Abstract
BackgroundMesenchymal stromal cells (MSCs) have been studied with increasing intensity as clinicians and researchers strive to understand the ability of MSCs to modulate disease progression and promote tissue regeneration. As MSCs are used for diverse applications, it is important to appreciate how specific physiological environments may stimulate changes that alter the phenotype of the cells. One need for neuroregenerative applications is to characterize the spectrum of MSC responses to the cerebrospinal fluid (CSF) environment after their injection into the intrathecal space. Mechanistic understanding of cellular biology in response to the CSF environment may predict the ability of MSCs to promote injury repair or provide neuroprotection in neurodegenerative diseases.MethodsIn this study, we characterized changes in morphology, metabolism, and gene expression occurring in human adipose-derived MSCs cultured in human (hCSF) or artificial CSF (aCSF) as well as examined relevant protein levels in the CSF of subjects treated with MSCs for amyotrophic lateral sclerosis (ALS).ResultsOur results demonstrated that, under intrathecal-like conditions, MSCs retained their morphology, though they became quiescent. Large-scale transcriptomic analysis of MSCs revealed a distinct gene expression profile for cells cultured in aCSF. The aCSF culture environment induced expression of genes related to angiogenesis and immunomodulation. In addition, MSCs in aCSF expressed genes encoding nutritional growth factors to expression levels at or above those of control cells. Furthermore, we observed a dose-dependent increase in growth factors and immunomodulatory cytokines in CSF from subjects with ALS treated intrathecally with autologous MSCs.ConclusionsOverall, our results suggest that MSCs injected into the intrathecal space in ongoing clinical trials remain viable and may provide a therapeutic benefit to patients.
Highlights
Mesenchymal stromal cells (MSCs) are increasingly being employed in clinical trials to treat neurodegenerative diseases despite a lack of mechanistic investigations into the phenotypes of MSCs when injected into the central nervous system (CNS) compartment
MSCs cultured in 100% human cerebrospinal fluid (CSF) for 24 or 48 h remain morphologically unchanged To analyze the morphological changes of adiposederived MSCs in CSF, all four lines of MSCs were cultured in control media (CM), platelet lysatefree (PLF) media, or Human cerebrospinal fluid (hCSF) for 24 or 48 h
Consistent transcriptomic patterns are dependent on culture condition To determine how the transcriptomes of MSCs change in response to CSF, we examined gene expression profiles in the four lines of MSCs cultured in CM, PLF media, and artificial CSF (aCSF) for 24 or 48 h using high-throughput RNASeq analysis
Summary
Mesenchymal stromal cells (MSCs) are increasingly being employed in clinical trials to treat neurodegenerative diseases despite a lack of mechanistic investigations into the phenotypes of MSCs when injected into the central nervous system (CNS) compartment. For many current trials for neurological diseases, MSCs are extracted from adipose tissues or bone marrow, expanded in vitro, and injected into the intrathecal cerebrospinal fluid (CSF) of the CNS to bypass the blood-brain barrier. Mesenchymal stromal cells (MSCs) have been studied with increasing intensity as clinicians and researchers strive to understand the ability of MSCs to modulate disease progression and promote tissue regeneration. Mechanistic understanding of cellular biology in response to the CSF environment may predict the ability of MSCs to promote injury repair or provide neuroprotection in neurodegenerative diseases
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