Korean J Hematol 2010; 45(4):
Published online December 31, 2010
https://doi.org/10.5045/kjh.2010.45.4.219
© The Korean Society of Hematology
Director, Catholic High-Performance Cell Therapy Center, The Catholic University of Korea, Seoul, Korea.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Historical studies have shown that bone marrow contains non-hematopoietic cells in addition to hematopoietic cells. The non-hematopoietic cells adhere to plastic dishes and can differentiate into mesenchymal tissues such as osteoblasts, chondrocytes, adipocytes, or myoblasts, and are hence referred to as mesenchymal stem cells. However, the unfractionated mesenchymal cells obtained from bone marrow or other tissues are characterized by extensive heterogeneity, and cell populations that can satisfy the criteria for being stem cells are very rare. Therefore, to clarify the gap between nomenclature and function, the International Society for Cell Therapy 2005 has adopted the term "mesenchymal stromal cells (MSCs)" rather than mesenchymal stem cells.
Notably, these plastic-adherent MSCs can be easily cultured
While contributions of MSCs by direct differentiation into specific types of tissue were limited, MSCs were shown to secrete a variety of molecules, including bioactive and extracellular matrix factors. Interestingly, the secretion of bioactive factors by MSCs was regulated in a manner tightly associated with their growth and differentiation, i.e., each cellular condition of MSCs gave rise to a distinct set of secreted factors. These observations suggested that one of the primary and key functions of MSCs is to secrete large amounts of bioactive molecules in response to local environmental conditions [2]. Moreover, MSCs have been shown to migrate to the site of local tissue injury or inflammation, penetrating across the endothelial layers of vessels; this migration is dependent on the specific interaction of adhesion molecules such as P-selectin or VCAM-1 in endothelial cells. Taken together, these observations now suggest that the therapeutic effects of MSCs may be specific delivery of bioactive factors that can facilitate the regeneration of tissues at the site of local injury. These effects, termed "trophic activity" by A. Caplan [2], exhibit a common mode of action of bioactive molecules, i.e., (1) inhibition of apoptosis and limitation of the field of damage or injury; (2) inhibition of fibrosis or scarring at sites of injury; (3) stimulation of angiogenesis to bring in new blood supply; and (4) stimulation of mitosis of tissue-specific and "endogenous" stem cells. Other secretary factors include factors for immune modulation to inhibit activation of T-cells, chronic inflammatory processes, or autoimmune reactions. Furthermore, MSCs secrete factors that can promote vasculogenesis, such as VEGF. Thus, it is possible that the intrinsic function of MSCs is not to replace damaged cells but rather to provide a regenerative microenvironment.
In fact, the hypothesis that MSCs may comprise a regenerative microenvironment for tissue-specific stem cells has been supported by studies on the bone marrow model. It was shown that hematopoietic stem cells (HSCs) reside in a specialized structure of bone marrow, called niche, either in the endosteal or perivasular region. The endosteal niche is comprised mainly of osteoblasts in the endosteal surface of trabecules, whereas the perivascular niche is comprised mainly of reticular cells adjacent to sinus endothelial cells (SECs). Notably, recent studies have shown that a specific population of MSCs that express CD146 can form colony-forming units of fibroblasts (CFU-Fs) and retain the potential to regenerate both endosteal and perivascular niches. These findings strongly suggest that the cellular structures for both types of niches originate from a common source, which was referred to as skeletal stem cells (SSCs) (Fig. 1) as reviewed by in our previous study [3]. On the other hand, a recent study demonstrated that pericytes located in the peri-vascular areas of various organs were analogous to MSCs, capable of differentiating into multiple cell types such as osteoblasts, adipocytes, and myoblasts. Thus, one striking inference about the
This new insight on MSCs, that they function as a regenerative microenvironment, opens an exciting field of future studies, specifically the dissection of the cross-talk that may occur between the mesenchymal niche cells and tissue-specific stem cells at the injury site. These interactions between the MSC niche and tissue-specific stem cells and their signals are now being actively revealed, as reviewed in our recent study [4]. Therefore, dissecting the cross-talk in the stem cell niche may help identify strategies to coax an optimal microenvironment in the tissue, which will then boost the use of MSCs in cell therapy. On the other hand, it should be also mentioned that safety is the most important factor to be considered. While MSCs have been found to be safe in most clinical trials, it was shown that the size of
New insights on the
Table 1 Representative examples of MSC-based cell therapy trials.
Abbreviations: MSCs, Mesenchymal stromal cells; GVHD, graft-versus-host disease.
