Bio

Bio


Dr. Zhao is currently a postdoctoral scholar at Stanford University. He received his MD degree from Tongji Medical College, Huazhong University of Science and Technology in 2018.

Boards, Advisory Committees, Professional Organizations


  • Member, International Society for Stem Cell Research (2019 - Present)
  • Member, Orthopaedic Research Society (2018 - Present)

Professional Education


  • Doctor of Medicine, Huazhong University Of Science & Technology (2018)

Stanford Advisors


Publications

All Publications


  • Articular cartilage regeneration by activated skeletal stem cells. Nature medicine Murphy, M. P., Koepke, L. S., Lopez, M. T., Tong, X., Ambrosi, T. H., Gulati, G. S., Marecic, O., Wang, Y., Ransom, R. C., Hoover, M. Y., Steininger, H., Zhao, L., Walkiewicz, M. P., Quarto, N., Levi, B., Wan, D. C., Weissman, I. L., Goodman, S. B., Yang, F., Longaker, M. T., Chan, C. K. 2020

    Abstract

    Osteoarthritis (OA) is a degenerative disease resulting in irreversible, progressive destruction of articular cartilage1. The etiology of OA is complex and involves a variety of factors, including genetic predisposition, acute injury and chronic inflammation2-4. Here we investigate the ability of resident skeletal stem-cell (SSC) populations to regenerate cartilage in relation to age, a possible contributor to the development of osteoarthritis5-7. We demonstrate that aging is associated with progressive loss of SSCs and diminished chondrogenesis in the joints of both mice and humans. However, a local expansion of SSCs could still be triggered in the chondral surface of adult limb joints in mice by stimulating a regenerative response using microfracture (MF) surgery. Although MF-activated SSCs tended to form fibrous tissues, localized co-delivery of BMP2 and soluble VEGFR1 (sVEGFR1), a VEGF receptor antagonist, in a hydrogel skewed differentiation of MF-activated SSCs toward articular cartilage. These data indicate that following MF, a resident stem-cell population can be induced to generate cartilage for treatment of localized chondral disease in OA.

    View details for DOI 10.1038/s41591-020-1013-2

    View details for PubMedID 32807933

  • Geriatric fragility fractures are associated with a human skeletal stem cell defect. Aging cell Ambrosi, T. H., Goodnough, L. H., Steininger, H. M., Hoover, M. Y., Kim, E., Koepke, L. S., Marecic, O., Zhao, L., Seita, J., Bishop, J. A., Gardner, M. J., Chan, C. K. 2020: e13164

    Abstract

    Fragility fractures have a limited capacity to regenerate, and impaired fracture healing is a leading cause of morbidity in the elderly. The recent identification of a highly purified bona fide human skeletal stem cell (hSSC) and its committed downstream progenitor cell populations provides an opportunity for understanding the mechanism of age-related compromised fracture healing from the stem cell perspective. In this study, we tested whether hSSCs isolated from geriatric fractures demonstrate intrinsic functional defects that drive impaired healing. Using flow cytometry, we analyzed and isolated hSSCs from callus tissue of five different skeletal sites (n=61) of patients ranging from 13 to 94years of age for functional and molecular studies. We observed that fracture-activated amplification of hSSC populations was comparable at all ages. However, functional analysis of isolated stem cells revealed that advanced age significantly correlated with reduced osteochondrogenic potential but was not associated with decreased in vitro clonogenicity. hSSCs derived from women displayed an exacerbated functional decline with age relative to those of aged men. Transcriptomic comparisons revealed downregulation of skeletogenic pathways such as WNT and upregulation of senescence-related pathways in young versus older hSSCs. Strikingly, loss of Sirtuin1 expression played a major role in hSSC dysfunction but re-activation by trans-resveratrol or a small molecule compound restored in vitro differentiation potential. These are the first findings that characterize age-related defects in purified hSSCs from geriatric fractures. Our results provide a foundation for future investigations into the mechanism and reversibility of skeletal stem cell aging in humans.

    View details for DOI 10.1111/acel.13164

    View details for PubMedID 32537886

  • NR1D1 modulates synovial inflammation and bone destruction in rheumatoid arthritis CELL DEATH & DISEASE Liu, H., Zhu, Y., Gao, Y., Qi, D., Zhao, L., Zhao, L., Liu, C., Tao, T., Zhou, C., Sun, X., Guo, F., Xiao, J. 2020; 11 (2): 129

