Communication via gap junctions underlies early functional and beneficial interactions between grafted neural stem cells and the host

Abstract

How grafted neural stem cells (NSCs) and their progeny integrate into recipient brain tissue and functionally interact with host cells is as yet unanswered. We report that, in organotypic slice cultures analyzed by ratiometric time-lapse calcium imaging, current-clamp recordings, and dye-coupling methods, an early and essential way in which grafted murine or human NSCs integrate functionally into host neural circuitry and affect host cells is via gap-junctional coupling, even before electrophysiologically mature neuronal differentiation. The gap junctions, which are established rapidly, permit exogenous NSCs to influence directly host network activity, including synchronized calcium transients with host cells in fluctuating networks. The exogenous NSCs also protect host neurons from death and reduce such signs of secondary injury as reactive astrogliosis. To determine whether gap junctions between NSCs and host cells may also mediate neuroprotection in vivo, we examined NSC transplantation in two murine models characterized by degeneration of the same cell type (Purkinje neurons) from different etiologies, namely, the nervous and SCA1 mutants. In both, gap junctions (containing connexin 43) formed between NSCs and host cells at risk, and were associated with rescue of neurons and behavior (when implantation was performed before overt neuron loss). Both in vitro and in vivo beneficial NSC effects were abrogated when gap junction formation or function was suppressed by pharmacologic and/or RNA-inhibition strategies, supporting the pivotal mediation by gap-junctional coupling of some modulatory, homeostatic, and protective actions on host systems as well as establishing a template for the subsequent development of electrochemical synaptic intercellular communication.

How stem cells speak with host immune cells in inflammatory brain diseases

“…Interestingly, mouse NPCs are resistant to FasL-induced cell death and activation of Fas increases NPC survival through upregulation of the inhibitor of apoptosis protein (IAP), Birc3 (Knight et al, 2010). Junctional coupling via connexins was first described between grafted NPCs and host Purkinje neurons in B05/ + spinocerebellar ataxia type 1 (SCA1) mice in vivo, and has been associated with neuronal rescue and behavior via the transcellular transfer of small molecules and Ca 2+ waves (Jaderstad et al, 2010). More recently, connexin43 + cellular contacts have been described between endogenous macrophages and grafted NPCs in mice with experimental contusion SCI (Fig.…”

“…Data in Table 1 are in part summarized in (Chamberlain et al, 2008;Hall et al, 2006;Martino and Pluchino 2006;Pluchino et al, 2009b;Rojewski et al, 2008;Uccelli et al, 2008;Yuan et al, 2011). (Cusimano et al, 2012;Jaderstad et al, 2010) aracrine IDO-kynurenine MSCs (h) T cells, DCs T cell apoptosis, inhibition of antigen presentation (Lanz et al, 2010;Matysiak et al, 2008Matysiak et al, , 2011Meisel et al, 2004;Plumas et al, 2005 Bonnamain et al, 2012;Chabannes et al, 2007;Moll et al, 2011) Paracrine VEGF NPCs Microglia/macrophages Inhibition of microglial activation, proliferation and phagocytosis (Horie et al, 2011;Kim et al, 2009a;Mosher et al, 2012) Paracrine LIF NPCs Th17 cells Inhibition of Th17 cell differentiation (Cao et al, 2011;Horie et al, 2011;Kim et al, 2009a;Mosher et al, 2012) Paracrine Galectins MSCs/NPCs T cells Inhibition of T cell proliferation (Gieseke et al, 2010;Sioud 2011;Yamane et al, 2010Yamane et al, , 2011 Endocrine/Paracrine TSG-6 MSCs Macrophages Inhibition of macrophage activation, proliferation and phagocytosis (Fisher-Shoval et al, 2012;Lee et al, 2009;Roddy et al, 2011) EVs miR transfer MSCs/NPCs Multiple Post-transcriptional regulation (Bruno et al, 2009;Chen et al, 2010;…”

Non-classical Signalling Mechanisms in Stem Cells

“…Moreover, transient increases in intracellular Ca 2+ can also stimulate differentiation and neurite outgrowth of different NS/PC cells, but whether such Ca 2+ signalling occurs through gap junction-mediated waves remains to be determined (Carey and Matsumoto, 1999;Gomez and Spitzer, 1999;Gu and Spitzer, 1995). Recent transplantantion studies by Jaderstad et al (2010) showed that establishment of GJIC that allows synchronized Ca 2+ waves is important for grafted NS/PC to integrate functionally to the host neural circuitry. Such GJIC between grafted NS/PC and host cells thus provided a neuroprotective effect in mouse models of neurodegeneration (Jaderstad et al, 2010).…”

“…In addition, NS/PC from other species have also been demonstrated to express Cx43 and communicate via GJIC (Wen et al, 2008) (Russo et al, 2008), suggesting a conserved and critical role of GJIC in NS/PC self-renewal and differentiation. Finally, it is notable that gap junctions appear to be important for establishing functional interactions between grafted NS/PC and host (Jaderstad et al, 2010).…”

What do we know about the neurogenic potential of different stem cell types?

“…It is accounted as an essential step in the functional integration of grafted murine and human NSCs into the host neural circuitry, even before mature electrochemical synaptic communication has been established. In addition, gap junction formation apparently prevents death of host neurons and inhibits gliosis, thus yielding stem cells to exert a protective effect on host cells 48 . In the in vivo microenvironment, many molecules play important roles in the homeostasis of endogenous stem cells.…”