Aging of Skeletal Stem Cells

Butler, Morgan; Ambrosi, Thomas H.; Murphy, Matthew P.; Chan, Charles

doi:10.20900/agmr20220006

Cited by 4 publications

(3 citation statements)

References 112 publications

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“…The reduced mineralization capacity of human BMSCs treated in vitro with Denosumab during osteogenic induction raise some concerns about a putative effect on SSC functions in patients receiving this therapy, especially in the case of elderly individuals, which for physiological reasons already have lower SSC fitness. Indeed, also in the skeletal system, the natural process of aging is accompanied by a decline in the capacity of adult stem cells to maintain tissue integrity, owing to mechanisms only partially elucidated and comprising downregulation of Wnt signaling and of negative regulators of cellular senescence, skewed differentiation towards stroma, reduced transcriptomic diversity and epigenetic mechanisms [ 58 ]. Based on our results, the defective regenerative potential of SSCs in the elderlies might be further reduced by RANKL pharmacological blockade.…”

Section: Discussionmentioning

confidence: 99%

Rankl genetic deficiency and functional blockade undermine skeletal stem and progenitor cell differentiation

Schiavone,

Crisafulli,

Camisaschi

et al. 2024

Stem Cell Res Ther

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Background Skeletal Stem Cells (SSCs) are required for skeletal development, homeostasis, and repair. The perspective of their wide application in regenerative medicine approaches has supported research in this field, even though so far results in the clinic have not reached expectations, possibly due also to partial knowledge of intrinsic, potentially actionable SSC regulatory factors. Among them, the pleiotropic cytokine RANKL, with essential roles also in bone biology, is a candidate deserving deep investigation. Methods To dissect the role of the RANKL cytokine in SSC biology, we performed ex vivo characterization of SSCs and downstream progenitors (SSPCs) in mice lacking Rankl (Rankl−/−) by means of cytofluorimetric sorting and analysis of SSC populations from different skeletal compartments, gene expression analysis, and in vitro osteogenic differentiation. In addition, we assessed the effect of the pharmacological treatment with the anti-RANKL blocking antibody Denosumab (approved for therapy in patients with pathological bone loss) on the osteogenic potential of bone marrow-derived stromal cells from human healthy subjects (hBMSCs). Results We found that, regardless of the ossification type of bone, osteochondral SSCs had a higher frequency and impaired differentiation along the osteochondrogenic lineage in Rankl−/− mice as compared to wild-type. Rankl−/− mice also had increased frequency of committed osteochondrogenic and adipogenic progenitor cells deriving from perivascular SSCs. These changes were not due to the peculiar bone phenotype of increased density caused by lack of osteoclast resorption (defined osteopetrosis); indeed, they were not found in another osteopetrotic mouse model, i.e., the oc/oc mouse, and were therefore not due to osteopetrosis per se. In addition, Rankl−/− SSCs and primary osteoblasts showed reduced mineralization capacity. Of note, hBMSCs treated in vitro with Denosumab had reduced osteogenic capacity compared to control cultures. Conclusions We provide for the first time the characterization of SSPCs from mouse models of severe recessive osteopetrosis. We demonstrate that Rankl genetic deficiency in murine SSCs and functional blockade in hBMSCs reduce their osteogenic potential. Therefore, we propose that RANKL is an important regulatory factor of SSC features with translational relevance.

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Section: Discussionmentioning

confidence: 99%

Rankl genetic deficiency and functional blockade undermine skeletal stem and progenitor cell differentiation

Schiavone,

Crisafulli,

Camisaschi

et al. 2024

Stem Cell Res Ther

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“…For instance, the axolotl salamander ( Ambystoma mexicanum ) can heal large chondral defects and regenerate normal hyaline AC and joint structure even if limb amputation, whereas our human beings cannot [ 31 ]. Particularly noteworthy is that the endogenous cartilage repair potential decreases with aging, phylogeny, and ontogeny due to ESPCs exhaustion [ 32 , 33 ]. It implies that young and juvenile patients hold greater potential for endogenous cartilage healing than the elderly [ 34 ].…”

Section: The Vital Roles Of Espcs Chemokines Cytokines and Growth Fac...mentioning

confidence: 99%

Engineered biochemical cues of regenerative biomaterials to enhance endogenous stem/progenitor cells (ESPCs)-mediated articular cartilage repair

Zhou

Schwab

et al. 2023

Bioactive Materials

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“…Aging affects bone differently from normal trauma-induced inflammation in that inflammation processes become less organized under aging conditions in which the NF-kB signaling pathway plays a key role (de Gonzalo-Calvo et al, 2010). Further, aged skeletal stromal cells showed decreased Wnt signaling, increased senescence, impaired cell function, and reduced osteogenic capacity that was partially rescued with administration of a dietary antioxidant resveratrol (Ambrosi et al, 2020;Clarke, 2021;Butler et al, 2022). For example, Wnt10b deficiency resulted in age-dependent loss of bone mass and progressive reduction in MSCs (Stevens et al, 2010).…”

Section: Aging Oxidative Stress and Compromised Bone Defectsmentioning

confidence: 99%

Revolutionizing bone regeneration: advanced biomaterials for healing compromised bone defects

et al. 2023

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In this review, we explore the application of novel biomaterial-based therapies specifically targeted towards craniofacial bone defects. The repair and regeneration of critical sized bone defects in the craniofacial region requires the use of bioactive materials to stabilize and expedite the healing process. However, the existing clinical approaches face challenges in effectively treating complex craniofacial bone defects, including issues such as oxidative stress, inflammation, and soft tissue loss. Given that a significant portion of individuals affected by traumatic bone defects in the craniofacial area belong to the aging population, there is an urgent need for innovative biomaterials to address the declining rate of new bone formation associated with age-related changes in the skeletal system. This article emphasizes the importance of semiconductor industry-derived materials as a potential solution to combat oxidative stress and address the challenges associated with aging bone. Furthermore, we discuss various material and autologous treatment approaches, as well as in vitro and in vivo models used to investigate new therapeutic strategies in the context of craniofacial bone repair. By focusing on these aspects, we aim to shed light on the potential of advanced biomaterials to overcome the limitations of current treatments and pave the way for more effective and efficient therapeutic interventions for craniofacial bone defects.

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Aging of Skeletal Stem Cells

Cited by 4 publications

References 112 publications

Rankl genetic deficiency and functional blockade undermine skeletal stem and progenitor cell differentiation

Rankl genetic deficiency and functional blockade undermine skeletal stem and progenitor cell differentiation

Engineered biochemical cues of regenerative biomaterials to enhance endogenous stem/progenitor cells (ESPCs)-mediated articular cartilage repair

Revolutionizing bone regeneration: advanced biomaterials for healing compromised bone defects

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