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Mesenchymal Stem Cells: Aesthetic Applications
Adult stem cells may have significant aesthetic surgery
applications. Their replicative capacity and plasticity
may be useful in engineering autologous grafts for soft
tissue and facial skeletal augmentation. Another possibility is that increasing the concentration of mesenchymal stem cells in the facial soft tissue at regular
intervals during adulthood will maintain volume and
elasticity. (Aesthetic Surg J 2003;23:504-506.)
I
dentification of multipotential mesenchymal stem
cells (MSCs) derived from adult human tissues has
led to exciting prospects for cell-based tissue engineering and regeneration. Ongoing research in regenerative medicine may enable us to use living cells and their
signaling mediators to repair and rejuvenate tissue. In
aesthetic surgery, these therapeutic strategies may be
used in the future not only to treat physical signs of aging
but also to prevent them.
Several strategies are under investigation. Stem cells
can be processed and implanted directly or modified ex
vivo before implantation. They can also be combined
with biomaterials that provide structural support and
growth factors. In addition, endogenous stem cells may
be activated by the administration of signaling factors.
Characteristics of Adult MSCs
A stem cell is a cell from the embryo, fetus, or adult
that can undergo extensive proliferation before senescence and can be differentiated to specialized cells of
body tissues and organs.1 These cells remain in their
undifferentiated state through suppression by some
intrinsic or extrinsic factor until stimulated. As stem cells
self-renew in vivo, their progeny include both new stem
cells and committed progenitors with a more restricted
differentiation potential. These progenitors, in turn, give
rise to differentiated cell types.
The quintessential pluripotent cell is the embryonic
stem cell (ESC), which has the ability to differentiate into
all bodily tissues. This cell type has been isolated and cultured from 2 sources: (1) the inner cell mass of human
embryos at the blastocyst stage, and (2) fetal tissue from
terminated pregnancies.2,3 During embryonic develop504
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ment, the pluripotency of
the ESC is narrowed to tissue-specific determined stem
cells. The determined stem
cells differentiate into committed progenitor cells that
retain a limited capacity to
replicate. Despite the
J. Peter Rubin, MD,
pluripotency of ESCs, legal
Pittsburgh, PA, is a plastic
and moral controversies
surgeon. Co-author Siamak
Agha-Mohammadi, MD, PhD,
concerning their therapeutic
Pittsburgh, PA, is a fellow in
and clinical application
plastic surgery.
have prompted examination
of adult MSCs.
Most cells in adult organs are composed of differentiated cells with specific phenotypic and genotypic characteristics. In the past decade, undifferentiated stem cells
with varying capacity to develop into different mature tissues have been identified in mesenchymal tissues of adult
humans. These quiescent adult stem or progenitor cells
have been isolated from many anatomic sites, including
brain, pancreas, liver, skin, fat, muscle, blood, bone marrow, lung, and tooth pulp. Adult stem cells may be activated for tissue regeneration during the natural processes
of cell turnover and wound healing. As direct precursor
cells for mature tissue, adult MSCs differentiate to several
lineages, including chondrocytes, adipocytes, lymphocytes, fibroblasts, marrow stroma, osteocytes, myoblasts,
cardiomyoblasts, and astrocytes. MSCs not only have the
capacity to make specialized cells for the immediate
repair or replacement of tissue, but also retain a high
regenerative potential to guarantee correct function and
cell turnover over time, possibly for a lifetime.4
Adult MSCs were thought to develop into a narrow
range of cell types that reflected the tissue composition
from which they were isolated. However, in recent laboratory experimentation, adult stem cells have exhibited
unexpected flexibility, differentiating into many tissue
types.5 The term transdifferentiation is being used to
describe this capacity. The plasticity of adult stem cells is
thought to be similar to that of ESCs, creating new hope
for their use in cell-based therapies.6 In addition, MSCs
demonstrate a high capacity for replication, with about
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2003
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38 ± 4 population doublings before senescence.7 This
replication would allow a small population of harvested
cells to be expanded in culture before use.
Currently there is no unifying definition of MSCs or
list of specific markers that define cell types characterized
as MSCs. Instead they are currently defined by their ability to differentiate along specific mesenchymal lineages
when induced. MSC potential is routinely determined
with the colony-forming–unit fibroblast assay, and MSCs
are identified by their expression of Thy-1 (CD90) vascular cell adhesion molecule-1 (CD106), and hyaluronate
receptor (CD44).8 Although antibodies to several cell surface antigens can be used to recognize MSCs, specific
molecular probes do not exist to unequivocally identify
these cells in situ. Consequently, it is difficult to quantify
their actual numbers or identify their precise locations.
Moreover, it is speculated that MSCs are a heterogenous
population containing cells with varying capacities for
lineage-specific differentiation.
