The concept of stem cell plasticity or trans-dedifferentiation created a high degree of hope, excitement, and later on some disappointment. The reason for this was an assumption that hematopoietic stem cells (HSC) isolated from relatively easily accessible sources such as bone marrow (BM), mobilized peripheral blood, or cord blood, could be subsequently employed as precursors for other stem cells necessary for regeneration of various solid organs (e.g., heart, brain, liver, or pancreas). In all of these deliberations concerning stem cell plasticity the concept that BM may contain heterogeneous populations of stem cells was surprisingly not taken carefully enough into consideration. We postulate that the regeneration studies that show the contribution of donor-derived HSC to tissues without excluding this possibility by not including the proper controls, could lead to the wrong interpretations. Thus, the presence of heterogeneous populations of stem cells in BM tissue should be considered first; before experimental evidence is interpreted simply as trans-dedifferentiation/plasticity of HSC. In this paper we presented evidence that BM cells are heterogeneous.

As indicated above, the paper describes a new strategy to identify and isolate non-hematopoietic stem cells from BM. We found that these cells, similarly as HSC, express CXCR4 and respond to an SDF-1 gradient; however, in contrast to HSC, these cells are CD45 negative. We provided data, both at the mRNA and protein level, that BM contains, in addition to HSC, a population of heterogeneous tissue-committed stem/progenitor cells (TCSC). Some of these cells possess markers which are characteristic of pluripotent stem cells. Another important observation is that these cells, similarly as HSC, could be mobilized from the BM into peripheral blood in situations of stress and, via the blood stream, may reach distinct organ locations to contribute to tissue repair/regeneration.

I have a long-standing interest in stem cell research. I was trained as a bone marrow transplantologist and was involved for many years in research aimed at developing new optimal strategies to expand HSC for clinical applications. The concept of stem cell trans-dedifferentiation was for me, from the beginning, somehow against the physiology of the stem cell compartment. Thus, my team began to work on an alternative explanation of this phenomenon that was reported by some investigators a few years ago. This was our first paper in which we presented evidence that bone marrow cells are heterogeneous and this fact may explain all of the controversial data on plasticity of HSC that accumulated in the literature.

Mankind is searching for a key to longevity and there is no doubt that stem cells could be an important answer to this problem. The concept of stem cell plasticity or trans-dedifferentiation created a high degree of hope and excitement. The supporters of stem cell plasticity postulated that stem cells isolated from easily accessible sources, such as bone marrow tissue, can be trans-dedifferentiated to stem cells for other organs (e.g., liver, pancreas, neural tissue, skeletal muscles, or heart). Thus HSC isolated from bone marrow could be employed for all types of tissue repair/regeneration. After the first optimistic reports, these promising results were not confirmed by other investigators. To solve these obvious discrepancies in the field, we proposed an alternative explanation of the plasticity of bone marrow-derived cells. We provided evidence that bone marrow, in addition to HSC, contains an admixture of very rare tissue-committed stem/progenitor cells— for liver, pancreas, neural tissue, skeletal muscles, or heart—which in some experimental models gave a "false" impression that HSC changed their tissue commitment. It is an important observation which questions the concept of stem cell plasticity and points out that we should consider other sources of stem cells for tissue repair and regeneration (e.g., embryonic stem cells).