A fascinating new paper by Deepa Bhartiya and colleagues from the Stem Cell Facility at the All India Institute of Medical Sciences in New Delhi, India hits upon a crucial problem with the way we presently make bone marrow extracts for stem cell treatments. This paper is scheduled to be published in the journal Stem Cells and Development, and the “epub” version of it has hit the web.
Bone marrow contains a wide variety of cells that have a wide range regenerative abilities. For example, the most well-characterized cell in bone marrow is the hematopoietic stem cell, which makes all the blood cells that presently circulate throughout our bodies. This blood-making stem cells can sometimes go awry and divide uncontrollably and form blood-based tumors called leukemias. Another stem cell found in bone marrow is the mesenchymal stem cell, which is part of the “stroma.” Stroma is a filigree of cells and extracellular tissue that acts as a scaffold for bone marrow. Also in bone marrow are the endothelial progenitor cells or EPCs. EPCs make blood vessels and can home to damaged tissue to help them form new blood vessels during healing. There are also a host of less well-characterized cells that are found in lower numbers in bone marrow, but may have tremendous regenerative potential. For example, marrow-isolated adult multilineage-inducible (MIAMI) stem cells can reduce inflammation, make new blood vessels and reduce necrosis (cell death) in laboratory animals that have injured limbs (see Rahnemai-Azar A, et al, Cytotherapy.2011 Feb;13(2):179-92). Also multipotent adult progenitor cells (MAPCs), which can also sustain the function of damaged limbs that have been deprived of oxygen (Aranguren XL, et al. J Clin Invest. 2008;118(2):505-14), help heal skin lesions (Herdrich BJ, Lind RC, Liechty KW. Cytotherapy. 2008;10(6):543-50), and can help suppress graft-versus-host disease (Highfill SL, et al. Blood. 2009;114(3):693-701), and VSELs or Very Small Embryonic-Like Cells. VSELs have remarkable regenerative abilities in mice (Wojakowski W. J Cardiovasc Transl Res.2011;4(2):138-44), and because these cells have been found in humans, there are high hopes for their use in human regenerative medicine (Zuba-Surma EK, et al. Cytometry A.2009 Jan;75(1):4-13).
According to Bhartiya et al., bone marrow contain VSELs, but the manner in which bone marrow is prepared for stem cell treatments, the VSELs are lost. As it turns out, the very small size of these cells causes their separation from the remaining stem cell populations during isolation. This means that one of the most potent cells in bone marrow is not present when bone marrow is used in stem bone marrow-based clinical trials.
This throws an entire new light on many bone marrow-based experiments. In particular. cardiac patients who have had bone marrow transplants from their own bone marrow. Some trials are positive, but a few are negative, and there has been a great deal of work to show that manner in which the bone marrow is isolated makes a difference. Others have argued that the manner in which the bone marrow was isolated in the negative studies is exactly the same way bone marrow is isolated when it is to be used in a bone marrow transplant. However in bone marrow transplants, the blood-making stem cells is the most important cell for the success of that procedure, not the VSELs. In the case of heart treatments, it is clear that the blood-making stem cell is not the most important cell.