BACKGROUND: 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. 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. METHODS: In 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). RESULTS: Our 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. CONCLUSIONS: Overall, our results suggest that MSCs injected into the intrathecal space in ongoing clinical trials remain viable and may provide a therapeutic benefit to patients.
BACKGROUND: 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. 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. METHODS: In 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). RESULTS: Our 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. CONCLUSIONS: Overall, our results suggest that MSCs injected into the intrathecal space in ongoing clinical trials remain viable and may provide a therapeutic benefit to patients.
Authors: B Oosthuyse; L Moons; E Storkebaum; H Beck; D Nuyens; K Brusselmans; J Van Dorpe; P Hellings; M Gorselink; S Heymans; G Theilmeier; M Dewerchin; V Laudenbach; P Vermylen; H Raat; T Acker; V Vleminckx; L Van Den Bosch; N Cashman; H Fujisawa; M R Drost; R Sciot; F Bruyninckx; D J Hicklin; C Ince; P Gressens; F Lupu; K H Plate; W Robberecht; J M Herbert; D Collen; P Carmeliet Journal: Nat Genet Date: 2001-06 Impact factor: 38.330
Authors: Dan Krakora; Patrick Mulcrone; Michael Meyer; Christina Lewis; Ksenija Bernau; Genevieve Gowing; Chad Zimprich; Patrick Aebischer; Clive N Svendsen; Masatoshi Suzuki Journal: Mol Ther Date: 2013-05-28 Impact factor: 11.454
Authors: Benjamin J Murdock; Tingting Zhou; Samy R Kashlan; Roderick J Little; Stephen A Goutman; Eva L Feldman Journal: JAMA Neurol Date: 2017-12-01 Impact factor: 18.302
Authors: Nathan P Staff; Nicolas N Madigan; Jonathan Morris; Mark Jentoft; Eric J Sorenson; Greg Butler; Dennis Gastineau; Allan Dietz; Anthony J Windebank Journal: Neurology Date: 2016-10-26 Impact factor: 9.910
Authors: Angelos Oikonomopoulos; Welmoed K van Deen; Aida-Rae Manansala; Precious N Lacey; Tamera A Tomakili; Alyssa Ziman; Daniel W Hommes Journal: Sci Rep Date: 2015-11-13 Impact factor: 4.379