SUMMARY Cardiac differentiation of human pluripotent stem cells (hPSCs) requires orchestration of dynamic gene regulatory networks during stepwise fate transitions, but often generates immature cell types that do not fully recapitulate properties of their adult counterparts, suggesting incomplete activation of key transcriptional networks. We performed extensive single-cell transcriptomic analyses to map fate choices and gene expression programs during cardiac differentiation of hPSCs, and identified strategies to improve in vitro cardiomyocyte differentiation. Utilizing genetic gain- and loss-of-function approaches, we found that hypertrophic signaling is not effectively activated during monolayer-based cardiac differentiation, thereby preventing expression of HOPX and its activation of downstream genes that govern late stages of cardiomyocyte maturation. This study therefore provides a key transcriptional roadmap of in vitro cardiac differentiation at single-cell resolution, revealing fundamental mechanisms underlying heart development and differentiation of hPSC-derived cardiomyocytes.

Long-term bisphosphonate therapy may increase the risk of unusual long bone mid-shaft fractures. This is probably due to prolonged suppression of bone turnover, which could lead to accumulation of microdamage and development of hypermineralized bone. At present, the scope of this complication in the larger context of patients receiving bisphosphonate therapy remains unknown, but appears to be small.

Better understanding of the physiological role of the vitamin-D system, in particular its potential effects on inflammatory and autoimmune conditions as well as on insulin secretion and possibly also on insulin resistance, increased the interest in its potential role in prevention and control of the diabetic condition, both type-1 and -2 diabetes. Both these conditions are associated with inflammation and type-1 diabetes also with an autoimmune pathology. Indeed, animal and human studies support the notion that adequate vitamin-D supplementation may decrease the incidence of type-1 and possibly also of type-2 diabetes mellitus and may improve the metabolic control in the diabetes state. However, the exact mechanisms by which vitamin-D and calcium supplementation exert their beneficial effects are not clear and need further investigation.

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