Improving the Post-Stroke Therapeutic Potency of Mesenchymal Multipotent Stromal Cells by Cocultivation With Cortical Neurons: The Role of Crosstalk Between Cells

Abstract

The goal of the present study was to maximally alleviate the negative impact of stroke by increasing the therapeutic potency of injected mesenchymal multipotent stromal cells (MMSCs). To pursue this goal, the intercellular communications of MMSCs and neuronal cells were studied in vitro. As a result of cocultivation of MMSCs and rat cortical neurons, we proved the existence of intercellular contacts providing transfer of cellular contents from one cell to another. We present evidence of intercellular exchange with fluorescent probes specifically occupied by cytosol with preferential transfer from neurons toward MMSCs. In contrast, we observed a reversed transfer of mitochondria (from MMSCs to neural cells). Intravenous injection of MMSCs in a postischemic period alleviated the pathological indexes of a stroke, expressed as a lower infarct volume in the brain and partial restoration of neurological status. Also, MMSCs after cocultivation with neurons demonstrated more profound neuroprotective effects than did unprimed MMSCs. The production of the brain-derived neurotrophic factor was slightly increased in MMSCs, and the factor itself was redistributed in these cells after cocultivation. The level of Miro1 responsible for intercellular traffic of mitochondria was increased in MMSCs after cocultivation. We conclude that the exchange by cellular compartments between neural and stem cells improves MMSCs' protective abilities for better rehabilitation after stroke. This could be used as an approach to enhance the therapeutic benefits of stem cell therapy to the damaged brain. STEM CELLS

The mobility of mitochondria: Intercellular trafficking in health and disease

“…Transfer of mitochondria between cells within an organism has also been demonstrated phylogenetically in an 11 000 year‐old canine transmissible venereal tumour and in mouse models of transplantable tumours . In other studies, mitochondrial transfer to damaged cells has been shown in mouse models of inflammation and following ischaemic brain, lung and cardiac injury . Additionally, isolated mitochondria can be taken up by cardiomyocytes and are cardioprotective in the ischaemic heart, and can be transferred to cancer cells with functional consequences …”

Why do anti-inflammatory signals of bone marrow-derived stromal cells improve neurodegenerative conditions where anti-inflammatory drugs fail?

“…In other studies, bm-SC-EVs were found to exert immune-suppressive effects by enforcing ARM macrophage polarization and stimulating T-cell induction as well as producing neurotrophic factors and anti-inflammatory cytokines, as a dedicated reaction of environmental vesicles or cytokines from degenerating, malfunctioning cells (Dostert et al 2017;Cizkova et al 2018;Harting et al 2018;Kim et al 2018;Wang et al 2018;Beers and Appel 2019;Shahjin et al 2019). This hypothesis, though, is still a hypothesis, and recently, the possibility that bm-SCs one way or the other might donate healthy mitochondria to neurons that harbor dysfunctional mitochondria has also been raised to explain their positive effects (Babenko et al 2015).…”

Mesenchymal Stromal Cell Therapies for Neurodegenerative Diseases

“…Finally, an intriguing new hypothesis to explain the positive effects of MSCs is that they may improve neuronal health by donating their mitochondria. 32 This mechanism of mitochondrial transfer has been observed between astrocytes and neurons in a stroke model, 33 as well as between MSCs and alveoli in a lung injury model. 34 Through this mechanism, MSCs conceivably could improve neuronal health by donating healthy mitochondria to neurons that harbor dysfunctional mitochondria.…”