A new study tracking human stem-cell-derived cardiovascular progenitors inside injured pig hearts has identified a molecular signal that may help explain how transplanted cells promote repair after a heart attack. The research, published in Nature Cardiovascular Research, uses time-series spatial transcriptomics to follow human cells and their surrounding pig tissue over time. The work reveals that the grafted cells do more than simply survive in the damaged myocardium: they progressively activate genetic programs linked to cardiac maturation, energy production, calcium regulation and the resolution of fibrosis. The study also points to Midkine, or MDK, a secreted growth factor produced by the human cells, as a potential driver of new blood-vessel formation in ischemic heart tissue.
Heart attacks destroy cardiomyocytes and disrupt the vascular network that supplies oxygen to the heart muscle. Because adult human cardiomyocytes have limited regenerative capacity, researchers have investigated whether cells produced from human pluripotent stem cells could restore damaged tissue or stimulate the heart’s own repair mechanisms. Cardiovascular progenitors are particularly attractive for this purpose because they can develop toward several heart-related lineages, including muscle, vascular and supportive stromal cells. Yet the behavior of transplanted cells after they are delivered into a living heart remains difficult to observe. Conventional molecular analyses often require tissue to be removed and homogenized, erasing the precise locations of cells and the interactions taking place between the graft and the host.
The team addressed this challenge by applying spatial transcriptomics at multiple time points after transplantation into a pig model of myocardial infarction. Spatial transcriptomics combines gene-expression profiling with positional information, allowing researchers to determine not only which genes are active but also where those genes are being expressed within a tissue section. In this study, the approach enabled the investigators to distinguish human xenograft signals from the surrounding porcine myocardium and to examine how both compartments changed as healing progressed. Instead of producing a single molecular snapshot, the time-series design provided a dynamic view of engraftment, revealing how the transplanted progenitors adapted to the hostile, oxygen-poor and fibrotic environment of an infarcted heart.
The analysis showed that the human cardiovascular progenitors gradually increased expression of genes associated with a more mature cardiac state. These included programs involved in oxidative metabolism, the process by which cells generate energy efficiently through mitochondrial respiration. The grafted cells also upregulated genes linked to calcium handling, a central function in cardiac contraction because calcium ions regulate the interaction between contractile proteins inside muscle cells. Such changes suggest that the transplanted progenitors were not remaining in an undifferentiated state. Instead, they appeared to be responding to the cardiac environment and moving toward a phenotype better suited to functioning within heart tissue.
The molecular data also indicated a shift in pathways related to fibrosis. Following myocardial infarction, excessive deposition of extracellular matrix proteins can stiffen the ventricular wall and interfere with electrical conduction and contraction. Although scar formation initially helps prevent the injured heart from rupturing, persistent fibrosis can contribute to long-term heart failure. The observed activation of gene programs associated with fibrosis resolution suggests that the grafted cells may influence the remodeling of the scar environment, either directly or through signals exchanged with host cells. The findings do not establish that the transplanted progenitors alone remove scar tissue, but they provide evidence that their presence is associated with a tissue environment moving toward repair rather than continued damage.
To identify the signals responsible for communication between the human graft and the pig heart, the researchers performed cell–cell communication analysis. This computational strategy examines ligand–receptor relationships: molecules released by one cell type are matched with receptors expressed by another, allowing scientists to predict which cellular conversations may be biologically important. Among the candidate signals, Midkine emerged as a prominent regulator connected to host neovascularization. MDK is a secreted growth factor involved in cell survival, migration and tissue remodeling. In the context of an infarcted heart, its production by the human progenitors suggested a mechanism through which transplanted cells could act at a distance, stimulating neighboring host cells rather than needing to become large numbers of new cardiomyocytes themselves.
The investigators then tested the MDK hypothesis experimentally. Immunohistochemistry was used to examine protein-level patterns in the tissue, providing an independent validation of the transcriptomic findings. They also used lentiviral gene delivery to increase MDK expression in the relevant cells and conducted functional assays to determine whether the factor altered endothelial behavior. Endothelial cells form the inner lining of blood vessels, and their ability to migrate is a key early step in angiogenesis. The experiments demonstrated enhanced endothelial cell migration when MDK activity was increased. In transplanted hearts, MDK overexpression was associated with greater density of CD31-positive vessels, with CD31 serving as a commonly used marker of endothelial cells and vascular structures.
These results place neovascularization at the center of the graft’s therapeutic activity. Restoring blood flow is crucial after infarction because surviving cardiomyocytes at the edge of the injury remain vulnerable to oxygen deprivation. New or remodeled vessels can improve nutrient delivery, remove metabolic waste and create conditions that support tissue stabilization. The findings suggest that human cardiovascular progenitors may function as biological signal generators, releasing factors such as MDK that recruit or activate the host’s own endothelial cells. This paracrine mechanism may be as important as, or potentially more important than, the direct replacement of lost heart muscle. It also creates a possible therapeutic strategy in which MDK or related pathways are targeted to promote vascular repair.
The study’s use of a pig model is significant because porcine hearts resemble human hearts in size, anatomy and aspects of cardiac physiology more closely than many small-animal systems. At the same time, the work remains preclinical. A higher density of CD31-positive structures indicates increased vascularization, but future studies will need to determine whether those vessels are fully functional, carry effective blood flow and improve measurable cardiac performance over the long term. Researchers will also need to assess the durability, safety and electrical behavior of the grafted cells, as well as the potential consequences of altering MDK activity in other organs. The immune response to human cells in a large-animal setting and the reproducibility of the treatment will be important considerations before clinical translation.
To make the extensive dataset accessible, the researchers have created a publicly available interactive Shiny atlas containing spatial and temporal transcriptomic information from pig hearts affected by myocardial infarction and treated with human xenografts. Interactive resources of this kind allow investigators to explore gene-expression patterns across tissue regions and recovery stages without relying solely on static figures. The atlas may help other groups compare candidate pathways, examine host–graft interactions and generate new hypotheses about cardiac repair. Together, the study and its accompanying resource offer a detailed molecular timeline of transplanted cardiovascular progenitors in an injured heart, while identifying MDK as a tractable target for therapeutic angiogenesis. The work shifts attention from asking only whether stem-cell grafts survive to understanding how they communicate with damaged tissue and recruit the body’s own repair machinery.
Subject of Research: Human pluripotent stem-cell-derived cardiovascular progenitors transplanted into infarcted pig hearts, with a focus on host–graft communication and MDK-mediated neovascularization.
Article Title: Spatiotemporal transcriptomics of human cardiovascular progenitors in pig hearts identifies Midkine as a positive regulator of neovascularization.
Article References: Adusumalli, S., Leong, K.S., Lim, S. et al. “Spatiotemporal transcriptomics of human cardiovascular progenitors in pig hearts identifies Midkine as a positive regulator of neovascularization.” Nature Cardiovascular Research 5, 744–762 (2026). https://doi.org/10.1038/s44161-026-00851-1
Image Credits: AI Generated
DOI: August 2026
Keywords: stem cell therapy, cardiac repair, myocardial infarction, spatial transcriptomics, cardiovascular progenitors, Midkine, MDK, neovascularization, angiogenesis, endothelial cells, pig model, regenerative medicine