    Abstract

    Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial hyperplasia, pannus formation, and cartilage and bone destruction. Nuclear receptor subfamily 1 group D member 1 (NR1D1) functions as a transcriptional repressor and plays a vital role in inflammatory reactions. However, whether NR1D1 is involved in synovial inflammation and joint destruction during the pathogenesis of RA is unknown. In this study, we found that NR1D1 expression was increased in synovial tissues from patients with RA and decreased in RA Fibroblast-like synoviocytes (FLSs) stimulated with IL-1β in vitro. We showed that NR1D1 activation decreased the expression of proinflammatory cytokines and matrix metalloproteinases (MMPs), while NR1D1 silencing exerted the opposite effect. Furthermore, NR1D1 activation reduced reactive oxygen species (ROS) generation and increased the production of nuclear transcription factor E2-related factor 2 (Nrf2)-associated enzymes. Mitogen-activated protein kinase (MAPK) and nuclear factor κB (NF-κB) pathways were blocked by the NR1D1 agonist SR9009 but activated by NR1D1 silencing. NR1D1 activation also inhibited M1 macrophage polarization and suppressed osteoclastogenesis and osteoclast-related genes expression. Treatment with NR1D1 agonist SR9009 in collagen-induced arthritis (CIA) mouse significantly suppressed the hyperplasia of synovial, infiltration of inflammatory cell and destruction of cartilage and bone. Our findings demonstrate an important role for NR1D1 in RA and suggest its therapeutic potential.

    View details for DOI 10.1038/s41419-020-2314-6

    View details for Web of Science ID 000517238700005

    View details for PubMedID 32071294

    View details for PubMedCentralID PMC7028921

  • Tantalum nanoparticles reinforced polyetheretherketone shows enhanced bone formation MATERIALS SCIENCE & ENGINEERING C-MATERIALS FOR BIOLOGICAL APPLICATIONS Zhu, H., Ji, X., Guan, H., Zhao, L., Zhao, L., Liu, C., Cai, C., Li, W., Tao, T., Reseland, J., Haugen, H., Xiao, J. 2019; 101: 232–42

    Abstract

    Polyetheretherketone (PEEK) has been used in orthopedic surgery for several decades. Numerous methods were invented to alter the properties of PEEK. By adding nanoparticles, fibers, etc., elastic modulus and strength of PEEK can be changed to meet certain demand. In this study, tantalum (Ta), a promising metal, was introduced to modify the properties of PEEK, in which PEEK was reinforced with different contents of tantalum nanoparticles (from 1 wt% to 9 wt%). Mechanical properties and biological functions (both in vitro and in vivo) were then investigated. The highest elastic modulus and compressive strength were observed in 3%Ta-PEEK. Cell experiments as cell adhesion, collagen secretion, biomineralization and osteogenesis related gene expression showed preferable results in 3%Ta-PEEK and 5%Ta-PEEK. Improved bone integration was shown in 3%Ta-PEEK and 5%Ta-PEEK in vivo. Above all, enhanced mechanical properties and promoted bone formation were proved for 3%Ta-PEEK and 5%Ta-PEEK compared to others groups both in vitro and in vivo, suggesting that the addition of tantalum nanoparticles modified the osseointegration ability of PEEK. This composite of tantalum and PEEK could have a clinical potential for orthopedic implants.

    View details for DOI 10.1016/j.msec.2019.03.091

    View details for Web of Science ID 000471359100022

    View details for PubMedID 31029316

  • Hesperetin suppresses RANKL-induced osteoclastogenesis and ameliorates lipopolysaccharide-induced bone loss JOURNAL OF CELLULAR PHYSIOLOGY Liu, H., Dong, Y., Gao, Y., Zhao, L., Cai, C., Qi, D., Zhu, M., Zhao, L., Liu, C., Guo, F., Xiao, J., Huang, H. 2019; 234 (7): 11009–22

    Abstract

    Destructive bone diseases caused by osteolysis are increasing in incidence. They are characterized by an excessive imbalance of osteoclast formation and activation. During osteolysis, the activation of nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways are triggered by receptor activator of NF-κB ligand (RANKL), inflammatory factors, and oxidative stress. Previous studies have indicated that the common flavanone glycoside compound hesperetin exhibits anti-inflammatory and antioxidant activity by inhibition of NF-κB and MAPK signaling pathways. However, the direct relationship between hesperetin and osteolysis remain unclear. In the present study, we investigated the effects of hesperetin on lipopolysaccharide (LPS)-induced osteoporosis and elucidated the related mechanisms. Hesperetin effectively suppressed RANKL-induced osteoclastogenesis, osteoclastic bone resorption, and F-actin ring formation in a dose-dependent manner. It also significantly suppressed the expression of osteoclast-specific markers including tartrate-resistant acid phosphatase, matrix metalloproteinase-9, cathepsin K, c-Fos, and nuclear factor of activated T-cells cytoplasmic 1. Furthermore, it inhibited osteoclastogenesis by inhibiting activation of NF-κB and MAPK signaling, scavenging reactive oxygen species, and activating the nuclear factor E2 p45-related factor 2/heme oxygenase 1 (Nrf2/HO-1) signaling pathway. Consistent with in vitro results, hesperetin effectively ameliorated LPS-induced bone loss, reduced osteoclast numbers, and decreased the RANKL/OPG ratio in vivo. As such, our results suggest that hesperetin may be a great candidate for developing a novel drug for destructive bone diseases such as periodontal disease, tumor bone metastasis, rheumatoid arthritis, and osteoporosis.

