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Adult mesenchymal stromal cells (MSC) have been the subject of concentrated laboratory research, preclinical and clinical work, mostly because of their use in regenerative therapy (1, 2), anti-inflammatory therapy (3) and for their cancer targeting capability (4). MSC, also known as mesenchymal stem cells (5) were identified first in bone marrow and isolated by in vitro plastic adherence and defined as CD45 negative cells expressing CD44, CD73, CD90, and CD105 (6–8). The isolated and expanded MSC were able to differentiate into mesenchymal lineages (adipogenic, angiogenic, osteogenic, myogenic, neurogenic, chondrogenic, and hepatic lineages) (7, 8–11), and it is their multipotentiality that makes MSC them an ideal cell type for repair and regeneration of various tissues (2). However, the scarcity of MSC in the bone marrow either requires ex vivo expansion or the use of an alternative source such as adipose tissue, in which they are present at a greater frequency (7) and reside in the adventitia of small blood vessels.

Bone Marrow and Adipose Tissue Derived MSC

  1. Top of page
  2. Bone Marrow and Adipose Tissue Derived MSC
  3. MSC in Clinical Applications
  4. MSC-Scaffold Hybrid Implants
  5. Mesenchymal and Neural Stem Cells in Brain Tissue Repair
  6. Acknowledgements
  7. Literature Cited

Adipose-derived stem cells (ASC) share many properties with bone marrow-derived MSC. Adipose tissue is now recognized as an abundant source of multiple mesodermal progenitors and stem-like cells including endothelial progenitors, pericytes, and supra-adventitial stromal cells (SA-ASC), a second layer of MSC-like cells that surround small vessels in an annular structure (10). The most recent work described by Zimmerlin et al. (11, in this Special Issue) supports the existence of a cellular pedigree among the pericytes and the AS-ASC subpopulations, including a low proliferative stem-like pericytic population expressing MSC markers in vivo, a transit-amplifying subset of the SA-ASC, and SA-ASC which are the most prevalent and homogeneous mesenchymal progenitors in adipose tissue. Zimmerlin et al. used multidimensional flow cytometry and immunofluorescent microscopy to determine the phenotypic relationship between adult MSC and the adipose stromal populations. The key findings were that only a third of adipose pericytes expressed an MSC-like phenotype (CD73+, CD105+, and CD90+), while all CD146+/CD34+ cells as well as SA-ASC co-expressed CD73, CD105, and CD90. In agreement with multipotent or pluripotent stem cell characteristics of pericytes, Montiel-Eulefi et al. (12) demonstrated that aorta-associated pericytes express the pluripotency marker stage-specific-embryonic antigen and can be induced to differentiate into neural phenotypes.

MSC in Clinical Applications

  1. Top of page
  2. Bone Marrow and Adipose Tissue Derived MSC
  3. MSC in Clinical Applications
  4. MSC-Scaffold Hybrid Implants
  5. Mesenchymal and Neural Stem Cells in Brain Tissue Repair
  6. Acknowledgements
  7. Literature Cited

Adipose derived as well as in vitro expanded bone marrow derived MSC are currently used in multitudes of clinical trials [summarized by Nery et al. (2, in this Special Issue)] treating a very broad range of conditions, including bone, heart, muscle, composite soft tissues such as craniofacial and breast tissue, and neurodegenerative diseases. Combining cellular therapies with the use of biodegradable scaffolds engineered to contain and release growth factors to direct cellular differentiation and tissue remodeling, wound healing and the reestablishment of organ functions, greatly expand their therapeutic capabilities. These composite grafts can be implanted in an autologous setting (the same donor as the MSC), reducing or eliminating the possibility of allograft rejection, or in an allogeneic setting (MSC and the recipient may not be matched for major histocompatibility antigens) to either repolarize inappropriate immune responses (20) or to home to tumors armed with cancer cell-targeting compounds (21).

