Boundary cap cells are peripheral nervous system stem cells that can be redirected into central nervous system lineages

Abstract

Boundary cap cells (BC), which express the transcription factor Krox20, participate in the formation of the boundary between the central nervous system and the peripheral nervous system. To study BC stemness, we developed a method to purify and amplify BC in vitro from Krox20Cre/+ , R26RYFP/+ mouse embryos. We show that BC progeny are EGF/FGF2-responsive, form spheres, and express neural crest markers. Upon growth factor withdrawal, BC progeny gave rise to multiple neural crest and CNS lineages. Transplanted into the developing murine forebrain, they successfully survived, migrated, and integrated within the host environment. Surprisingly, BC progeny generated exclusively CNS cells, including neurons, astrocytes, and myelin-forming oligodendrocytes. In vitro experiments indicated that a sequential combination of ventralizing morphogens and glial growth factors was necessary to reprogram BC into oligodendrocytes. Thus, BC progeny are endowed with differentiation plasticity beyond the peripheral nervous system. The demonstration that CNS developmental cues can reprogram neural crest-derived stem cells into CNS derivatives suggests that BC could serve as a source of cell type-specific lineages, including oligodendrocytes, for cell-based therapies to treat CNS disorders.dysmyelination | reprogramming | transplantation B oundary cap cells (BC) are neural crest (NC) derivatives and were first described as discrete cell clusters localized at the dorsal root entry zone and motor exit point of the embryonic spinal cord (1). Their specific location at the central nervous system (CNS) and peripheral nervous system (PNS) interface and genetic ablation (2) showed that BC are involved in the formation of PNS-CNS boundaries. BC maintain spinal cord integrity by inhibiting motoneuron cell bodies exit to the periphery (3). Fate mapping, based on the exclusive expression of the zinc finger transcription factor Krox20 by BC between embryonic day (E)10.5 and E15.5, showed that migrating BC derivatives differentiate into Schwann cells (SC) in spinal roots, and satellite cells and a subset of nociceptive neurons in dorsal root ganglia (DRG), suggesting their multipotency (2). HjerlingLeffler and collaborators (4) highlighted the presence of a pluripotent population in the E11 mouse DRG capable of selfrenewal and differentiation into multiple NC derivatives. We reported that BC have a defined molecular signature intermediate between NC cells and SC precursors (3). Furthermore, when transplanted remotely from a focal myelin lesion of the spinal cord, BC generated remyelinating SC and few oligodendrocytes. Overall, these results strongly suggest that BC are stem cells of the embryonic PNS. However, the definition of BC stemness has been hampered by the difficulty of purifying and amplifying this restricted population. In this study, we used cellfate mapping, FACS, and microdissection to isolate, expand, and assess BC stemness in vitro and in vivo. Our data show that BC progeny behave as stem cells that can acquire differentiation plasti...

Cell Therapy for Multiple Sclerosis

“…These cells, and specifically boundary cap cells, which form the border between the developing peripheral and CNS, generate myelinating Schwann cells [229]. Their increased migratory and myelinating properties [230], as well as their potential to also generate myelinating oligodendrocyte [231], make Schwann cells another promising candidate for cell replacement therapy in myelin disorders.…”

Glial Cell Development and Function in Zebrafish

“…In addition to this possible role, boundary cap cells can also function as stem cells, and may even be capable of generating CNS cell types including OLs (Zujovic et al 2011), although this has to be confirmed in vivo. Boundary cap cells have not yet been studied in detail in zebrafish but given the suitability of zebrafish for live-cell imaging and lineagebased studies, this is likely to be a very fruitful area of future research.…”

The Effect of Mesoporous Silica Particles on Stem Cell Differentiation

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