Novel C1q receptor-mediated signaling controls neural stem cell behavior and neurorepair.

Francisca Benavente,Paul D Gershon,Brianna G Feld,Anita Lakatos,Aileen Anderson,Mitra J Hooshmand,Katja M Piltti,Aileen A Nava,Dana Creasman

doi:10.7554/elife.55732

Abstract

C1q plays a key role as a recognition molecule in the immune system, driving autocatalytic complement cascade activation and acting as an opsonin. We have previously reported a non-immune role of complement C1q modulating the migration and fate of human neural stem cells (hNSC); however, the mechanism underlying these effects has not yet been identified. Here, we show for the first time that C1q acts as a functional hNSC ligand, inducing intracellular signaling to control cell behavior. Using an unbiased screening strategy, we identified five transmembrane C1q signaling/receptor candidates in hNSC (CD44, GPR62, BAI1, c-MET, and ADCY5). We further investigated the interaction between C1q and CD44 , demonstrating that CD44 mediates C1q induced hNSC signaling and chemotaxis in vitro, and hNSC migration and functional repair in vivo after spinal cord injury. These results reveal a receptor-mediated mechanism for C1q modulation of NSC behavior and show that modification of C1q receptor expression can expand the therapeutic window for hNSC transplantation.

Highlights

Therapeutic transplantation of human neural stem cells offers a promising approach for neural repair in neurodegenerative disorders and central nervous system (CNS) injuries
We have previously shown that polymorphonuclear neutrophils (PMNs), which infiltrate the spinal cord at acute time points post trauma (Beck et al, 2010), alter the responses of donor cells after acute spinal cord injury (SCI) transplantation
We investigated the effects of C1q on intracellular signaling in human neural stem cells (hNSC) by testing three physiological C1q concentrations that are produced by PMN [28 ng/mL ffi 0.1 nM] (Hooshmand et al, 2017), Mj [400 ng/mL ffi 1.0 nM] (Hooshmand et al, 2017), or present in plasma

Summary

Introduction

Therapeutic transplantation of human neural stem cells (hNSC) offers a promising approach for neural repair in neurodegenerative disorders and central nervous system (CNS) injuries. C1q induces ERK signaling in fetal cytotrophoblasts (Agostinis et al, 2010), and binds discoidin domain receptor 1 (DDR1), directly activating mitogen-activated protein kinases and PI3K/Akt in hepatocellular tumor cells (Lee et al, 2018) This result suggests that C1q could play additional non-traditional roles, functioning as a ligand that can initiate cell signaling and/or directly interact with a transmembrane receptor to mediate cell signaling. We hypothesize that there is receptor-mediated communication between the host immune system and endogenous and/or donor NSC in the injured, diseased, or aged CNS that is mediated by C1q Consistent with such a role, C1q protein/mRNA increases and persists locally in the CNS after injury and in aging/disease as a result of disruption to the blood–brain barrier and local synthesis by invading and resident inflammatory cells (Peterson and Anderson, 2014; Nguyen et al, 2008; Hooshmand et al, 2017; Dunkelberger and Song, 2010; Anderson et al, 2004). These findings reveal an important role of complement C1q in modulating NSC behavior and identify a novel element in the understanding of the neuro-immune interface and NSC biology

Results

Discussion

Materials and methods