    View details for DOI 10.1002/jcp.27924

    View details for Web of Science ID 000462645700101

    View details for PubMedID 30548260

  • Effects of Taxifolin on Osteoclastogenesis in vitro and in vivo FRONTIERS IN PHARMACOLOGY Cai, C., Liu, C., Zhao, L., Liu, H., Li, W., Guan, H., Zhao, L., Xiao, J. 2018; 9: 1286

    Abstract

    Osteoporosis is a highly prevalent disease which has been a major public health problem and considered to be associated with chronic low-grade systemic inflammation and oxidative damage. Taxifolin is a natural flavonoid and possesses many pharmacological activities including antioxidant and anti-inflammatory. Because flavonoids have been confirmed to fight osteoporosis and promote bone health, the aim of this study was to investigate the effects of taxifolin on the formation and function of osteoclast. In this study, we examined the effects of taxifolin on osteoclast using both in vitro and in vivo studies. Taxifolin suppressed the activation of nuclear factor-κB, C-Fos and mitogen-activated protein kinase, and also decreased osteoclast-specific genes expression, including Trap, Mmp-9, Cathepsin K, C-Fos, Nfatc1, and Rank. Taxifolin also prevented reactive oxygen species (ROS) production following RANKL stimulation. In addition, taxifolin alleviated ovariectomized-induced bone loss by repressing osteoclast activity and decreasing serum levels of tumor necrosis factor-α, interleukin-1β, interleukin-6 and receptor activator of nuclear factor-κB ligand (RANKL) in vivo. Our results indicated that taxifolin inhibits osteoclastogenesis via regulation of modulation of several RANKL signaling pathways. Therefore, taxifolin may be considered as a potential alternative therapeutic agent for treating osteoclast-related diseases.

    View details for DOI 10.3389/fphar.2018.01286

    View details for Web of Science ID 000449859200001

    View details for PubMedID 30483128

    View details for PubMedCentralID PMC6240596

  • REV-ERB agonism suppresses osteoclastogenesis and prevents ovariectomy-induced bone loss partially via FABP4 upregulation FASEB JOURNAL Song, C., Tan, P., Zhang, Z., Wu, W., Dong, Y., Zhao, L., Liu, H., Guan, H., Li, F. 2018; 32 (6): 3215–28

    Abstract

    REV-ERBs (REV-ERBα and REV-ERBβ) are transcription repressors and circadian regulators. Previous investigations have shown that REV-ERBs repress the expression of target genes, including MMP9 and CX3CR1, in macrophages. Because MMP9 and CX3CR1 reportedly participate in receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis, we inferred that REV-ERBs might play a role in osteoclastogenesis. In the present study, we found that the REV-ERBα level decreased significantly during RANKL-induced osteoclast differentiation from primary bone marrow-derived macrophages (BMMs). REV-ERBα knockdown by small interfering RNA in BMMs resulted in the enhanced formation of osteoclasts, whereas REV-ERBβ knockdown showed no effect on osteoclast differentiation. Moreover, the REV-ERB agonist SR9009 inhibited osteoclast differentiation and bone resorption. Intraperitoneal SR9009 administration prevented ovariectomy-induced bone loss; this effect was accompanied by decreased serum RANKL and C-terminal telopeptide of type I collagen levels and increased osteoprotegerin levels. Further investigation revealed that NF-κB and MAPK activation and nuclear factor of activated T cells, cytoplasmic 1, and c-fos expression were suppressed by SR9009. The level of reactive oxygen species was also decreased by SR9009, with NADPH oxidase subunits also being down-regulated. In addition, an expression microarray showed that FABP4, an intracellular lipid-binding protein, was up-regulated by REV-ERB agonism. BMS309403, an inhibitor of FABP4, partially prevented the suppression of osteoclastogenesis by SR9009 through stabilizing phosphorylation of p65. To summarize, our results proved that the REV-ERB agonism inhibited osteoclastogenesis partially via FABP4 up-regulation.-Song, C., Tan, P., Zhang, Z., Wu, W., Dong, Y., Zhao, L., Liu, H., Guan, H., Li, F. REV-ERB agonism suppresses osteoclastogenesis and prevents ovariectomy-induced bone loss partially via FABP4 upregulation.

