In metazoans, adult, tissue-specific stem cells function to naturally replace and regenerate components of organ systems
during life. The restorative power of adult stem cells has been best exploited clinically in bone marrow transplantation to treat
blood cancers and other disorders. With the discovery and characterisation of other adult stem cell types and pluripotent stem
cells capable of generating all tissues in the body, it has been postulated that stem cells may be of utility in replacing other tissues
which have stopped functioning due to age or disease. However, the potential application of stem cells to regenerative
medicine is vast and more multi-faceted than simply furnishing replacement tissue in failing organ systems. In this minithematic
issue of Current Drug Delivery, we explore these other applications focusing on current knowledge about the regulation
of stem cells, its implications for pathogenesis in cancer and cell therapy and how stem cells may be used as drug delivery
agents and as tools in disease modelling and drug discovery.
Adult stem cell function during homeostasis and in response to periods of physiological demand relies on strict intrinsic
regulation interwoven with complex extrinsic signals emanating from the micro-environment (or ‘niche’). That proper adult
stem cell function in vivo is dependent on its niche was the concept first invoked in the blood system in the 1970s and is an idea
that has gained considerable traction in this and other tissue systems more recently. The overall complexity of adult stem cell
niches is gradually being understood at the level of cellular constituents and molecular pathways controlling their behaviour. In
addition to its purely supportive role as a habitat for the stem cell, it is responsible for secreting growth factors and other regulatory
proteins that extrinsically regulate stem cell functionality. Crawford and colleagues review the role of pigment epitheliumderived
factor (PEDF), a critical regulator of neural stem cell self-renewal in the neural stem cell niche. The authors explore the
potential therapeutic role of PEDF where its opposing positive effect on stem cell behaviour and powerful anti-angiogenic effect
on cancers make it possible for it to operate as a selective drug in cancer while sparing or possibly boosting normal tissue
function through harnessing endogenous stem cell function.
It has also become increasingly clear how crucial the stem cell-niche collaboration is to the maintenance of normal tissue function:
in the blood system the potentially dire consequences of disturbing particular constituents of the niche are evident in decreased
stem cell function and the emergence of pre-cancerous and cancerous conditions in mouse models and select clinical syndromes.
The niche may also provide a sanctuary that protects already existent cancer from the effects of treatment (e.g. chemotherapy),
and enables eventual disease relapse. Bartos and Dubielecka-Szczerba explore how one potential component of the niche -
actin cytoskeleton- is impacted by the Bcr-abl oncogene in chronic myeloid leukaemia, leading to drug and therapy resistance.
Pluripotent stem cells, derived from the embryo (embryonic stem cells) or by reprogramming somatic cells to an embryonic
state (induced pluripotent stem cells), and adult stem cells may impact cellular therapy in two distinct ways. As alluded to, they
may directly replace damaged tissues in organ transplantation related strategies (see review by Stewart for examples using
pluripotent stem cell derived tissue). Less well established but becoming more appreciated is that stem cells can function and
act as drug delivery modalities, facilitating tissue replacement without formally integrating or replacing tissue. A case in point
is mesenchymal stem/stromal cells (MSCs), which as English and colleagues discuss, have potent immune modulatory function
that could be deployed to facilitate acceptance of allogeneic organ transplantation or to ameliorate graft versus host disease, a
potentially fatal side-effect of allogeneic bone marrow transplantation (for another example, see Falanga and colleagues review
of the use of MSCs to treat chronic wounds).
Shinya Yamanaka was awarded the Nobel Prize in Physiology and Medicine in 2012 for discovering induced pluripotent
stem cells (iPSCs), underscoring their potential to revolutionise therapies for a plethora of debilitating and fatal diseases via cell
replacement therapy or drug discovery. For example, the capacity to make iPSCs from a somatic cell of a patient afflicted with
a given disease offers an unprecedented opportunity to peer into the evolution of that disease by essentially rewinding its history
in vitro and modelling the earliest pathological steps associated with it, with an ultimate view of identifying drug targets
for treatment. Stewart reviews and explains progress made to date with disease specific iPSCs in this context set against a historical
perspective of the pluripotent stem cell biology field.
Finally, translating the potential of pluripotent stem cell derived tissue or adult stem cells (e.g. MSCs) into both safe and
effective clinical therapies in any setting involving administration of cellular products requires adherence to Good Manufacturing
Practice (GMP) supervised by the Food and Drug Administration (FDA) regulatory framework in the United States and by
the European Medicines Agency (EMA) in Europe. Falanga and colleagues outline the laborious yet essential strategy required
to establish a GMP lab for these purposes and describe their experience with using the laboratory to manipulate MSCs that will
encourage chronic wound healing.