Mitochondrial transfer from mesenchymal stem cells to neural stem cells protects against the neurotoxic effects of cisplatin

Boukelmoune, Nabila; Chiu, Gabriel Sean-Hang; Kavelaars, Annemieke; Heijnen, Cobi J.

doi:10.1186/s40478-018-0644-8

Cited by 106 publications

(114 citation statements)

References 48 publications

Supporting

Mentioning

104

Contrasting

Unclassified

Order By: Relevance

“…Accumulating evidence has shown that mitochondrial transfer occurs via TNTs, gap junctions, microvesicles, cell fusion and transfer of isolated mitochondria [132,[242][243][244][245]. So far, mitochondrial transfer from MSCs has demonstrated protective effects in lung injury, bronchial epithelial injury, allergic diseases, damaged cardiomyocytes, alkali-burnt corneal epithelial cells, kidney injury, ischemic damage, neurotoxicity, and spinal cord injury [132,[246][247][248][249][250][251][252][253]. Numerous studies have identified several signals including release of damaged mitochondria, mtDNA and mitochondrial products along with elevated ROS levels that trigger mitochondrial transfer from MSCs to the recipient cells [241].…”

Section: Mitochondrial Transfermentioning

confidence: 99%

Mechanisms underlying the protective effects of mesenchymal stem cell-based therapy

Fan

Zhang

et al. 2020

Cell. Mol. Life Sci.

369

282

View full text Add to dashboard Cite

Mesenchymal stem cells (MSCs) have been extensively investigated for the treatment of various diseases. The therapeutic potential of MSCs is attributed to complex cellular and molecular mechanisms of action including differentiation into multiple cell lineages and regulation of immune responses via immunomodulation. The plasticity of MSCs in immunomodulation allow these cells to exert different immune effects depending on different diseases. Understanding the biology of MSCs and their role in treatment is critical to determine their potential for various therapeutic applications and for the development of MSC-based regenerative medicine. This review summarizes the recent progress of particular mechanisms underlying the tissue regenerative properties and immunomodulatory effects of MSCs. We focused on discussing the functional roles of paracrine activities, direct cell-cell contact, mitochondrial transfer, and extracellular vesicles related to MSC-mediated effects on immune cell responses, cell survival, and regeneration. This will provide an overview of the current research on the rapid development of MSC-based therapies. Keywords Regenerative potential • Integration of MSCs • Immunomodulation • Soluble factors • Cell-cell contact • Mitochondrial transfer • Extracellular vesicles Abbreviations AHR Airway hyper-responsiveness Alix ALG-2-interacting protein X Ang-1 Angiopoietin-1 ASCs Adipose-derived stem cells BAX BCL-2-associated X protein BCL-2 B-cell lymphoma 2 CASP3 Caspase 3 CX43 Connexin 43 CXCR4 Chemokine receptor type 4 DC Dendritic cell Cellular and Molecular Life Sciences

show abstract

Section: Mitochondrial Transfermentioning

confidence: 99%

Mechanisms underlying the protective effects of mesenchymal stem cell-based therapy

Fan

Zhang

et al. 2020

Cell. Mol. Life Sci.

369

282

View full text Add to dashboard Cite

show abstract

“…Oxygen consumption rates were normalized to the total protein content of each well. Basal respiration, maximal respiratory capacity, and spare respiratory capacity were determined as described previously (Boukelmoune et al, 2018).…”

Section: Analysis Of Mitochondrial Bioenergeticsmentioning

confidence: 99%

“…Mitochondrial transfer from one cell type to another is not exclusive to astrocytes and neurons. For example, we and others have shown that mesenchymal stem cells transfer mitochondria to damaged neuronal stem cells thereby improving stem cell survival and mitochondrial membrane potential in the recipient cells (Boukelmoune et al, 2018;Gheusi and Lledo, 2014; M. L. Babenko et al, 2018). Transfer of mitochondria from one cell to another occurs via multiple mechanisms such as release and uptake of vesicles, transfer via gap junctions, and transfer via F-actin based tunneling nanotubes (Rogers and Bhattacharya, 2013;.…”

Section: Introductionmentioning

confidence: 99%

“…Mitochondrial Rho-GTPase 1 (Miro-1) is a calcium-sensitive adaptor protein that drives movement of mitochondria along microtubules (Jackson and Robinson, 2015). Miro-1 is involved in transferring mitochondria from mesenchymal stem cells to neuronal stem cells (Boukelmoune et al, 2018), but its contribution to mitochondrial transfer from astrocytes to neurons is unknown.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Astrocytes improve neuronal health after cisplatin treatment through mitochondrial transfer

