Hematopoietic Stem Cells:
Hematopoietic stem cell (HSC) transplant was first successfully applied in 1959 when bone marrow cells were transplanted from the identical twin of a patient suffering from acute leukemia. The first successful HSC donor was subjected to twenty or more bone marrow aspirations on four separate occasions in order to yield sufficient cell numbers for the transplant. The discovery that granulocyte colony-stimulating factor (GCSF) can efficiently mobilize HSC from the bone marrow to the peripheral blood has made HSC donation a much less painful process and has facilitated the expansion of bone marrow registries. There are phenotypic differences between HSC of different sources. An HSC transplant, performed from peripheral blood HSC, repopulates the hematopoietic system more rapidly than transplanted bone marrow. Peripheral blood stem cells, however, confer increased risk of chronic GvHD (graftversus-host disease) when compared to bone marrow-derived cells. Adding further complexity, it appears that various stem cell sources perform differently in distinctive patient populations. While the vast majority of adult HSC transplantations are performed using peripheral blood stem cells mobilized with GCSF, because of their ease of harvest, pediatric patients have better outcomes when they receive bone marrow transplants, rather than HSC from peripheral blood. HSC transplantation is the only stem cell therapy widely used in clinical practice, despite extensive research to advance other stem cell populations into the clinic. Many of the lessons learned from HSC applications may help instruct new technologies as they continue to advance.
The presence of non-hematopoietic cells within the bone marrow was first demonstrated by Friedenstein et al in 1970’s (Friedenstein, 1974; Friedenstein, 1976). Fibroblast-like cells in the bone marrow were already suggested by observations made by Cohnheim, a German pathologist, in 1867, more than 140 years ago, where he described wound invasion by contractile cellular elements derived from leukocytes (Prockop, 1997). Friedenstein et al used a protocol that is still in use today to isolate multipotent marrow stromal cells from bone marrow. This protocol uses the ability of these cells to adhere to plastic, whereas hematopoietic stem cells were washed away after 4 hours. Heterogeneous cells from small colonies of 2 to 4 cells and remain dormant for some days. After this initial phase, colonies start to grow and cells proliferate and become homogeneously fibroblastic (Pittenger, 1999). In vitro, these cells can also form small deposits resembling bone or cartilage (Friedenstein, 1974; Friedenstein, 1976). MSC can differentiate into osteoblasts, chondrocytes, adipocytes and myoblasts in vitro (Friedenstein, 1987; Howlett, 1986; Keating, 1990; Wakitani, 1995). Due to their expansion and multilineage differentiation ex vivo, these cells were called mesenchymal stem cells. They were more recently renamed multipotent mesenchymal stromal cells, as of a consensus stated by the International Society for Cellular Therapy (Horwitz, 2005). The terminology “mesenchymal stem cells” should be used only for cells from primary tissues that can generate colony forming units-fibroblasts (CFU-F), and tissue
repopulation with multilineage differentiation in vivo (Horwitz, 2005).