The mMSCs isolated from the inbred mice strains shared the characteristics of rapid proliferation as represented by the single colony forming ability of the low density plated cells when the mMSCs showed a nearly sevenfold increase in growth rate. The cells also differed in their optimal growth requiring media content. The cells showed variation in the surface epitope profiles.
Adult Stem Cells in Vascular Regeneration
The development of adult stem cells for clinical application has undergone a paradigm shift compared to the rest of the stem cell therapeutic approaches. The adult stem cells are present in the circulation, bone marrow, or within specific tissue types as residents. Neovascularization therapies have included mainly circulating or bone marrow derived stem cell approaches. The application of adult stem cells in the vasculogenesis was set up with the discovery of a subpopulation of vasculogenic endothelial progenitor cells (EPCs) by Asahara in 1997. The idea has gone on to be used in recent clinical trials. The commonly used surface markers for EPC identification include the markers that are not endothelial lineage specific like CDR10 and CD133.
The standardization of EPC culturing, purifying, and harvesting are not yet fully elucidated. Thus, methodological variation compounds semantic confusion. The EPCs may be considered a mixed population of different lineage of progenitor cells. True endothelial progenitors constitute this population of cells that gets incorporated within the vascular network while the secretion of angiogenic cytokines makes up the contribution of the hematopoietic progenitors. The EPCs give rise to “late outgrowth” or “early outgrowth” colonies in cell culture. Cells originating from the early outgrowth colonies express hematopoietic lineage markers and are quite evidently not of endothelial origin. These cells are different from the late outgrowth cells morphologically. The late outgrowth cells are reminiscent of endothelial cells and grow in a cobblestone like pattern. The early endothelial progenitor distinguishing surface markers are yet to be clearly established. The best possible approach for morphologically defining the endothelial lineage is by the use of tubulogenesis assays. In matrigel, the endothelial progenitors form tubular networks and get incorporated into the networks made by the differentiated endothelial cells. It has been generally accepted that the EPCs are formed from earlier progenitors known as hemangioblast that also act as the progenitors for hematopoietic stem cells. Pre-clinical studies have indicated that the EPCs circulate at very low levels in the blood (less than 0.01% of white circulating cells) and reside in the marrow (adhered to the stem cell niche constituting supporting stromal cells). Their presence in the blood changes with the type of stimuli. VEGF expression gets increased by ischemia resulting in the release of EPCs (CD34+/cKit+) by activating the matrix metalloproteinases and cleaving the kit-ligand. The EPCs so mobilized home to the ischemic site after entering the circulation. Ischemia mobilized bone marrow derived cells get incorporated within the vasculature and differentiate into pericytes, endothelial cells or smooth muscle cells. Besides, they may induce local angiogenesis through the paracrine factor elaboration. A number of animal studies including coronary- and hind limb-ischemia models suggest that the EPCs can be expanded and harvested ex vivo and administered to stimulate perfusion, capillary density, and organ function. In humans, G-CSF expanded peripheral blood mononuclear cells (PBMNCs) and autologous bone marrow mononuclear cells (BMNCs) have been contemplated for vascular regeneration in patients with peripheral and coronary arterial disease. Phase I and II trials are now completed with acute chronic ischemic and myocardial infarction patients. Currently, to substantiate the initial findings, several international Phase II trials are underway that can determine the efficacy and safety of the earlier results.
Application of Adult Stem Cell Therapy
Greater attention and controversy regarding stem cell therapy has mostly been in connection with embryonic stem cells, which are often difficult to procure and harvest. However, adult stem cells have recently been found to be applicable for therapeutic purposes, and a number of studies in this vein have followed confirming their therapeutic efficacy. Adult stem cells have been used to replace aging and damaged cells as they are present throughout the adult body, particularly in the bone marrow and blood, from which they can be harvested easily. The blood stem cells have been used in the treatment of leukemia and other cancers. However, owing to aggressive radiation or immune suppression so as to kill the cancer cells, the death rate is alarmingly high. Such treatment is thus regarded as extremely dangerous in cases of life-threatening diseases. It was estimated in a review by Burt et al. that the death rate was nearly 13 percent in patients who received aggressive bone marrow suppressing treatments.
While less aggressive treatments, such as non-myeloablative transplant, accounted for less than 1 percent of deaths. In cases of cancer, the best result is achieved with the use of less aggressive treatments that kill the cancer and are followed by transplantation of the highly purified blood adult stem cells. This approach has been tried in the treatment of a number of diseases, including cardiovascular ailments. However, the most important application of blood adult stem cells has been in the treatment of leukemia. Adult stem cells that have permanently settled within their niche in the bone marrow can be remobilized with the application of cytokines, such as leukocyte stimulating growth factors. It has been demonstrated that the granulocyte colony stimulating factor (GCSF) is the most commonly used stem cell mobilizing pharmaceutical agent. Such hematopoietic stem cells, when leaving their niche from the bone marrow for a small time interval, can be collected from the peripheral blood. The technique has now replaced surgical bone marrow harvesting in many clinical settings as it offers a similar quality of bone marrow stem cell collection but is less invasive for the donors. Such ease of bone marrow stem cell collection means that the stem cells can be used easily for therapeutic purposes in the necessary amounts.
Therefore, significant advances have been made in the field of blood adult stem cell isolation and the application of these stem cells for therapeutic purposes. A number of ongoing clinical trials point toward their successful implementation in the treatment of different, complicated diseases.
Syed Feroj Ahmed
CSIR–Indian Institute of Chemical Biology
See Also: Blood Adult Stem Cell: Development and Regeneration Potential; Blood Adult Stem Cell: Existing or Potential Regenerative Medicine Strategies; Leukemia and Lymphoma Cancer Stem Cells.
Further Readings
Bruserud, Oystein, et al. “New Strategies in the Treatment of Acute Myelogenous Leukemia: Mobilization and Transplantation of Autologous Peripheral Blood Stem Cells in Adult Patients.” Stem Cells, v.18/5 (2000).
Dimmeler, Stefanie, et al. “Cell-Based Therapy of Myocardial Infarction.” Arteriosclerosis Thrombosis and Vascular Biology, v.28/2 (2008).
Sekiya, Ichiro, et al. “Expansion of Human Adult Stem Cells From Bone Marrow Stroma.” Stem Cells, v.20/6 (2002).
Sumanasinghe Ruwan, D., et al. “Osteogenic Differentiation of Human Mesenchymal Stem Cells in Collagen Matrices.” Tissue Engineering, v.12/12 (2006).
Takayuki, Asahara and Atsuhiko Kawamoto. “Endothelial Progenitor Cells for Postnatal Vasculogenesis.” American Journal of Physiology Cell Physiology, v.287/3 (2004).
Blood Adult Stem Cell: Development and Regeneration Potential
Blood Adult Stem Cell: Development and Regeneration Potential
99
102
Blood Adult Stem Cell: Development and Regeneration Potential
Adult (somatic) stem cells are undifferentiated cells and have been found to exist in small numbers in almost all tissues and organs, even the heart and the brain. Although their origin in some tissues is still under investigation, their primary function is to maintain and repair the tissues in which they are found. They have generated a lot of excitement because of their potential for transplantation, as their sourcing would not be controversial, like that of embryonic stem cells.
Blood