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Indian Journal of Transfusion Medicine
  Indian Journal of Transfusion Medicine Indian Journal of Transfusion Medicine

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Regenerative Medicine - Progress and Potentials
 

                                                                                                                                                             Dr. Chandra Vishvanathan
                                                                                                                                                                   
MD (Pathology)

Compared to traditional medicine, regenerative medicine (RM) uses a new concept of regeneration by exploiting the regenerative potential of stem cells for replacing or repairing tissues or organs that are affected by disease, trauma or aging. While the present medical therapies focus on the pathobiology of the illness, elimination of cell death, and tissue protection, regenerative medicine attempts to stimulate the body's own natural healing processes by activating its inherent ability to repair and regenerate.

Using the three components namely cells, an extra cellular matrix to support the cells (i.e. a scaffold), and cell communicators (or signaling systems) either alone or in combination, regenerative medicine promotes tissue regeneration by stimulating the cells, and their surrounding environment to grow and develop into new tissue.

 
     
  Types of stem cells used:  
 
  • Stem cells are undifferentiated cells found in various tissues of the body. These cells have the potential to multiply and regenerate damaged tissues. The cells could be derived from various sources including embryo, fetal or adult tissues.
  • Embryonic stem cells [ESC] are totipotent cells and have the potential to self-renew and differentiate into almost all the tissues in the body. ES cells currently face issues that are related to ethics, religion, tumour formation etc. and hence the use of these cells in clinical application is not yet approved. However research on ESC helps in understanding organogenesis and the various pathways that govern the formation of individual cell types.
  • Adult Stem cells have the ability to differentiate into more than one cell type, but unlike ESC they have restricted “lineage” specific differentiation capacity. These cells could be derived from the patient’s own body (autologous cells) or from an unrelated donor (allogeneic cells). In certain clinical applications, it is necessary to use the patients’ own cells in order to prevent an immunologic response of the new tissue.  Regardless of cell type, the stem cells due to their high multiplication potential are propagated in the laboratory to create large cell banks. In clinical applications, the cells are implanted either directly or through the appropriate route, to encourage differentiation in an appropriate milieu or are differentiated in advance into specific cells before implantation.
  • Fetal and Cord blood derived cells are classified as adult stem cells and are normally used in allogeneic conditions. As indicated under the adult stem cells, these cells are derived from specified tissues. The cells have high multiplication potential and can undergo lineage specific differentiation as well as trans-differentiation.

The second component is the extra-cellular matrix (or 3-D scaffold] that provides the structural support to the cells and creates the physiological environment for appropriate action. The Tissue engineering branch of regenerative medicine is a convergence of these components that brings about the right environment for regeneration.

The third component consists of cell communicators. These include cellular proteins, growth factors or cytokines. These signaling molecules provide specific cues during development and regeneration. Specific factors are added to the stem cells at various stages to induce cell growth and differentiation. Administration of specific signaling molecules into damaged tissues are known to induce tissue regeneration.

 
     
  Derivation of specific cell types from human embryonic stem cells:  
 

Cardiomyocytes derived from ESCs is a matter of interest to most researchers. ESC derived cardiomyocyte differentiation is possible, albeit with a relatively low efficiency. These cardiomyocytes are similar to fetal cardiomyocytes, respond to adrenalin and coupled via gap junctions. They are therefore able to communicate with each other and beat together in a coordinated manner. Transplantation of cardiomyocytes into a mouse model heart has demonstrated that they can integrate into host tissue. The current goals world over include increasing the cell numbers available for transplantation, increasing their long term survival and determining if they are able to mediate functional recovery after applying on a myocardial infarction model. ESC derived Neuronal cells and glial cells are under intensive research in view of the unmet medical needs in this domain.

Accordingly OPC’s, Dopaminergic cells, serotonergic cells etc are cells being tried from the endometric cells. Besides, ESC has been used for the derivation of ectodermal specific neuronal and endodermal specific pancreatic and hepatocyte cells with varying degrees of success. It has been recently shown that the propensity of ESC to differentiate into lineages specific cells depends on the ES cell line.

Haematopoietic development of human ESC to form blood and endothelium is highly significant.  The differentiated cells are characterized by the early expression of some specific stem cell markers and a cluster of haematopoietic transcription factors that are expressed in the early stages of development.

RLS has developed several human ESC lines.  The cells derived from these cell lines have been differentiated to various lineages including neural, pancreatic, hepatic and cardiac cells. Studies on these cell lines help in understanding the differentiation pathways followed by these cells during development as well as the physiological effect produced by these cells following their implantation in various disease models.