Korean J Hematol 2010; 45(4): 219-221
Published online December 31, 2010 https://doi.org/10.5045/kjh.2010.45.4.219
Copyright © The Korean Society of Hematology.
Il-Hoan Oh, M.D. Ph.D.
Director, Catholic High-Performance Cell Therapy Center, The Catholic University of Korea, Seoul, Korea.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Historical studies have shown that bone marrow contains non-hematopoietic cells in addition to hematopoietic cells. The non-hematopoietic cells adhere to plastic dishes and can differentiate into mesenchymal tissues such as osteoblasts, chondrocytes, adipocytes, or myoblasts, and are hence referred to as mesenchymal stem cells. However, the unfractionated mesenchymal cells obtained from bone marrow or other tissues are characterized by extensive heterogeneity, and cell populations that can satisfy the criteria for being stem cells are very rare. Therefore, to clarify the gap between nomenclature and function, the International Society for Cell Therapy 2005 has adopted the term "mesenchymal stromal cells (MSCs)" rather than mesenchymal stem cells.
Notably, these plastic-adherent MSCs can be easily cultured
While contributions of MSCs by direct differentiation into specific types of tissue were limited, MSCs were shown to secrete a variety of molecules, including bioactive and extracellular matrix factors. Interestingly, the secretion of bioactive factors by MSCs was regulated in a manner tightly associated with their growth and differentiation, i.e., each cellular condition of MSCs gave rise to a distinct set of secreted factors. These observations suggested that one of the primary and key functions of MSCs is to secrete large amounts of bioactive molecules in response to local environmental conditions [2]. Moreover, MSCs have been shown to migrate to the site of local tissue injury or inflammation, penetrating across the endothelial layers of vessels; this migration is dependent on the specific interaction of adhesion molecules such as P-selectin or VCAM-1 in endothelial cells. Taken together, these observations now suggest that the therapeutic effects of MSCs may be specific delivery of bioactive factors that can facilitate the regeneration of tissues at the site of local injury. These effects, termed "trophic activity" by A. Caplan [2], exhibit a common mode of action of bioactive molecules, i.e., (1) inhibition of apoptosis and limitation of the field of damage or injury; (2) inhibition of fibrosis or scarring at sites of injury; (3) stimulation of angiogenesis to bring in new blood supply; and (4) stimulation of mitosis of tissue-specific and "endogenous" stem cells. Other secretary factors include factors for immune modulation to inhibit activation of T-cells, chronic inflammatory processes, or autoimmune reactions. Furthermore, MSCs secrete factors that can promote vasculogenesis, such as VEGF. Thus, it is possible that the intrinsic function of MSCs is not to replace damaged cells but rather to provide a regenerative microenvironment.
In fact, the hypothesis that MSCs may comprise a regenerative microenvironment for tissue-specific stem cells has been supported by studies on the bone marrow model. It was shown that hematopoietic stem cells (HSCs) reside in a specialized structure of bone marrow, called niche, either in the endosteal or perivasular region. The endosteal niche is comprised mainly of osteoblasts in the endosteal surface of trabecules, whereas the perivascular niche is comprised mainly of reticular cells adjacent to sinus endothelial cells (SECs). Notably, recent studies have shown that a specific population of MSCs that express CD146 can form colony-forming units of fibroblasts (CFU-Fs) and retain the potential to regenerate both endosteal and perivascular niches. These findings strongly suggest that the cellular structures for both types of niches originate from a common source, which was referred to as skeletal stem cells (SSCs) (Fig. 1) as reviewed by in our previous study [3]. On the other hand, a recent study demonstrated that pericytes located in the peri-vascular areas of various organs were analogous to MSCs, capable of differentiating into multiple cell types such as osteoblasts, adipocytes, and myoblasts. Thus, one striking inference about the
This new insight on MSCs, that they function as a regenerative microenvironment, opens an exciting field of future studies, specifically the dissection of the cross-talk that may occur between the mesenchymal niche cells and tissue-specific stem cells at the injury site. These interactions between the MSC niche and tissue-specific stem cells and their signals are now being actively revealed, as reviewed in our recent study [4]. Therefore, dissecting the cross-talk in the stem cell niche may help identify strategies to coax an optimal microenvironment in the tissue, which will then boost the use of MSCs in cell therapy. On the other hand, it should be also mentioned that safety is the most important factor to be considered. While MSCs have been found to be safe in most clinical trials, it was shown that the size of
New insights on the
Table 1 . Representative examples of MSC-based cell therapy trials..
Abbreviations: MSCs, Mesenchymal stromal cells; GVHD, graft-versus-host disease..
New insights on the