Abstract
The selection of pluripotent stem cell (PSC)‐derived cells for tissue modeling and cell therapy will be influenced by their response to the tissue environment, including the extracellular matrix (ECM). Whether and how instructive memory is imprinted in adult ECM and able to impact on the tissue specific determination of human PSC‐derived developmentally fetal mesodermal precursor (P‐meso) cells is investigated. Decellularized ECM (dECM) is generated from human heart, kidney, and lung tissues and recellularized with P‐meso cells in a medium not containing any differentiation inducing components. While P‐meso cells on kidney dECM differentiate exclusively into nephronal cells, only beating clusters containing mature and immature cardiac cells form on heart dECM. No tissue‐specific differentiation of P‐meso cells is observed on endoderm‐derived lung dECM. P‐meso‐derived endothelial cells, however, are found on all dECM preparations independent of tissue origin. Clearance of heparan‐sulfate proteoglycans (HSPG) from dECM abolishes induction of tissue‐specific differentiation. It is concluded that HSPG‐bound factors on adult tissue‐derived ECM are essential and sufficient to induce tissue‐specific specification of uncommitted fetal stage precursor cells.
Highlights
The results show that Decellularized ECM (dECM) retains distinct tissue-specific memory, which is imprinted in adult extracellular matrix (ECM)-decorating heparin-binding growth factors and act on immature embryonic stage precursor cells
The use of ECM as a bioactive matrix for cells in vitro and in vivo is based on its interactive properties and tissue-specific imprints, which are recognized as cues by cells to adopt tissuespecific phenotypes
The addition of differentiation-inducing factors in the culture media, and the use of non-human and non-standardized dECM preparations made it difficult to distinct the role of the ECM in the observed organotypic determination.[24,25]
Summary
The mesodermal markers-expressing hiPSC-derived P-meso cells arise early in human embryogenesis and are plastic mesendodermal precursor cells committed to develop into a wide range of mesodermal cell types, including muscle, kidney, endothelia, and connective tissues We posited that these cells are better suited than pluripotent cells or further tissue committed renal, cardiac, or endothelial precursor cells to elucidate the influence of adult ECM on cellular plasticity. Immunostaining for markers of differentiated renal or cardiac cells did not show expression on the respective kidney and heart dECM-HSPG on day 7 or day 14 (Figure 6; Figure S6, Supporting Information) This revealed that ECM-inductive cues essential for renal and cardiac lineage differentiation and organizational patterning are dependent on HSPG and factors bound to HS. Ex vivo or in situ ECM-modulation and cell stage selection could improve stem cell integration and stem cell based repair in such compromised tissues, and our model provides new means for in vitro testing of such applications
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