Stem Cells, a Promising Tool for Regenerative Medicine
Viswanathan, senior vice president, Regenerative Medicine Group,
Reliance Life Sciences
Regenerative medicine is a new way of treating diseases using human
stem cell-based therapies. Unlike most molecular medicines for chronic
conditions, regenerative medicine has the potential of returning the
patient to health.
Stem cells are unspecialized ‘master’ cells in the
human body having a unique capacity to multiply and differentiate into
many types of specialized cells and tissues. Stem cells exist
at all stages of human development from early embryos to fetuses to
adults. In general, there are three types of stem cells:
embryonic, fetal and adult. Embryonic stem cells, although very
versatile, continue to face ethics related controversies.
Mesenchymal stem cells
Mesenchymal stem cells (MSCs) are classically defined as CD34 negative,
CD45 negative, SH2 and SH4 positive, and Thy-1 (CD90) positive cells.
These are adult stem cells traditionally isolated from bone marrow (BM)
aspirates. These are spindle-shaped, and during culture, adhere to
plastic. These can be expanded in culture while maintaining their
‘stemness’. These have the capacity to
differentiate into a wide variety of mesenchymal tissues and also cross
lineage boundaries. MSCs qualify to serve as a broadly applicable stem
cell source for regenerative medicine, repopulating injured tissues and
clinically ablated diseased tissues with healthy, terminally
differentiated and tissue-specific cells. Thus, so far, several hundred
patients have received systemically and locally infused MSCs for
various indications, and there are good observations made from those.
MSCs have the capacity to differentiate into mature cells and populate
the resident tissue, giving them a therapeutic potential for
regenerative medicine; secrete cytokines or other soluble mediators and
serve as a vehicle for delivery of proteins i.e. gene therapy may be
tried through one or more routes using different dosages.
Since the mid 1990s, the safety of MSCs has been established, after
which there has been an effort to show that co-infusion of MSC could
hasten the time for hematopoietic stem cell engraftment, since they
could possibly rebuild the marrow micro-environment. More recently, the
immunosuppressive capacity of MSC has taken center stage, but the
mechanism is still under debate.
Literature review suggests that soluble factors released by the MSC are
key elements in their mechanism of action for most, if not all, of the
systemic effects. MSC secrete stromal derived factor-1 (SDF-1), which
plays a critical role in the homing of haematopoietic stem cells to the
marrow niche. In vitro, MSCs constitutively secrete several
interleukins, macrophage colony-stimulating factor (M-CSF), Flt-3
ligand and stem cell factor. Upon IL-1α stimulation, MSC are
induced to express further IL-1α, leukemia inhibitory factory
(LIF), granulocyte-colony stimulating factor (G-CSF) and granulocyte
macrophage colony-stimulating factor (GM-CSF) and several chemokine
MSCs are also thought to secrete biochemical mediators unrelated to the
lymphohematopoietic system like the brain-derived neurotropic factor
(BDNF) and nerve growth factor (β-NGF). Currently, the search
for indescribed mediators generated by MSCs from several
non-traditional sources like placenta, umbilical cord, fat tissue and
so on is an active area of investigation and will probably reveal a new
array of important signaling secreted molecules.
The isolation, culture expansion conditions and the tissue source of
stem cells may significantly affect gene expression and therefore the
bioactivity of the cells. Such conditions include the seeding density,
culture media, serum supplementation, extent of ex vivo expansion etc.
Furthermore, bioreactors in contrast to conventional plastic culture
flasks may affect gene expression. These observations suggest that the
cell-processing protocols can modify expression of specific genes to
optimize the cytokine profile for a given clinical indication.
Observations so far
These observations suggest a new paradigm for the therapeutic
application of MSCs. Systemically infused MSC exert a therapeutic
effect primarily through the release of soluble mediators that act on
local and possibly distant target tissues. Rather than serving as stem
cells to repair tissues, they serve as cellular factories secreting
mediators to stimulate the repair of tissues or modulate the local
microenvironment to foster requisite beneficial effects. In the future,
the lack of human leukocyte antigen (HLA) expression in certain MSC
types may also allow allogenic usage applications.
MSCs can also serve as progenitors. For local therapy, such as in
spinal cord injury, non-healing fractures etc. MSCs seem to
differentiate into nerve, bone and muscle tissue to foster healing.
They have also been reported to reduce the risk of graft failure after
haplo-identical transplant. Similarly, pre-clinical models of
MSC-based cell therapy for acute myocardial infarction, neuronal
disease, injury such as stroke and autoimmune disorders appear very
Secretion of soluble mediators seems to be the predominant mechanism of
action of MSCs. We must demonstrate precise processing protocols that
could generate populations of MSC especially suited for specific
clinical indications from specific sources.
Another intriguing prospect for the future is the use of MSCs to create
‘off-the-shelf’ MSC banks. To fully harness the
potential of these cells, future studies should be directed to
ascertain their cellular and molecular characteristics for optimal
identification, isolation and expansion, and to understand the natural,
endogenous role(s) of MSCs in normal and abnormal tissue functions.
In this way, we will continue to move the field forward and, hopefully,
the promise of MSCs to address unmet medical needs can be fully