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

Abstract

Neurodegenerative disorders share the final degenerative pathway, the inflammation-induced apoptosis and/or necrosis, irrespective of their etiology, be it of acute and chronic traumatic, vascular and idiopathic origin. Although disease-modifying strategies are an unmet need in these disorders, lately, (pre)clinical studies suggested favorable effects after an intervention with bone marrow-derived stromal cells (bm-SC). Recent interventions with intrathecal transplantation of these cells in preclinical rodent models improved the functional outcome and reduced the inflammation, but not anti-inflammatory drugs. The benefit of bm-SCs was demonstrated in rats with an acute (traumatic spinal cord injury, tSCI) and in mice with a chronic [amyotrophic lateral sclerosis (ALS)-like FUS 1-358 or SOD1-G93-A mutation] neurodegenerative process. Bm-SCs, were found to modify underlying disease processes, to reduce final clinical SCI-related outcome, and to slow down ALS-like clinical progression. After double-blind interventions with bm-SC transplantations, Vehicle (placebo), and (non) steroidal anti-inflammatory drugs (Methylprednisolone, Riluzole, Celecoxib), clinical, histological and histochemical findings, serum/spinal cytokines, markers for spinal microglial activation inclusive, evidenced the cell-to-cell action of bm-SCs in both otherwise healthy and immune-deficient tSCI-rats, as well as wild-type and FUS/SOD1-transgenic ALS-like mice. The multi-pathway hypothesis of the cell-to-cell action of bmSCs, presumably using extracellular vesicles (EVs) as carriers of messages in the form of RNAs, DNA, proteins, and lipids rather than influencing a single inflammatory pathway, could be justified by the reported differences of cytokines and other chemokines in the serum and spinal tissue. The mode of action of bm-SCs is hypothesized to be associated with its dedicated adjustment of the pro-apoptotic glycogen synthase kinase-3β level towards an anti-apoptotic level whereas their multi-pathway hypothesis seems to be confirmed by the decreased levels of the pro-inflammatory interleukin (IL)-1β and tumor necrosis factor (TNF) as well as the level of the marker of activated microglia, ionized calcium binding adapter (Iba)-1 level.

Naive BM-derived stem cells (Neuro-Cells) may modify acute and chronic neurodegenerative disorders by modulating macrophage behaviors

“…Conforming to previous studies with stem cell implantations [70][71][72] , intrathecal Neuro-Cells implants, but not interventions with riluzole and/or celecoxib in 10-week old asymptomatic FUS(1-358) and SOD1(G93A) mutant ALS-like mice were found to significantly delay motor dysfunction, as well as muscle atrophy and the loss of spinal lumbar motor neuron as seen in transgenic mice [61] . Interventions with Neuro-Cells in 12week old asymptomatic FUS(1-358) frontotemporal lobe degeneration-like mice significantly delayed signs of depression and anxiety, cognitive deficits, and abnormal social behavior compared to FUS-tg placebotreated animals.…”

Anti-inflammatory Effects of Naïve Stem Cells Dampen Systemic/Compartmental Overreactive Immune Responses

“…Activated microglia and macrophages play an important role in this secondary inflammation. Cytotoxic IRMs (see figure 1), here were found responsible for the enhanced production of pro-inflammatory cytokines 5 . The intrathecal application of a standardized human Bm-SC product (fresh not-manipulated autologous bone marrow containing high concentrations of viable hematopoietic and mesenchymal stem cells obtained by centrifugation and positive depletion of erythrocytes, monocytes and lymphocytes, suspended in Ringers lactate, and reduced in volume for intrathecal application: Neuro-Cells, manufactured by Neuroplast BV, The Netherlands) did reduce the levels of pro-inflammatory cytokines as well as the neuropathologic signs in the central nervous system.…”

“…Their cell-to-cell communication here may play a major role and future research must elucidate the content of stem cell-secreted EVs in modulating inflammatory micro-environment(s) and the systemic effect thereof. If the effects of bm-SCs are directly related to the way of administration and the differentiation state of the stem cells, naïve bm-derived stem cells may be superior 5 . Therefore, subsequent studies on the systemic intravenous application of bm-derived stem cells in systemic CRS, and in compartmental CRS diseases via a direct injection (intercompartmental like intrathecal or injections in the joint) need to be done to address this question.…”

“…A more recent approach of treating such disorders with intrathecal transplants of fresh bone marrow-derived stromal cells (bm-SCs) seemed more promising 12,54,55 . Intrathecal application of naïve bm-SCs in SCI-rats within 24 h after the lesioning inhibited the conversion of state-2 (IRM) into state-3 (ARM) microglia, decreased neuronal apoptosis as well as the activators of IL-6 expression (TNF and IL-1β) in serum and spinal tissue when compared to the vehicle-treated animals 5,12,55 . These bm-SCs were found to dampen the downstream IL-6 signaling pathways, with improved clinical outcomes in experimental SCI-rats with evident features of a cytokine-driven hyperimmune reaction.…”

“…Indeed, in TBI and SCI, direct trauma-induced necrosis is followed by a secondary inflammatory reaction, which incites an excessive IRM response that will eliminate even the surviving cells in the immediate vicinity (the penumbra). In brain and spinal cord injuries, unfortunately, treatment with anti-inflammatory drugs have produced mixed results at best and can produce serious adverse events, unless the result of insufficient dosage or bioavailability, delayed time points of delivery, and/or or the taking-over of the eventually inhibited pathway by other single or downstream pathways 5,9,10,[51][52][53] . As the blood-brain-barrier is usually very tight, the systemic access of these drugs to the brain might also be hampered.…”