Besides, this it is well known that ESC based therapies are still far from the clinic, most researchers supply cells to companies working on new drug development wherein toxicity of drugs are tested on these individual cell types.

Earlier, some drug development groups also used embryos to study invitro toxicity, due to issues related to studies on animal models.

 
     
  Adult stem cells and their potential:  
 

Human body has adult stem cells in most organs, which are multipotent. The clinical use of these cells has been approved in several countries and the cells are currently being used widely for treating several diseases on an experimental basis.  Previously adult stem cells were thought to differentiate only along their lineage of origin. But recent experimental evidence has shown that they are also capable of differentiating into cells of other lineages. For example, the trans-differentiation of mesenchymal origin cells to endodermal and ectodermal lineages. Thus, in the event of injury this resident population of stem cells could help in regenerating lost cell population.

Traditionally bone marrow was considered as the main source of adult stem cells. Bone marrow contains two types of stem cells namely the hematopoeitic cells and non-hematopoietic cell types. Hematopoietic cells grow and mature on a meshwork of non-hematopoietic cells, referred to as Mesenchymal Stem cells (MSCs). Mesenchymal stem cells are of mesodermal origin and can differentiate into other mesodermal cells like osteoblasts, chondrocytes etc. Although bone marrow is the main source of MSCs, only 0.01% to 0.0001% of the cells are MSCs. In addition, the donor’s age also affects the multiplication and differentiation potential of the cells. Several studies have indicated alternate sources of MSCs which include adipose tissue, umbilical cord blood, umbilical cord, amniotic fluid, placenta, dental pulp, skeletal muscle, synovial membrane, synovial fluid, wharton’s jelly etc.. There are several advantages of using Umbilical cord blood and Umbilical cord as potential sources for MSCs. These tissues are discarded after child birth and hence can be collected easily and are non controversial.

Upon activation, MSCs secrete extra cellular matrix proteins, growth factors and chemokines which help in maintaining tissue homeostasis. These cells express a wide array of specific surface antigens that can be used for differentiating them from other contaminating cells including hemaotopoietic stem cells.  One of the important features of MSCs is their lack of major Histocompatibility Complex –II (HLA-DR) and co-stimulatory receptor molecules expression. Following its implantation, there was minimal T cell migration, prevented T cell activation and the cells escaped immunological recognition by lymphocytes. Several factors expressed by MSCs have been attributed to its immunomodulatory properties.  Thus, both autologous as well as allogeneic MSCs could serve as an attractive target for future cell therapies.

At RLS, MSCs derived from bone marrow, umbilical cord and cord blood are being developed as  cell therapies to address diseases like ischemic limb disease, myocardial infarction, Parkinson’s disease, spinal cord injuries to name a few.

 
     
  Tissue Specific Stem cells  
 

Several tissues in the body carry tissue specific stem cells which help in regeneration. However, under certain conditions the cells are either non-functional or their numbers are insufficient to induce regeneration. In such conditions, cells have been derived from other locations of the corresponding tissues or other closely related tissues to induce regeneration.

In case of Limbal stem cell deficiencies, the cells derived from the limbus of the contralateral eye are used in the regeneration of the damaged limbus with promising results. Similarly conjunctival cells have also been used in regeneration. These two cell therapies are currently being offered to patients at several centers including RLS at autologous mode.

 
     
  Progress in tissue engineering  
 

Tissue engineering is an emerging multidisciplinary field involving biology, medicine, and engineering that is likely to revolutionize the ways we improve the health and quality of life. Since the development of bio-engineered skin to heal chronic non-healing wounds and burns, many exciting breakthroughs have been witnessed in this field in the last two decades. With the help of scaffolds, tissue engineering provides a 3-D structure to repair bone and cartilage, close septal heart defects, repair a pelvic floor prolapse, and rejuvenate aged skin, transfers stem cells to a particular location and retains it for sufficiently long etc.

From the rapid progress of research in the field of Tissue engineering, one can envisage the development of novel therapies such as conduits for neural regeneration, a platform to deliver cells for treating diabetes and cardiac failure. As the field of biology immunology and material sciences advances, the field may succeed in building three dimensional organs like bladders, livers, hearts, and kidneys. Some of the commercialized tissue engineered products are used for the treatment of burns, diabetic foot ulcers, vitiligo, and osteoarthritis.

