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 stem cells, also known as hematopoietic stem cells (HSCs), were the first stem cells to be identified. They are located in the bone marrow of the femur, pelvis, the vertebrae, and the rib cage. They can also be extracted from peripheral blood, umbilical cord blood (UCB), and the placenta. These stem cells differentiate into all types of blood cells in the body; they may be required to produce more than 500 billion of these cells daily. This demonstrates the multipotency as well as extensive self-renewal capacity of the blood stem cells. HSCs are located in a specific “stem cell niche” in the bone marrow.
The stem cells may go through various stages, such as quiescence, self-renewal, differentiation, or apoptosis, with these processes being controlled by the internal environment of the cells themselves. Experiments have identified GRP94, an endoplasmic reticulum chaperone, as an intrinsic factor present in the HSCs, which is required to maintain them within the niche. It also plays a role in regulating early T- and B-cell lymphopoiesis. However, it is now suspected, according to the niche hypothesis, that the microenvironment of the niche also plays a role in the maturation of the HSCs. In fact, the latest research suggests that bone cells (osteoblasts and osteocytes) may not only regulate the microenvironment of the niche but also modulate immune cell differentiation.
It is now possible to induce these stem cells to move into the bloodstream, from where they can be easily harvested and genetically modified. This strategy has been successfully used for the treatment