English

Shepherd

Nzor³

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

Neurodegenerative disorders, including chemotherapy-induced cognitive impairment, are associated with neuronal mitochondrial dysfunction. Cisplatin, a commonly used chemotherapeutic, induces neuronal mitochondrial dysfunction in vivo and in vitro. Astrocytes are key players in supporting neuronal development, synaptogenesis, axonal growth, metabolism and, potentially, mitochondrial health. We tested the hypothesis that astrocytes transfer healthy mitochondria to neurons after cisplatin treatment to restore neuronal health.We used an in vitro system in which astrocytes containing mito-mCherry-labeled mitochondria were cocultured with primary cortical neurons damaged by cisplatin. Culture of primary cortical neurons with cisplatin reduced neuronal survival and depolarized neuronal mitochondrial membrane potential. Cisplatin induced abnormalities in neuronal calcium dynamics characterized by increased resting calcium levels, reduced calcium responses to stimulation with KCl, and slower calcium clearance. The same dose of cisplatin that caused neuronal damage did not affect astrocyte survival or astrocytic mitochondrial respiration. Co-culture of cisplatin-treated neurons with astrocytes increased neuronal survival, restored neuronal mitochondrial membrane potential, and normalized neuronal calcium dynamics especially in those neurons that had received mitochondria from astrocytes. These beneficial effects of astrocytes were associated with transfer of mitochondria from astrocytes to cisplatin-treated neurons. The Rho-GTPase Miro-1 is known to contribute to mitochondrial motility and transfer. We show that siRNA-mediated knockdown of Miro-1 in astrocytes reduced mitochondrial transfer from astrocytes to neurons and prevented the normalization of neuronal calcium dynamics.In conclusion, we identified transfer of mitochondria from astrocytes to neurons damaged by cisplatin as an important repair mechanism to protect cortical neurons against the toxic effects of this chemotherapeutic. Significance statementChemotherapy-induced neurotoxicity is a serious health problem and little is known about the underlying mechanisms.Especially neurons are very sensitive to cisplatin treatment. We show that astrocytes can protect neurons damaged by cisplatin by improving neuronal survival, mitochondrial health, and calcium dynamics in vitro. This beneficial effect of astrocytes is dependent on the transfer of mitochondria from astrocytes to the damaged neurons. Our findings provide evidence for an important endogenous protective neuro-glial mechanism that could contribute to prevention of neuronal death as a result of cisplatin treatment and thereby aid in sustaining brain health of patients during chemotherapy.

show abstract

“…Mitochondrial transfer from one cell type to another is not exclusive to astrocytes and neurons [19]. For example, we and others have shown that mesenchymal stem cells transfer mitochondria to damaged neuronal stem cells thereby improving stem cell survival and mitochondrial membrane potential in the recipient cells [20][21][22]. Transfer of mitochondria from one cell to another occurs via multiple mechanisms such as release and uptake of vesicles, transfer via gap junctions, and transfer via F-actin based tunneling nanotubes [17,23].…”

Section: Introductionmentioning

confidence: 99%

Astrocytes rescue neuronal health after cisplatin treatment through mitochondrial transfer

English

Shepherd

Uzor

et al. 2020

acta neuropathol commun

Self Cite

View full text Add to dashboard Cite

Neurodegenerative disorders, including chemotherapy-induced cognitive impairment, are associated with neuronal mitochondrial dysfunction. Cisplatin, a commonly used chemotherapeutic, induces neuronal mitochondrial dysfunction in vivo and in vitro. Astrocytes are key players in supporting neuronal development, synaptogenesis, axonal growth, metabolism and, potentially mitochondrial health. We tested the hypothesis that astrocytes transfer healthy mitochondria to neurons after cisplatin treatment to restore neuronal health. We used an in vitro system in which astrocytes containing mito-mCherry-labeled mitochondria were co-cultured with primary cortical neurons damaged by cisplatin. Culture of primary cortical neurons with cisplatin reduced neuronal survival and depolarized neuronal mitochondrial membrane potential. Cisplatin induced abnormalities in neuronal calcium dynamics that were characterized by increased resting calcium levels, reduced calcium responses to stimulation with KCl, and slower calcium clearance. The same dose of cisplatin that caused neuronal damage did not affect astrocyte survival or astrocytic mitochondrial respiration. Co-culture of cisplatin-treated neurons with astrocytes increased neuronal survival, restored neuronal mitochondrial membrane potential, and normalized neuronal calcium dynamics especially in neurons that had received mitochondria from astrocytes which underlines the importance of mitochondrial transfer. These beneficial effects of astrocytes were associated with transfer of mitochondria from astrocytes to cisplatin-treated neurons. We show that siRNA-mediated knockdown of the Rho-GTPase Miro-1 in astrocytes reduced mitochondrial transfer from astrocytes to neurons and prevented the normalization of neuronal calcium dynamics. In conclusion, we showed that transfer of mitochondria from astrocytes to neurons rescues neurons from the damage induced by cisplatin treatment. Astrocytes are far more resistant to cisplatin than cortical neurons. We propose that transfer of functional mitochondria from astrocytes to neurons is an important repair mechanism to protect the vulnerable cortical neurons against the toxic effects of cisplatin.

show abstract

Mitochondrial transfer from mesenchymal stem cells to neural stem cells protects against the neurotoxic effects of cisplatin

Cited by 106 publications

References 48 publications

Mechanisms underlying the protective effects of mesenchymal stem cell-based therapy

Mechanisms underlying the protective effects of mesenchymal stem cell-based therapy

Astrocytes improve neuronal health after cisplatin treatment through mitochondrial transfer

Astrocytes rescue neuronal health after cisplatin treatment through mitochondrial transfer

Contact Info

Product

Resources

About