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  1. Paracrine effects of haematopoietic cells on human mesenchymal stem cells. Zhou S. Sci. Rep. 2015; 5:10573. https://doi.org/10.1038/srep10573
    This manuscript dissects the interactions of hematopoietic stem cells (HSCs) and stromal cells (MSCs) in human marrow. Although products of the HSCs support proliferation, differentiation, and rejuvenation of MSCs, the innate inflammogen, TNF-α, is elevated in HSCs from elders and counteracts their beneficial effects on MSCs. Thus, in vivo immunosenescence of HSCs contributes to the age-related decline in MSC proliferation and differentiation. These findings support the reduction of inflammatory mediators in adults by diet, exercise, and agents.
  2. Vitamin D metabolism and regulation in pediatric MSCs. Ruggiero B, Padwa BL, Christoph KM, Zhou S, Glowacki J. J Steroid Biochem Mol Biol. 2016;164:287-91. https://doi.org/10.1016/j.jsbmb.2015.09.025
    This study with pediatric MSCs shows the feasibility of research with cells from children and revealed that vitamin D metabolism takes place in those MSCs and is regulated as in cells from adults. Finding vitamin D biosynthesis in MSCs indicates the importance of vitamin D status for skeletal health.
  3. Dehydroepiandrosterone stimulation of osteoblastogenesis in human MSCs requires IGF-I signaling. Liang X, Glowacki J, Hahne J, Xie L, LeBoff MS, Zhou S. J Cell Biochem  2016;117:1769-7.  https://doi.org/10.1002/jcb.254754
    DHEA is the most abundant hormone in the human circulation and declines with age.  This study examines its osteoanabolic effects on MSCs from elders.  DHEA stimulated osteoblast differentiation in a dose/response manner. The action required intracellular IGF-I signaling with multiple mechanisms and may be safer than direct use of IGF-I or other agents that through IGF-I to promote bone formation.
  4. Synergistic effect of 1α,25-dihydroxyvitamin D3 and 17β-estradiol on osteoblast differentiation of pediatric MSCs. Li J, Padwa BL, Zhou S, Mullokandova J, LeBoff MS, Glowacki J.  J Steroid Biochem Mol Biol. 2018;177:103-8.  https://doi.org/10.1016/j.jsbmb.2017.07.032
    This manuscript with MSCs from pre-pubertal subjects describes the unexpected synergy of low doses of 1α,25-dihydroxyvitamin D3 and 17β-estradiol to stimulate osteoblast differentiation in hMSCs. It reveals the mechanism that each agent upregulates the receptor for the other and indicates that it may be possible to use safer, low doses of potent sex hormones to stimulate bone formation while reducing systemic risks.
  5. DHEA and bone. Zhou S, Glowacki J. Vitamin Hormones 2018;108:251-71. https://doi.org/10.1016/bs.vh.2018.01.005
    This invited review concerns the positive effects of the adrenal hormone, dehydroepiandrosterone (DHEA) on bone and its role in osteoporosis. DHEA is important in skeletal aging because its concentration in blood decreases with age. This paper reveals that the mechanism of DHEA stimulation of hMSCs requires insulin-like growth factor-I (IGF-I) and its signaling pathways. It also shows how DHEA inhibits hMSC secretion of IL-6, a potent bone resorbing agent. This paper concludes that restoration of DHEA should be considered in treating bone diseases and aging through its two important effects – stimulation of anabolic IGF-I and inhibition of skeletal catabolic IL-6.
  6. Chronic kidney disease and vitamin D metabolism in human bone marrow-derived MSCs. Zhou S, Glowacki J. Ann N Y Acad Sci. 2017;1402:43-55. https://doi.org/10.1016/bs.vh.2018.01.005
    This invited review summarizes the latest information about vitamin D metabolism in MSCs, its regulation, similarities with renal biosynthesis of active vitamin D, effects of age, and the discovery of dysregulation in MSCs from subject with impaired kidney function.  Our studies indicate that MSC from subjects with high, healthy eGFR levels show greater osteoblast differentiation in vitro.  MSCs from subjects with lower eGFR values would be expected to be less useful for tissue engineering applications.
  7. Megalin mediates 25-hydroxyvitamin D actions in human mesenchymal stem cells. Gao Y, Zhou S, Luu S, Glowacki J.  FASEB J. 2019;33:7684-93.  https://doi.org/10.1096/fj.201802578
    This manuscript identifies the cell membrane receptor, megalin as essential for the complex of 25(OH)-vitamin D and the D binding protein to stimulate hMSCs and refutes the current dogma that only “free” (unbound) vitamin D is active. Experiments show a range of constitutive expression of megalin in MSCs, with the highest levels being associated with greater stimulation of osteoblastogenesis by 25(OH)-vitamin D. Variable expression of megalin may account for differential responses of subjects to vitamin D therapy, especially in fracture prevention trials.