In any clinical application, the cells implanted have to be well characterized: the dose, purity, sterility, safety, and potency of implanted cells required for therapeutic effect should be known and documented. The product suitability must be determined in each therapeutic context by cytometric, molecular and functional in vitro techniques. Therefore, the field of regenerative medicine is dependent on the development and availability of robust, automated, GMP-compatible methods for the identification and isolation of human MSC as well as other stem/progenitor cell subpopulations. Cytometry and flow cytometric sorting are powerful and robust methodologies used for the identification and isolation of stem/progenitor population from heterogeneous “liquid tissues” such as blood and bone marrow, as well as various solid tissues, as long as single cell suspensions can be obtained (7, 8, 10, 13–18). Multidimensional flow cytometry coupled with immuno-histology have the potential to advance the study of solid tissue differentiation, maintenance, repair, and regeneration and provide an important analytical and preparative tool for the characterization of MSC and other stem cell populations used in therapy.

MSC-Scaffold Hybrid Implants

  1. Top of page
  2. Bone Marrow and Adipose Tissue Derived MSC
  3. MSC in Clinical Applications
  4. MSC-Scaffold Hybrid Implants
  5. Mesenchymal and Neural Stem Cells in Brain Tissue Repair
  6. Acknowledgements
  7. Literature Cited

In addition to the engraftment of undifferentiated or predifferentiated cells into their corresponding niches supported by growth factors promoting survival and functional integration in the host tissue or stimulating endogenous tissue repair, as suggested for brain repair (19, in this Special Issue), an important challenge is the in vitro production of organs from patient's own stem cells which then will be used for implantation instead of cadaveric donor-derived organs. Autologous in vitro generated organs obtained from the differentiation of patient's own stem cells represents a current frontier of regenerative medicine.

Mesenchymal and Neural Stem Cells in Brain Tissue Repair

  1. Top of page
  2. Bone Marrow and Adipose Tissue Derived MSC
  3. MSC in Clinical Applications
  4. MSC-Scaffold Hybrid Implants
  5. Mesenchymal and Neural Stem Cells in Brain Tissue Repair
  6. Acknowledgements
  7. Literature Cited

MSC have turned into promising tools for tissue regeneration in neurodegenerative diseases including Parkinson's disease and amyotrophic lateral sclerosis as well as in spinal-chord injury (Ref. 2, in this issue). However, the transplanted cells often do not incorporate into the neural network and subsequently undergo cell death, further forming new necrotic foci. The regenerating stem cell niche, necessary for recruiting endogenous stem and progenitor cells to the place of injury, is a critical component of MSC transplantation and may even provide an alternative to a direct implantation of stem cells to the injured area.

A previous review (20) has focused on the importance of neurotransmitters and ligands of G-protein-coupled receptors for directing neurogenesis in the developing and adult brain as well as in stem-cell models for neural differentiation. The induction of neurogenesis and brain repair by a direct application of growth factors (Ref. 19, in this Special Issue) has supported the idea that an appropriate stem cell niche needs to be created to enable functional engraftment of endogenous or transplanted stem cells. The concept of trans-differentiation of MSC is still controversial and conclusive evidence is needed for a direct formation of functional neurons from MSC. A plausible mechanism for the beneficial effects seen from engrafted MSC could be the secretion of survival and differentiation-inducing factors forming an appropriate stem cell niche and leading to a more favorable environment capable of attracting endogenous neural stem cells. Therefore, any knowledge regarding the composition of stem cell niche is not only important for the basic understanding of tissue repair but also opens possible therapeutic strategies, incorporating genetically engineered stem cells which are capable of secretion of neurotrophic substances right at the engraftment site.

Literature Cited

  1. Top of page
  2. Bone Marrow and Adipose Tissue Derived MSC
  3. MSC in Clinical Applications
  4. MSC-Scaffold Hybrid Implants
  5. Mesenchymal and Neural Stem Cells in Brain Tissue Repair
  6. Acknowledgements
  7. Literature Cited