The impact of spaceflight on the immune system has been investigated extensively during spaceflight missions and in model experiments conducted on Earth. Data suggest that the spaceflight environment may affect the development of acquired immunity, and immune responses. Herein we summarize and discuss the influence of the spaceflight environment on acquired immunity. Bone marrow and the thymus, two major primary lymphoid organs, are evidently affected by gravitational change during spaceflight. Changes in the microenvironments of these organs impair lymphopoiesis, and thereby may indirectly impinge on acquired immunity. Acquired immune responses may also be disturbed by gravitational fluctuation, stressors, and space radiation both directly and in a stress hormone-dependent manner. These changes may affect acquired immune responses to pathogens, allergens, and tumors.

Runt-related transcription factor 2 (Runx2) is an essential transcriptional regulator of osteoblast differentiation and its haploinsufficiency leads to cleidocranial dysplasia because of a defect in osteoblast differentiation during bone formation through intramembranous ossification. The cellular origin and essential period for Runx2 function during osteoblast differentiation in intramembranous ossification remain poorly understood. Paired related homeobox 1 (Prx1) is expressed in craniofacial mesenchyme, and Runx2 deficiency in Prx1⁺-derived cells (Runx2_prx1^−/− mice) resulted in defective intramembranous ossification. Runx2 was heterogeneously expressed in Prx1-green fluorescent protein (GFP)⁺ cells located at the intrasutural mesenchyme in the calvaria of transgenic mice expressing GFP under the control of the Prx1 promoter. Double-positive cells for Prx1-GFP and stem cell antigen-1 (Sca1) (Prx1⁺Sca1⁺ cells) in the calvaria expressed Runx2 at lower levels and were more homogeneous and primitive as compared with Prx1⁺Sca1⁻ cells. Osterix (Osx) is another transcriptional determinant of osteoblast lineages expressed by osteoblast precursors; therefore, Osx is highly expressed by Prx1⁻Runx2⁺ cells at the osteogenic front and on the surface of mineralized bone in the calvaria. Runx2 deficiency in Osx⁺-derived cells (Runx2_osx^−/− mice) resulted in severe defects in intramembranous ossification. These findings indicate that the essential period of Runx2 function on intramembranous ossification would begin at the Prx1⁺Sca1⁺ mesenchymal stem cell stage and end at the Osx⁺Prx1⁻Sca1⁻ osteoblast precursor stage.

Bone marrow mesenchymal stem cells (MSCs) are critical regulators of postnatal bone homeostasis. Osteoporosis is characterized by bone volume and strength deterioration, partly due to MSC dysfunction. Cyclin-dependent kinase 8 (CDK8) belongs to the transcription-related CDK family. Here, CDK8 in MSCs was identified as important for bone homeostasis. CDK8 level was increased in aged MSCs along with the association with aging-related signals. Mouse genetic studies revealed that CDK8 in MSCs plays a crucial role in bone resorption and homeostasis. Mechanistically, CDK8 in MSCs extrinsically controls osteoclastogenesis through the signal transducer and transcription 1 (STAT1)-receptor activator of the nuclear factor κ Β ligand (RANKL) axis. Moreover, aged MSCs have high osteoclastogenesis-supporting activity, partly through a CDK8-dependent manner. Finally, pharmacological inhibition of CDK8 effectively repressed MSC-dependent osteoclastogenesis and prevented ovariectomy-induced osteoclastic activation and bone loss. These findings highlight that the CDK8-STAT1-RANKL axis in MSCs could play a crucial role in bone resorption and homeostasis.