  8. Clinical variables that influence properties of human mesenchymal stromal cells. Glowacki J, Alm JJ, Zhou S. Rengen Engin Transl Med.  IN PRESS.
    This paper concerns the use of MSC for tissue engineering applications and summarizes the data identifying the clinical variables that are associated with reduced potential for osteoblast differentiation.  Patients likely to benefit from bone tissue engineering are likely to have cellular deficits. Advanced age, vitamin D-deficiency, impaired kidney status, and osteopenia are associated with reduced MSC functions.  Obesity and certain medications are associated with improved MSC activities. Some deficits are modifiable and can be managed systemically or by treated the MSCs in vitro. These studies indicate a number of ways to optimize MSCs, some of which are reported in the following manuscripts.
  9. Fibroblast growth factor 23 counters vitamin D metabolism and action in human mesenchymal stem cells. Meng F, Bertucci C, Gao Y, Li J, LeBoff MS, Glowacki J, Zhou S. J Steroid Biochem Mol Biol.  IN PRESS.
    This manuscript identifies a mechanism by which Chronic Kidney Disease (CKD) impairs osteoblast differentiation. Orthopedic patients without known diagnosis of CKD showed a significant correlation between eGFR and in vitro osteoblast differentiation potential of their MSCs. Elevated serum FGF23 is an early marker of kidney impairment and directly impairs the beneficial in vitro effects of vitamin D in hMSCs. Similar to its effects on kidney cells, FGF23 reduced vitamin D activating enzymes and osteoblast stimulation by vitamin D metabolites. These findings stress the importance of vitamin D sufficiency for skeletal health, especially for individuals with chronic kidney disease.
  10. Obesity and leptin influence vitamin D metabolism and action in human marrow stromal cells. Li J, Gao Y, Lange JK, LeBoff MS, Gorska A, Luu S, Zhou S, Glowacki J. J Steroid Biochem Mol Biol. IN PRESS
    Obesity is associated with high serum levels of leptin, produced by fat  cells, and increased bone density.  MSCs from obese subjects showed significantly higher constitutive expression of the 25-hydroxylase and the vitamin D receptor (VDR), suggestive of greater responsiveness to vitamin D actions. We modeled that situation in vitro by treating MSCs from non-obese subjects with leptin. There was a dose-dependent increase in VDR and 25-hydroxylase, as well as in 1α-hydroxylase and in osteoblast differentiation.  There was a synergistic effect of leptin with vitamin D metabolites to stimulate osteoblastogenesis, which was explained by each hormone upregulating the receptor for the other. These studies support the use of leptin or an analog to promote bone formation.
  11. Antimicrobial CAMP/LL-37 is upregulated by vitamin D metabolites in human mesenchymal stem cells. Glowacki J, Gao Y, Luu S, Zhou S. 
    This report describes the discovery that the potent antimicrobial (bacteria, mycobacteria, viruses, fungi, parasites) peptide is expressed in human MSCs from many but not all subjects. Further, it is rapidly stimulated upon exposure of the cells to endotoxin, a surrogate for bacterial infection, and upon treatment with vitamin D metabolites. These novel findings suggest that bone marrow cells may contribute to infection resistance. As a bone infection, i.e. osteomyelitis, is notoriously difficult to treat, it may be possible to enlist MSCs to attenuate or eliminate the infectious agents by systemic treatment with vitamin D.

FUNDING and FUTURE DIRECTIONS

Research supported by the Stepping Strong Center formed the basis for two pending grant applications:

One pending application concerns a clinical test of the hypothesis that administration of vitamin D to orthopedic patients can reduce post-operative or post-fracture infections (Reference #11). For ease of subject recruitment, the first phase will concern elective joint replacement subjects.      

The second pending grant application builds upon our research with pediatric MSCs (References #2 and 4). It tests the hypothesis that MSCs from children undergoing the skeletal growth spurt associated with puberty are activated by novel factors that could be deployed safely in MSCs from elders and thus optimize fracture healing, prevent age-related bone loss, or manage other skeletal deficiencies. Pilot bioinformatics experiments with pediatric plasma (proteomics) and MSC RNA (RNAseq) showed the feasibility of this concept and revealed several interesting molecules that may be of importance in mediating the pubertal growth spurt and that showed age-related declines.

New funding will be sought to support a large animal study on the effectiveness of two classes of small molecules we showed to stimulate bone healing in mice. Partners holds our Intellectual Property for these agents and seeks licensing or partnerships for this effort.

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