**3. Mesenchymal stem cells: a historical outline**

The pathologist Cohnheim in 1867 could show the first evidence of nonhematopoietic stem cells in the bone marrow (BM) and their potency to be the source of fibroblasts involved in wound healing [50]. However, only a century later (50 years ago), the isolation and culture of these cells in an experimental condition successfully could be done. Friedenstein and his colleagues found that, when isolated cells from the rat bone marrow are cultured, a population of fibroblastic-shape nonhematopoietic cells that adhered to the plastic of the cell culture dish could be seen. Then these cells were called as a colonyforming unit fibroblast (CFU-F). These cells were capable of self-maintenance and multi-lineage differentiation like adipocytes, chondrocytes, and osteocytes in vitro and also could support hematopoietic stroma when a single cell was transplanted into animal models [51]. In 1988, Owen showed that a stromal system existed, with a stromal stem cell (CFU-F) at the base of the hierarchy, popularizing the stromal cell terminology [52]. Altogether, this information was generated from in vivo studies.

Only in 1992, Haynesworth and his colleagues enriched and expanded cells in culture with the osteochondrogenic potential of the human bone marrow [53]. In the early 1990s, the proliferation and differentiation potency of these cells in an experimental condition and also multipotency and self-renewal properties after transplantation lead to characteristics of the "stemness" [54]. Thus, the term mesenchymal stem cell (MSC) was proposed by Caplan for progenitor cells, which were isolated from the human adult bone marrow (BM) instead of the term "stromal" or "osteogenic" stem cell and acquired a broad recognition [55]. **Figure 1** shows the representation of the most imperative results related to MSC discovery, characterization, and clinical relevance.

#### **Figure 1.**

*Representation of the most significant findings associated with MSC discovery, description, and clinical purpose.*