 
     
  Probable mechanism of action  
 

The exact mechanism of action of the stem cells is still not known. However, it is postulated that these cells on implantation multiply and differentiate at the site of injury. The cells might either undergo fusion with the existing tissue and induce regeneration or secrete factors that stimulate the dormant stem cells in the tissues. On transplantation, it is believed that the cells might even de-differentiate and then re-differentiate. Research is currently in progress to get closer to the mechanism of action of the stem cells.

 
     
  Challenges  
 

Some of the challenges faced by the researchers include raw material source such as tissue availability, cell line instability, spontaneous differentiation and de-differentiation issues, and limited scalability. In pre-clinical studies the non-availability of appropriate animal models of human disease and extrapolation of data derived from animal studies to humans makes data interpretation a challenging task.  Other challenges include identifying and validating the right cell source, controlled manipulation of the cell signals, usage of the optimum bovine free medium, affordable cells extracts, modifying the microenvironment, gene modulation, scale up of stem cell therapies for mass-production etc.

For clinical applications all safety rules and regulations have to be strictly adhered to, so as to ensure the safety of the product. The cells have to be processed under controlled GMP conditions; all raw materials including media and buffers have to be well defined. It is mandatory to ensure all the materials used in the process are free-from harmful pathogens. The usages of animal derived components have to be avoided as far as possible.

With the need to produce replicable stem cell data and to identify effective protocols for producing cell lines grown under GMP conditions, the use of terms such as ‘defined media’, optimum, stable etc needs to be carefully understood. Further attention may also need to be given to the use of terms describing specific developmental stages because these are sometimes used in a general manner and may contribute to a lack of consistency in stem cell methodologies and their reproducibility. Academia and regulatory agencies must recognize this. Regenerative medicine world over has begun standardizing practices, which creates a common language, creates scientific authority in the absence of known, and enables work to proceed across incommensurable models and datasets. Decisions are to be made on what should be standardized, and what constitutes evidence.

In order to prevent false claims using stem cell therapies and recognize evidence based therapies, effective measures by the regulatory authorities should be followed to ensure the sustainability of RM. In India, the ICMR facilitates interactions between the Government and the scientists and helps in laying out the regulations for proper stem cell usage.

RM needs the convergence of bench scientists and clinicians, social scientists, engineers, material scientists and experts in robotics and bio-processing. Input from all these disciplines will be required to deliver products based on stem cell science in a timely manner. Furthermore, collaboration between these different fields should occur at an early stage if laboratory science is to be translated efficiently into mass and meaningful clinical application.
In a haste to commercialize the services, clinicians and researchers must not be tempted to take the shorter route. We know that the early stages of innovation in this field have been marked by trial and error, and a search for a viable technology and business model by the business houses. In this direction, a range of different technologies, diseases, cell types and products are being well analyzed and reviewed from time to time. The answer to the question of what will be commodified remains as unclear as does the public and private sources of support for this nascent industry.
Despite several forces that could dampen the enthusiasm of the researchers, scientific progress so far still points favorably towards the use of adult stem cells on account of  its immense potential in the treatment of conditions which are hitherto untreatable. Needless to say that all these are still in the experimental stage and data accrual from various studies will help better understanding of stem cell dynamics.
It is believed that with a cohesive Govt. initiative and appropriate funding, regenerative medicine in the near future will be the standard of care for replacing all tissue/organ systems in the body. In addition it would be widely used in the pharma industry for pharmaceutical testing. Some forecast from the industry watchers says that in 5 years, the research will offer multiple applications for skin, cartilage, bone, blood vessel and some urological products. Insurance reimbursable regenerative therapies will be documented. Regulatory standards for regenerative medicine therapy product will be established, cell sourcing issues will be solved,  researchers will have access to the materials they need to design and  specialized cell banks available for tissue storage, allowing  for the storage of viable ‘off the shelf’ products.
In the next 10 years, a better understanding of stem cell and progenitor cell biology with tissue engineering expertise will lead to smart degradable biocompatible scaffolds, developed using micro and nano-fabrication technologies to produce tissues with their own complete vascular circulation. Moreover, complex organ patches that could repair damaged pieces of the heart or other organs could de developed.

Till ex-vivo tissues and organs are generated, regenerative medicine could harness materials to produce in situ regeneration of diseased and damaged structures in many areas of the body. Thus like any technology in infancy, the progress of RM is balanced between opportunities and uncertainties, hope and hype, risk and benefits. Stem cell research is a complex and dynamic field, making it important to remain updated.

 
     
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Dr. CHANDRA VISWANATHAN
MD(PATHOLOGY), PH.D. (APPLIED BIOLOGY), DPB, DTM
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