Human osteogenic differentiation in Space: proteomic and epigenetic clues to better understand osteoporosis

Abstract

In the frame of the VITA mission of the Italian Space Agency (ASI), we addressed the problem of Space osteoporosis by using human blood-derived stem cells (BDSCs) as a suitable osteogenic differentiation model. In particular, we investigated proteomic and epigenetic changes in BDSCs during osteoblastic differentiation induced by rapamycin under microgravity conditions. A decrease in the expression of 4 embryonic markers (Sox2, Oct3/4, Nanog and E-cadherin) was found to occur to a larger extent on board the ISS than on Earth, along with an earlier activation of the differentiation process towards the osteogenic lineage. The changes in the expression of 4 transcription factors (Otx2, Snail, GATA4 and Sox17) engaged in osteogenesis supported these findings. We then ascertained whether osteogenic differentiation of BDSCs could depend on epigenetic regulation, and interrogated changes of histone H3 that is crucial in this type of gene control. Indeed, we found that H3K4me3, H3K27me2/3, H3K79me2/3 and H3K9me2/3 residues are engaged in cellular reprogramming that drives gene expression. Overall, we suggest that rapamycin induces transcriptional activation of BDSCs towards osteogenic differentiation, through increased GATA4 and Sox17 that modulate downstream transcription factors (like Runx2), critical for bone formation. Additional studies are warranted to ascertain the possible exploitation of these data to identify new biomarkers and therapeutic targets to treat osteoporosis, not only in Space but also on Earth.

Spaceflight Induced Disorders: Potential Nutritional Countermeasures

“…Role of miR-494 in the defect of osteogenesis (Qin et al, 2019). Effect of rapamycin in osteogenic differentiation (Gambacurta et al, 2019).…”

Guest Edited Collection: Gravitational biology and space medicine

“…The Guest Edited Collection ‘ Gravitational biology and space medicine ’ includes publications reporting on health concerns for astronauts and cosmonauts 14–16 during space missions, and physiological changes caused by short-term µ g 17 . Several studies investigating the impact of µ g on the behaviour and health of mice on the ISS were published in this Collection 18–23 , in addition to investigations at the cellular level in space 24 and in short-term µ g provided by PF maneuvers 25 . Moreover, cell studies in simulated (s-) µ g at ground-based facilities are included in this Collection 26–30 .…”

“…Gambacurta et al . 24 showed that rapamycin induces transcriptional activation of human blood-derived stem cells (BDSCs) towards osteogenic differentiation in space. These findings, applying proteomics and epigenetic methods, may represent the first step in identifying new biomarkers and therapeutic targets to treat osteoporosis in space and on Earth 24 .…”

Molecular Pharming to Support Human Life on the Moon, Mars, and Beyond

“…Current exploration medical capabilities are particularly vulnerable to this paradigm shift. The list of necessary supplies to address persistent exposures of space travel adds up quickly: includ ing countermeasures for increased radiation 3,4 , bone loss 5,6 , kidney stones 7,8 , vision impairment 9 , and adverse behavioral conditions 10 to name a few. The list of supplies begins to look unmanageab le when you add in intermittent, or even unanticipated, exposures such as microbial infection [11][12][13] , and implications of spaceflight-induced genome instability and metabolic changes 14 .…”