Cell Therapy Institute, Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University (PMU), 5020 Salzburg, Austria.
Berlin Institute of Health at Charité - Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), T Cell Epigenetics, Augustenburger Platz 1, 13353 Berlin, Germany.
Sci Transl Med. 2023 Mar 22;15(688):eabm7477. doi: 10.1126/scitranslmed.abm7477.
Multipotent stromal cells are considered attractive sources for cell therapy and tissue engineering. Despite numerous experimental and clinical studies, broad application of stromal cell therapeutics is not yet emerging. A major challenge is the functional diversity of available cell sources. Here, we investigated the regenerative potential of clinically relevant human stromal cells from bone marrow (BMSCs), white adipose tissue, and umbilical cord compared with mature chondrocytes and skin fibroblasts in vitro and in vivo. Although all stromal cell types could express transcription factors related to endochondral ossification, only BMSCs formed cartilage discs in vitro that fully regenerated critical-size femoral defects after transplantation into mice. We identified cell type-specific epigenetic landscapes as the underlying molecular mechanism controlling transcriptional stromal differentiation networks. Binding sites of commonly expressed transcription factors in the enhancer and promoter regions of ossification-related genes, including Runt and bZIP families, were accessible only in BMSCs but not in extraskeletal stromal cells. This suggests an epigenetically predetermined differentiation potential depending on cell origin that allows common transcription factors to trigger distinct organ-specific transcriptional programs, facilitating forward selection of regeneration-competent cell sources. Last, we demonstrate that viable human BMSCs initiated defect healing through the secretion of osteopontin and contributed to transient mineralized bone hard callus formation after transplantation into immunodeficient mice, which was eventually replaced by murine recipient bone during final tissue remodeling.
多能基质细胞被认为是细胞治疗和组织工程有吸引力的来源。尽管有许多实验和临床研究，但基质细胞治疗的广泛应用尚未出现。一个主要的挑战是可用细胞来源的功能多样性。在这里，我们研究了来自骨髓（BMSCs）、白色脂肪组织和脐带的临床相关人类基质细胞与成熟软骨细胞和皮肤成纤维细胞在体外和体内的再生潜力。尽管所有基质细胞类型都可以表达与软骨内骨化相关的转录因子，但只有 BMSCs 在体外形成软骨盘，在移植到小鼠后完全再生了关键性股骨缺损。我们确定了细胞类型特异性的表观遗传景观，作为控制转录基质分化网络的潜在分子机制。普遍表达的转录因子在骨形成相关基因的增强子和启动子区域的结合位点，包括 Runt 和 bZIP 家族，仅在 BMSCs 中可及，而在 extraskeletal 基质细胞中不可及。这表明存在一种依赖于细胞起源的预先确定的分化潜力，允许常见的转录因子触发不同的器官特异性转录程序，从而促进再生能力细胞来源的正向选择。最后，我们证明了可行的人类 BMSCs 通过分泌骨桥蛋白启动了缺陷愈合，并在移植到免疫缺陷小鼠后有助于短暂的矿化骨硬痂形成，最终在最终的组织重塑过程中被小鼠受体骨取代。