Stem Cell Procurement
Bone marrow aspirate is considered the most enriched
source of MSCs. Given the wide distribution of MSC
sources, the bone marrow stroma may be the source of a
common pool of multipotent cells that access various tissues by way of the circulation, subsequently adopting
characteristics that meet the requirements of maintenance
and repair of a specific tissue type. This hypothesis is supported by the finding that liver cells with a donor genotype can be found in the bone marrow of transplant
recipients.9
To be practical, MSC harvest would have to carry a
very low morbidity. Although bone marrow aspiration is
not a high-risk procedure, pain at the donor site can be
considerable. The ideal source of MSCs for aesthetic use
would be tissue that is easily accessible and readily
expendable. Zuk and associates10 have shown that adipose tissue, especially lipoplasty aspirate, is a source of
MSCs with the potential for differentiation of adiposederived stem cells into myogenic, osteogenic, chondrocytic, and adipocytic cells. Moreover, lipoaspirate can be
easily processed to yield large numbers of stem cells.11
Aesthetic Applications
There are several possible strategies for using adult
stem cells for aesthetic applications. Although large-scale
clinical trials using stem cells for aesthetic indications
have not yet begun, current research is under way in
many laboratories, laying the foundation for this work in
the near future.
Mesenchymal Stem Cells: Aesthetic Applications
AESTHETIC
One approach is to harness the replicative capacity
and plasticity of adult stem cells to engineer autologous
grafts for soft tissue and facial skeletal augmentation.
Skin substitutes engineered from human cells are already
in clinical use (eg, Apligraf [Organogenesis, Canton,
MA]) and have generated great enthusiasm for the use of
in vitro–engineered cells to generate cartilage, muscle,
soft tissue, and bone.12 For example, adult stem cells
could be harvested from lipoplasty aspirate and induced
to differentiate (in vitro) to osteocytes. These new cells
could then be seeded onto a biodegradable scaffold containing osteogenic growth factors and implanted back
into the patient as a malar onlay graft. Once in place, the
implant assumes the structure of autologous bone. A similar approach can be used for soft tissue augmentation.
Adipose-derived adult stem cells may be extracted and
stimulated to differentiate in vitro to an adipocyte lineage. The cells would be suspended in a hydrogel and
injected with precision as an autologous graft. The problem of variable fat resorption (with standard lipoaugmentation of harvested fat) may be avoided because the
newly generated adipocytes demonstrate near-complete
engraftment and growth.
A second strategy is to simply deliver undifferentiated
adult stem cells in high concentrations to a specific
anatomic site. A “critical mass” of transplanted stem cells
may serve to initiate a cascade of angiogenesis and repair
in local tissues.13 A growing body of literature indicates
that the number of MSCs decreases with age and/or systemic disease and that their relative presence can control
the outcome of reparative events of skeletal tissues.
Simply increasing the concentration of MSCs in the facial
soft tissue at regular intervals during the aging process
has the potential to maintain volume and elasticity of the
treated structures. Furthermore, adult stem cells can serve
as gene-delivery systems; harvested stem cells can be
transfected with genes, coding for a range of vital growth
factors before implantation. The transfected cells would
actively secrete these agents into the surrounding
microenvironment.14,15
A third approach involves activating and manipulating
endogenous adult stem cells in situ. Administering
growth factors, cytokines, and other signaling agents
would activate local MSCs and induce migration of distant MSCs, such as bone marrow, to a specific region.
Encapsulating these agents in biodegradable polymers
would create a sustained-delivery system capable of
releasing different signals during key steps in the process
of cell differentiation. This strategy could be used for the
prevention and treatment of the stigmata of facial aging.
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Clearly the in vivo management of MSCs will require a
more detailed understanding of the molecular steps of
each differentiation pathway and the regulatory mechanisms that inhibit such differentiation in quiescent cells.16
Conclusion
Manipulation of adult stem cells may play an important role in future aesthetic surgery. Ongoing research to
define the cellular and molecular fingerprints of MSCs
and to elucidate their role in normal and abnormal tissue
functions will lay the groundwork for clinical trials
involving the treatment and prevention of aesthetic deformities. ■
References
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and units in evolution. Cell 2000;100:157-68.
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pluripotent stem cells from cultured human primordial germ cells.
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Embryonic stem cell lines derived from human blastocysts. Science
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12. Ballas CB, Zielske SP, Gerson SL. Adult bone marrow stem cells for
cell and gene therapies: implications for greater use. J Cell Biochem
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13. Carmeliet P. Luttun A. The emerging role of the bone marrow–derived
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2001;86:289-297.
14. Bonadio J. Tissue engineering via local gene delivery: update and
future prospects for enhancing the technology. Adv Drug Deliv Rev
2000;44:185-194.
15. Morizono K, De Ugarte DA, Zhu M, Zuk P, et al. Multilineage cells
from adipose tissue as gene delivery vehicles. Hum Gene Ther
2003;14:59-66.
16. Griffith LG, Naughton G. Tissue engineering: current challenges and
expanding opportunities. Science 2002;295:1009-1014.
Reprint requests: Peter Rubin, MD, University of Pittsburgh Plastic and
Reconstructive Surgery, Scaife Hall, Suite 682, 3550 Terrace St,
Pittsburgh, PA 15261; e-mail: [email protected].
Copyright © 2003 by The American Society for Aesthetic Plastic Surgery, Inc.
1090-820X/2003/$30.00 + 0
doi:10.1016/j.asj.2003.87
7. Caplan AI, Bruder SP. Mesenchymal stem cells: building blocks for
molecular medicine in the 21st century. Trends Mol Med
20017;6:259-264.
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Volume 23, Number 6