. 39 (2019). doi: 10.1042/BSR20182417

2. Morrison, T. J. et al. Mesenchymal stromal cells modulate macrophages in clinically relevant lung injury models by extracellular vesicle mitochondrial transfer. Am. J. Respir. Crit. Care Med. 196, 1275–1286 (2017). doi: 10.1164/rccm.201701-0170OC

3. Yao, Y. et al. Connexin 43-Mediated Mitochondrial Transfer of iPSC-MSCs Alleviates Asthma Inflammation. Stem Cell Reports 11, 1120–1135 (2018). doi: 10.1016/j.stemcr.2018.09.012

4. Boukelmoune, N., Chiu, G. S., Kavelaars, A. & Heijnen, C. J. Mitochondrial transfer from mesenchymal stem cells to neural stem cells protects against the neurotoxic effects of cisplatin. Acta Neuropathol. Commun. 6, 139 (2018). doi: 10.1080/15384101.2018.1445906

5. Tseng, N. et al. Mitochondrial transfer from mesenchymal stem cells improves neuronal metabolism after oxidant injury in vitro: The role of Miro1. J. Cereb. Blood Flow Metab. 0271678X2092814 (2020). doi: 10.1177/0271678X20928147

6. Yang, Y. et al. Transfer of mitochondria from mesenchymal stem cells derived from induced pluripotent stem cells attenuates hypoxia-ischemia-induced mitochondrial dysfunction in PC12 cells. Neural Regen. Res. 15, 464 (2020). doi: 10.4103/1673-5374.266058

7. Jiang, D. et al. Mitochondrial transfer of mesenchymal stem cells effectively protects corneal epithelial cells from mitochondrial damage. Cell Death Dis. 7, (2016). doi: 10.1038/cddis.2016.358

8. Zhang, Y. et al. iPSC-MSCs with High Intrinsic MIRO1 and Sensitivity to TNF-α Yield Efficacious Mitochondrial Transfer to Rescue Anthracycline-Induced Cardiomyopathy. Stem Cell Reports 7, 749–763 (2016). doi: 10.1016/j.stemcr.2016.08.009

9. Lin, H. Y. et al. Mitochondrial transfer from Wharton’s jelly-derived mesenchymal stem cells to mitochondria-defective cells recaptures impaired mitochondrial function. Mitochondrion 22, 31–44 (2015). doi: 10.1016/j.mito.2015.02.006

10. Lin, T. K. et al. Mitochondrial transfer of Wharton's jelly mesenchymal stem cells eliminates mutation burden and rescues mitochondrial bioenergetics in rotenone-stressed MELAS fibroblasts. Oxid. Med. Cell. Longev. 2019, (2019). doi: 10.1155/2019/9537504