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SLIT2 regulates the skeletal stem cell niche through sympathetic innervation

ABSTRACT: Sympathetic tone has long been known as a central signaling axis inhibiting osteogenesis. However, the mechanism of this nerve to bone influence remains elusive, especially regarding the specific cellular targets of sympathetic activity. Recently, a bona fide tissue-resident stem cell giving rise to skeletal cell types, skeletal stem cells (SSCs), have been identified. To explore if and how nerves impact SSCs, we utilized mice with conditional deletion of SLIT2, a classic axonal repellent, finding that neural (Slit2syn1 mice) and sympathetic (Slit2th mice) but not bone stem/progenitor (Slit2prx1 mice) or sensory (Slit2adv mice) deletion of Slit2, led to osteopenia due to impaired bone formation associated with an increase in sympathetic innervation and a decrease in the numbers of SSCs. Consistent with this, pharmacological or surgical sympathectomy caused expansion of the SSC pool. More directly, wild type (WT) SSCs transplanted orthotopically into the bones of Slit2th mice with increased sympathetic innervation displayed impaired osteogenic capability, demonstrating that sympathetic nerves functionally contribute to the SSC niche. In line with these findings, the increased sympathetic innervation in Slit2th mice disrupted bone regeneration and bone fracture healing by reducing SSC expansion. Transcriptomic profiling in sympathetic neurons identified Follistatin-like 1 (FSTL1) as a SLIT2-regulated soluble factor that suppressed SSC self-renewal and osteogenic capacity. Accordingly, ablation of Fstl1 in sympathetic neurons enhanced SSC-driven osteogenesis and attenuated the bone loss seen in Slit2th mice in vivo. Altogether, our study both newly establishes SLIT2 as a regulator of skeletal sympathetic innervation and establishes sympathetic nerves as a key component of the SSC niche, providing new therapeutic opportunities to augment SSC function to treat skeletal disorders.

ORGANISM(S): Mus musculus

PROVIDER: GSE284991 | GEO | 2025/07/28

REPOSITORIES: GEO

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Project description:Low bone mass is strongly associated with multiple neurologic diseases such as Alzheimer’s disease (AD), however it remains unclear if this represents direct specific biologic sequalae of the primary disease process or rather a non-specific finding attributable to alterations in behavior and activity. The recent discovery of skeletal stem cells (SSCs) generating bone forming osteoblasts offers a new opportunity to understand both AD effects on bone and broader neural effects on bone by determining whether there are neural contributions to the SSC niche. Deletion of p75NTR (an essential neurotrophin receptor) was used to probe the contributions of peripheral innervation to the SSC niche. p75NTR deletion either broadly in neurons (p75NTRsyn1 mice) or more specifically in sensory nerves (p75NTRadv mice) but not osteogenic cells (p75NTRocn and p75NTRprx1 mice) or sympathetic nerves (p75NTRth mice), led to decrease in sensory innervation, impaired SSC homeostasis, and bone loss. Consistent with this, pharmacological sensory denervation resulted in a decrease in SSC numbers. More directly, wild-type SSCs transplanted orthotopically into the bones of p75NTRadv host mice with reduced sensory innervation displayed an impaired osteogenic capability, indicating that sensory nerves comprise part of the SSC niche. Decreased sensory innervation in p75NTRadv mice further impaired fracture healing by suppressing SSC expansion. Transcriptomic profiling to identify sensory nerve derived mediators of the SSC niche effect identified that p75NTR regulates expression of Osteopontin (SPP1) in neurons of the dorsal root ganglion (DRG), and SPP1 in turn acts as to promote SSC self-renewal and osteogenic capacity. Lastly, this p75NTR-SPP1 axis is impaired in AD mice, providing a new, direct mechanism for osteopenia in AD both impacting basal bone turnover and fracture repair. Altogether, our findings newly establish sensory nerves as a key component of SSC niche that is disrupted in AD, providing new therapeutic opportunities to augment SSC function to treat bone disorders such as Alzheimer’s associated osteopenia.

Project description:The expression of Prx1 has been used as a marker to define the skeletal stem cells (SSC) populations found within the bone marrow and periosteum that contribute to bone regeneration. However, Prx1 expressing SSCs (Prx1-SSCs) are not restricted to the bone compartments, but are also located within the muscle and able to contribute to ectopic bone formation. Little is known however, about the mechanism(s) regulating Prx1-SSCs that reside in muscle and how they participate in bone regeneration. This study compared both the intrinsic and extrinsic factors of the periosteum and muscle derived Prx1-SSCs and analyzed their regulatory mechanisms of activation, proliferation, and skeletal differentiation. There was considerable transcriptomic heterogeneity in the Prx1-SSCs found in muscle or the periosteum however in vitro cells from both tissues show tri-lineage (adipose, cartilage and bone) differentiation. At homeostasis, periosteal derived Prx1 cells were proliferative and low levels of BMP2 were able to promote their differentiation, while the muscle derived Prx1 cells were quiescent and refractory to comparable levels of BMP2 that promoted periosteal cell differentiation. The transplantation of Prx1-SCC from muscle and periosteum into either the same site from which they were isolated, or their reciprocal sites showed that periosteal cell transplanted onto the surface of bone tissues differentiated into bone and cartilage cells but was incapable of similar differentiation when transplanted into muscle. Prx1-SSCs from the muscle showed no ability to differentiate at either site of transplantation. Both fracture and ten times the BMP2 dose was needed to promote muscle-derived cells to rapidly enter the cell cycle as well as undergo skeletal cell differentiation. This study elucidates the diversity of the Prx1-SSC population showing that cells within different tissue sites are intrinsically different. While muscle tissue must have factors that promote Prx1-SSC to remain quiescent, either bone injury or high levels of BMP2 can activate these cells to both proliferate and undergo skeletal cell differentiation. Finally, these studies raise the possibility that muscle SSCs are potential target for skeletal repair and bone diseases.

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SLIT2 regulates the skeletal stem cell niche through sympathetic innervation

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