Myocardial infarction is a leading cause of mortality. While advances in the acute treatment have been made, the late-stage mortality is still high, driven by an incomplete understanding of cardiac remodeling processes1,2. Here we used single-cell gene expression, chromatin accessibility and spatial transcriptomic profiling of different physiological zones and timepoints of human myocardial infarction and human control myocardium to generate an integrative high-resolution map of cardiac remodeling. This approach allowed us to increase spatial resolution of cell-type composition and provide spatially resolved insights into the cardiac transcriptome and epigenome with identification of distinct cellular zones of injury, repair and remodeling. We here identified and validated mechanisms of fibroblast to myofibroblast differentiation that drive cardiac fibrosis. Our study provides an integrative molecular map of human myocardial infarction and represents a reference to advance mechanistic and therapeutic studies of cardiac disease.

Human adult mesenchymal stem cells (hMSC) are particularly suitable cells for autologous tissue engineering and cell-based therapies. They can be isolated from various tissues, such as bone marrow, adipose tissue, dental pulp or umbilical cords. Due to their primitive developmental stage, umbilical cord-derived hMSC are assumed to have a higher proliferation and differentiation capacity than hMSC from adult tissues. We isolated hMSC from bone marrow (BM) and umbilical cords (UC) and compared the cells regarding their surface epitopes, proliferation and differentiation capacity.Flow cytometry of specific surface epitopes showed that both BM-MSC and UC-MSC display the characteristic MSC phenotype. Cells from both sources were readily differentiated into adipocytes, osteoblasts and chondrocytes according to standard protocols. Interestingly, only UC-MSC spontaneously formed three-dimensional aggregates when cultured under post-confluent conditions. The cells of these aggregates were viable and spontaneously differentiated into several specialized cell types akin to the well-known differentiation of embryoid bodies. Besides, UC-MSC expressed the pluripotency-associated gene NANOG as well as genes characteristic for the mesodermal and ectodermal fate. Thus, UC-MSC resemble BM-MSC but additionally show a spontaneous embryoid body-like aggregation and differentiation in vitro. These results indicate that UC-MSC are less restricted than BM-MSC and may thus extend the limits of BM-MSC based therapies. Citation: Adamzyk C, Labude N, Schneider RK, et al. Human umbilical cord-derived mesenchymal stem cells spontaneously form 3d aggregates and differentiate in an embryoid body-like manner. Keywords

Stem cells reside in a highly specialized, complex microenvironment that is known as the stem cell niche. The stem cell niche can be described as an anatomically defined space where the stem cell is localized and nourished and stem cell quiescence, proliferation and differentiation are maintained. Tissue engineering aims to imitate the stem cell niche to (I) induce a directed differentiation, (II) maintain the self-renewal capacity or (III) find a regulated balance between self-renewal and differentiation. Mesenchymal stem or stromal cells (MSC) can differentiate in three-dimensional collagen gels into functional osteoblasts when subjected to a phosphate-rich cultivation medium. Furthermore, they acquire a prosynthetic, matrix remodeling, contractile phenotype. Medial artery calcification in patients with chronic kidney disease also proceeds through intramembranous ossification resulting from osteoblast-induced calcification of the collagen extracellular matrix. Thus, the influence of uremic cultivation conditions as a pathophysiological stimulus on MSC and endothelial cells was analyzed with special regards to matrix remodeling, vascularization and calcification. The results showed that BMP-2/4 mediated MSC (mal)differentiation into osteoblasts with acquired matrix remodeling phenotype and loss of proangiogenic capacity. These studies have led to the conclusion that uremia has detrimental effects on the stem cell niche and promotes the continuous calcification by osteogenic (mal)differentiation. In summary, recent studies have shown the conducting and regulating effect of the stem cell niche under physiological conditions that can be applied and mimicked for tissue engineering applications. However, under pathological conditions the stem cell niche can have detrimental effects on stem cell function and can promote disease progression.

The data support the theory that MSC are involved in tissue regeneration both via their differentiation capacity and their trophic characteristics. We identified different MSC/biomaterial combinations which are suitable for stem cell-based bone tissue engineering.