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Age-Related Inflammation Triggers Skeletal Stem/Progenitor Cell Dysfunction

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Age-Related Inflammation Triggers Skeletal Stem/Progenitor Cell Dysfunction Age-related inflammation triggers skeletal stem/ progenitor cell dysfunction Anne Marie Josephsona,b, Vivian Bradaschia-Correaa, Sooyeon Leea, Kevin Leclerca, Karan S. Patela, Emma Muinos Lopeza, Hannah P. Litwaa, Shane S. Neibarta, Manasa Kadiyalaa, Madeleine Z. Wonga, Matthew M. Mizrahia, Nury L. Yima, Austin J. Rammea, Kenneth A. Egola, and Philipp Leuchta,b,1 aDepartment of Orthopedic Surgery, New York University School of Medicine, New York, NY 10003; and bDepartment of Cell Biology, New York University School of Medicine, New York, NY 10016 Edited by Helen M. Blau, Stanford University, Stanford, CA, and approved February 25, 2019 (received for review June 21, 2018) Aging is associated with impaired tissue regeneration. Stem cell Results number and function have been identified as potential culprits. We Skeletal Stem Cell Frequency Decreases with Aging. To investigate a first demonstrate a direct correlation between stem cell number and clinically relevant age-associated effect on skeletal stem cell fre- time to bone fracture union in a human patient cohort. We then quency and function, we first examined iliac crest bone graft devised an animal model recapitulating this age-associated decline in (ICBG) samples from 36 patients (20 male, 16 female) with ages bone healing and identified increased cellular senescence caused by a ranging from 24 to 89 y who underwent operative fixation of an systemic and local proinflammatory environment as the major contrib- upper- or lower-extremity fracture. FACS with CD271 as a human utor to the decline in skeletal stem/progenitor cell (SSPC) number and skeletal stem cell marker (8–11) revealed that SSPC frequency function. Decoupling age-associated systemic inflammation from chro- significantly declined with increasing age (Fig. 1 A and B). It is Nfkb1 nological aging by using transgenic KO mice, we determined generally well accepted among orthopedic surgeons that fractures in that the elevated inflammatory environment, and not chronological elderly subjects heal more slowly and less reliably, and therefore we age, was responsible for the decrease in SSPC number and function. asked whether SSPC frequency correlates with time to bony union. By using a pharmacological approach inhibiting NF-κB activation, we We prospectively evaluated clinical and radiographic fracture union demonstrate a functional rejuvenation of aged SSPCs with decreased in this cohort and discovered that a lower SSPC number was as- senescence, increased SSPC number, and increased osteogenic function. sociated with longer time to fracture union (Fig. 1C). To identify the MEDICAL SCIENCES Unbiased, whole-genome RNA sequencing confirmed the reversal of mechanism involved in this decline in SSPC number and function, the aging phenotype. Finally, in an ectopic model of bone healing, we we chose a mouse model to further investigate the process of demonstrate a functional restoration of regenerative potential in aged SSPCs. These data identify aging-associated inflammation as the cause skeletal stem cell aging. of SSPC dysfunction and provide mechanistic insights into its reversal. Aging Impairs Bone Regeneration. To evaluate the extent to which the process of aging affects bone healing, we first employed a regeneration | skeletal stem cell | senescence | inflammation | standardized tibial monocortical defect model in young (12-wk- bone healing old) and middle-aged (52-wk-old) male C57BL/6 mice. We an- alyzed bone healing by using histology, histomorphometry, and ll tissues are affected by aging, but diseases that weaken the micro-CT (μCT). Two weeks after surgery, the injury sites were Askeleton constitute the most prevalent chronic impairment analyzed by histology. Whereas injuries in the young animals in the United States (1). Although skeletal diseases and conditions showed abundant woven bone within the defect site (Fig. 2 A and are seldom fatal, they can significantly compromise function and diminish quality of life. Perhaps most importantly, age-related Significance changes in skeletal health may be traced back to the skeletal stem cell. Like other stem-cell pools, skeletal stem/progenitors are As we age, our capacity for tissue repair and regeneration in impacted by aging. For example, skeletal stem cells from people response to injury declines. Accordingly, bone repair is delayed older than age 65 y, even if they are healthy, make less bone than and impaired in older patients. At the cornerstone of bone stem cells from younger individuals, irrespective of sex (2). Instead healing is the skeletal stem/progenitor cell (SSPC), whose func- of becoming bone-producing osteoblasts, skeletal stem cells from tion and number diminishes with age. However, the mechanisms older people differentiate into fat-producing adipocytes (3), and driving this decline