Three-dimensional Engineered Microenvironments to Study Stem Cell Niches in vitro Milan Manchandia Biochemistry 118Q March 16, 2009Stem cells are unique cells in that they posses the quality of maintaining the undifferentiated state through self-renewal and the capacity to differentiate into specialized cell types [1]. The two broad types of stem cells are pluripotent embryonic stem cells that are isolated from the inner cell mass of the blastocyst and give rise to all three primary germ layers and adult stem cells that act as a repair system for the body and maintain normal turnover of regenerative organs by replenishing specialized cells [1,2]. Stem cell therapy is a form of regenerative medicine in which adult of embryonic stem cells are used to repair damaged tissue or treat diseases [1]. However, due to the controversial destruction of human embryos in obtaining embryonic stem cells, stem cell therapy over the past decade has been severely limited. Therefore, current therapies in medicine mostly involve prevention, manipulation, and control of diseases through chemical or biological molecules [2]. However, a few stem cell therapies have been established in the clinical setting, as bone marrow transplantation has been used over the past few decades to treat certain types of leukemia [1,3]. In this case, hematopoietic stem cells from a healthy donor are injected into the irradiated bones of the leukemia patient where they will produce healthy leukocytes [1,3]. Furthermore, in 2005, a trial at Queen Victoria Hospital made use of stem cells to redevelop the cornea, which restored eyesight to 40 people [4]. Recently, doctors in Spain were able to carry out the world’s first tissue-engineered whole organ transplant by using the patient’s own stem cells to reconstruct a whole bronchial tube [5]. This successful transplantation sheds hope on the future therapeutic potential of stem cells in that a patient’s own stem cells can be used to reconstruct damaged tissues and organs without risking the chance of donor rejection and need for immunosuppressive drugs. Moreover, Yamanaka and Takahashi’s finding of the specific transcription factors Oct-3/4, SOX2, c-Myc, Klf4, and NANOG needed to reprogram human skin cells into induced pluripotent stem cells (IPSCs) [6]was a major breakthrough by providing an ethical source of pluripotent stem cells that could potentially be differentiated into any tissue layer. These findings greatly support the notion that the future of stem cell therapy will involve the differentiation of one’s own IPSCs into cells of a specific tissue layer, which would then be transplanted into the damaged tissue in the body. This type of stem cell therapy has broader implications in current stem cell research of stroke and brain damage, cancer, spinal cord injury, Parkinson’s disease, Huntington’s disease, heart reconstruction, and diabetes mellitus [1]. The true potential of pluripotent stem cells comes from their ability to differentiate into cells that give rise to all three germ layers. The proliferation and differentiation of stem cells are due to specific environmental regulatory signals and intrinsic programs that maintain stem cell properties [7]. This physiologically limited microenvironment that supports stem cells has been termed the “niche” and is generally used to describe the cellular components of the microenvironment surrounding stem cells as well as the interacting signals from the support cells [7,8]. The stem cell niche was first hypothesized by Schofield in 1978 and subsequently supported by various coculture experiments in vitro and by bone marrow transplantation [7]. Although these studies provided supportive evidence towards the niche theory, they did not describe the exact structure of the stem cell niche in vivo. Due to the difficulty in identifying and characterizing stem cell niches in mammals, the Drosophila and C. elegans model systems have been used to study the stem cell niches in Drosophila ovary and testis and the germ line stem cell niche in C. elegans [7,8]. The research in these genetic model systems has consequently lead to a better understanding of mammalian hematopoietic, epithelial, intestinal, and neural stem cell niches with respect to the physical contacts and diffusible factors involved in niche organization and regulation [7,8]. Studies of stem cell niches in Drosophila and C. elegans as well asmammalian tissues have lead to common features, structures, and functions that characterize the stem cell niche. The stem cell niche comprises of a group of cells in a special tissue location for the maintenance of stem cells, functions as a physical anchor by providing adhesion molecules such as integrin, generates extrinsic factors that control stem cell fate and number, and exhibits an asymmetric structure such that after cell division, one daughter cell is maintained in the niche while the other one leaves the niche and becomes a functionally mature cell [7]. Thus, recent studies have resulted in significant progress in establishing the fundamental principles of the stem cell niche and further investigation of the niche’s cellular and molecular components will provide important insights for identification of the stem cell niche in different systems. Furthermore, the ability to recreate the stem cell niches in vitro will allow for the better understanding of the maintenance and expansion of stem cells as well as their therapeutic applications to human degenerative diseases since the efficiency of future stem cell transplantation will come to rely on culturing the transplanted cells to a state as similar as possible to the state of the stem cells found in vivo. In order to investigate these stem cell niches in vitro, it is important to design three-dimensional microenvironments that mimic the microenvironments of stem cells in vivo [9,10]. The behavior and differentiation patterns of stem cells as they occur within the body can only be best understood when researched under similar conditions of signal molecule gradients. Therefore, to study stem cells in their proper niches, an artificial, engineered microenvironment is needed that allows for the construction of the stem cell microenvironment and observation of the cells through a time-course in order to study their behavior [9]. Thus, the field of biomaterials engineering is an important contributor in the development of stem cell
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