    View details for DOI 10.1096/fj.201600825RRR

    View details for Web of Science ID 000432546000026

    View details for PubMedID 29401617

  • YAP1 is essential for osteoclastogenesis through a TEADs-dependent mechanism BONE Zhao, L., Guan, H., Song, C., Wang, Y., Liu, C., Cai, C., Zhu, H., Liu, H., Zhao, L., Xiao, J. 2018; 110: 177–86

    Abstract

    Yes-associated protein 1 (YAP1), the core effector of the Hippo signaling pathway, has been identified as a key regulator of tissue homeostasis and organ development by controlling cell proliferation and differentiation. Previous studies have shown that YAP1 regulates multiple steps during skeletal development and bone remodeling, including the self-renewal and differentiation of mesenchymal stem cells (MSCs). However, its role in osteoclastogenesis remains largely unknown. Here, we report that YAP1 is an essential regulator for osteoclast differentiation and activity. Both mRNA and protein levels of YAP1 were downregulated during RANKL-induced osteoclastogenesis. Short hairpin RNA-mediated knockdown of YAP1 in bone marrow-derived macrophages (BMM) prevented the formation and function of multinucleated osteoclasts, and markedly abrogated the expression of osteoclast marker genes. Furthermore, the suppression of osteoclastogenesis and bone resorption activity were also observed in the BMM treated with verteporfin, a small molecule that inhibits the association of YAP1 with the transcriptional enhancer-associated domain (TEAD) family of transcription factors, the major partner of YAP1. Mechanistically, the interaction of YAP1/TEADs with AP-1 and cooperation on downstream gene transcription were confirmed, and RANKL-induced NF-κB signaling was also impaired in the YAP1-inhibited condition. Our results revealed the essential role of YAP1 and the YAP1-TEADs complex in regulating osteoclastogenesis and related gene expression.

    View details for DOI 10.1016/j.bone.2018.01.035

    View details for Web of Science ID 000429630700020

    View details for PubMedID 29432919

  • Recent advances in 3D bioprinting for the regeneration of functional cartilage REGENERATIVE MEDICINE Ji Xiongfa, Zhu Hao, Zhao Liming, Xiao Jun 2018; 13 (1): 73–87

    Abstract

    The field of regeneration for functional cartilage has progressed tremendously. Conventional approaches for regenerating the damaged tissue based on integrated manufacturing are limited by their inability to produce precise and customized biomimetic tissues. On the other hand, 3D bioprinting is a promising technique with increased versatility because it can co-deliver cells and biomaterials with proper compositions and spatial distributions. In the present article, we review recent progress in the complete 3D printing process involved in functional cartilage regeneration, including printing techniques, biomaterials and cells. We also discuss the combination of 3D in vivo hybrid bioprinting with spheroids, gene delivery strategies and zonal cartilage design as a future direction of cartilage regeneration research.

    View details for DOI 10.2217/rme-2017-0106

    View details for Web of Science ID 000425270600008

    View details for PubMedID 29350587

  • Dihydromyricetin Protects against Bone Loss in Ovariectomized Mice by Suppressing Osteoclast Activity FRONTIERS IN PHARMACOLOGY Zhao, L., Cai, C., Wang, J., Zhao, L., Li, W., Liu, C., Guan, H., Zhu, Y., Xiao, J. 2017; 8: 928

    Abstract

    Dihydromyricetin (DMY), the main flavonoid component of Ampelopsis grossedentata, possesses pharmacological activities useful for treatment of diseases associated with inflammation and oxidative damage. Because osteoclasts are often involved in chronic low-grade systemic inflammation and oxidative damage, we hypothesized that DMY may be an effective treatment for osteoclast-related diseases. The effects of DMY on osteoclast formation and activity were examined in vitro. Female C57BL/6 mice were ovariectomized to mimic menopause-induced bone loss and treated with DMY, and femur samples were subjected to bone structure and histological analysis, serum biochemical indicators were also measured. DMY suppressed the activation of nuclear factor-κB, c-Fos and mitogen-activated protein kinase, and prevented production of reactive oxygen species. DMY decreased expression of osteoclast-specific genes, including Trap, Mmp-9, Cathepsin K, C-Fos, Nfatc1, and Rank. In addition, DMY prevented bone loss and decreased serum levels of tumor necrosis factor-α, interleukin-1β, and interleukin-6, and with a decrease in the ratio between receptor activator of nuclear factor-κB (RANK) ligand (RANKL) and osteoprotegerin (OPG) in vivo. These findings demonstrate that DMY attenuates bone loss and inhibits osteoclast formation and activity through modulation of multiple pathways both upstream and downstream of RANKL signaling. DMY may thus be a useful option for treatment of osteoclast-related diseases such as rheumatoid arthritis and osteoporosis.

    View details for DOI 10.3389/fphar.2017.00928

    View details for Web of Science ID 000418273500001

    View details for PubMedID 29311931

    View details for PubMedCentralID PMC5742133

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