remain unclear. Here, we identify age- this may partly explain why bone-forming ability declines with associated inflammation (“inflamm-aging”)asthemainculpritof increasing age (3, 4). SSPC dysfunction and provide support for a central role of NF-κB Chronic inflammation in the elderly (“inflamm-aging”) is thought as a mediator of inflamm-aging. Our results show that modifica- to be a major contributor to the decline in the regenerative capacity tion of the inflammatory environment may be a translational ap- of the skeleton (5). In contrast to a well-balanced inflammatory re- proach to functionally rejuvenate the aged SSPC, thereby sponse after trauma, which is crucial for successful bone repair (6), improving the regenerative capacity of the aged skeleton. chronic unbalanced elevation of proinflammatory cytokines inhibits regeneration in a variety of other tissues (7). Its effect on the skeletal Author contributions: A.M.J., V.B.-C., S.L., K.L., and P.L. designed research; A.M.J., V.B.-C., S.L., K.L., K.S.P., E.M.L., H.P.L., S.S.N., M.K., M.Z.W., M.M.M., N.L.Y., A.J.R., K.A.E., and P.L. stem/progenitor cell (SSPC) is yet unknown. To address this performed research; A.M.J., V.B.-C., S.L., K.L., K.S.P., E.M.L., H.P.L., and P.L. analyzed data; knowledge gap, we hypothesized that chronic inflammation me- and A.M.J. and P.L. wrote the paper. diated by NF-κB activation—irrespective of age—contributes to a The authors declare no conflict of interest. deterioration of the regenerative function of the stem-cell pool by This article is a PNAS Direct Submission. inducing cellular senescence and decreasing SSPC number and Published under the PNAS license. function. Our data provide convincing evidence that pharmacologic 1To whom correspondence should be addressed. Email: [email protected]. κ inhibition of NF- B activation leads to a functional rejuvenation of This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. the SSPC pool, resulting in bone regeneration equal to that seen in 1073/pnas.1810692116/-/DCSupplemental. young animals. Published online March 20, 2019. www.pnas.org/cgi/doi/10.1073/pnas.1810692116 PNAS | April 2, 2019 | vol. 116 | no. 14 | 6995–7004 Downloaded by guest on September 28, 2021 vicinity, commencing a vicious cycle that results in a functional decline of the entire tissue and organ (14, 15). We hypothesized that serum from middle-aged mice contains proinflammatory SASP factors and that this cytokine milieu leads to a functional decline of the skeletal stem cell. SSPCs from young (12-wk-old) mice were exposed to sera from middle-aged (52-wk-old) mice in vitro (Fig. 4A). Compared with the homochronic control group (young serum/young cells), which demonstrated a linear increase in cell proliferation over a 7-d time course, the heterochronic group (middle-aged serum/young cells) exhibited a functional Fig. 1. Skeletal stem/progenitor cell frequency declines in the aging pa- tient. (A) FACS analysis of ICBG samples from 36 patients (20 male and 16 female) of varying ages revealed a significant (P < 0.05) negative corre- lation between age and SSPC number. (B) SSPC frequency is significantly decreased in patients older than 50 y of age (P < 0.05). (C) SSPC number is negatively correlated with time to bony union (P < 0.05). Green dots identify fractures that healed clinically and radiographically within 6 mo. Red dots mark patients with fracture union after 6 mo. C), the injuries in the middle-aged animals exhibited a smaller area of woven bone, with bone formation predominantly be- tween the cortical edges (Fig. 2 B and D). μCT imaging and 3D rendering confirmed this finding (Fig. 2 E and F). Histo- morphometry using μCT demonstrated a smaller callus volume [bone volume/total volume (BV/TV)], trabecular number (Tb. N), and trabecular thickness (Tb.Th) and increased trabecular spacing (Tb.Sp; Fig. 2G). This first experiment demonstrated that 52-wk-old WT mice exhibit a phenotype of age-related im- paired bone regeneration. Thus, we elected to use this age group for the subsequent experiments aimed at understanding the ef- fect of aging on bone healing and SSPC function. Aging Leads to a Decrease in SSPC Number. The key ingredient to successful bone regeneration is the SSPC. To determine whether a decline in SSPC number is responsible for the impaired re- generative capacity of the aging skeleton, as seen in our human cohort, we used FACS with the inclusive SSPC marker LepR − − − + + (12). CD45 CD31 Ter-119 LepR cells (LepR cells) comprise + + + + a heterogeneous mix of Sca-1 , PDGFRα , CD51 , and CD105 SSPCs (SI Appendix, Fig. S1), and Morrison and coworkers (12) + demonstrated that LepR cells make up 0.3% of bone marrow cells; they differentiate into bone, cartilage, and fat in vivo and in vitro and, most importantly, give rise to bone postnatally and in response to injury. Bones from middle-aged mice contained + significantly fewer LepR cells compared with bones from young mice (Fig. 3 A and B), and cfu assays confirmed this finding (Fig.
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