Stem cells niche and therapeutic applications
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Stem cells niche and therapeutic applications
- 1. STEM CELLS NICHE AND THERAPEUTIC APPLICATIONS Dr. Pradeep Mahajan Stem Cells Transplant Expert | Founder @ StemRx Bioscience Solutions Pvt, Ltd. India drpvmahajan@gmail.com www.stemrx.in
- 2. OUTLINE Stem Cells What is Stem Cells Niche? Activation of Stem Cells Different types of niches Types of adhesions between stem cells and niche cells Signaling pathways Stem Cells and Therapeutic Applications
- 3. Stem Cells An Adult Human once a tiny cell, is a self assembling machine made of trillions of microscopic components… Source :What Are Stem Cells? Louisiana Life Federation
- 4. What is Stem cells niche and what does it consist of? Somatic Cells Niche Cells Stem Cells Signals CXCL2 SCF Bone marrow niche – Dynamic/Hyperactive Neural niche – Slow reactive Balance between quiescence and differentiation Niche cells display a strong interaction in keeping this dynamic system functional. The communication and information play a major role in deciding the fate of the stem cells.
- 5. Niches may be composed of cells, or cells together- extracellular matrix (ECM). They may be sources of secreted or cell surface factors – including members of the Notch, Wnt, fibroblast growth factor (FGF), epidermal growth factor (EGF), transforming growth factor (TGF)- β, stem cell factor (SCF), and chemokine families – that control stem cell renewal, maintenance, and survival. They may consist of just a single cell type, or a whole host of interacting cells. They may derive from cells outside the stem cell’s lineage, or they may derive primarily from the stem cell’s own descendants. Niche : Where stem cells reside, get activated to differentiate and proliferate Components niche cells, stem cells, differentiated cells, progenitor cells, CAM , ECM, physiochemical environment like pH, O2 tension , ionic strength (Ca2+ concentration), metabolite like ATP’s are also important. Mof proteins Cyclin Ds Lamins
- 6. Activation of stem cells
- 7. Niche Cells Activate Stem Cells Extrinsic and Intrinsic signals Self Renewal LTSC STSC Self Renewal can be Symmetric or Asymmetric which is in the pool of quiescent stem cells. in vivo studies of niche are difficult to perform in human beings Source: Nature, Niche structure
- 8. SELF RENEWAL PROLIFERATION MIGRATION DIFFERENTIATION Activated stem cells go for. . .
- 9. A Glance at Different Types of Niches Source:Compartmentalized organization: a common and required feature of stem cell niches?- hypothesis by Valentina Greco Shangqin Guo
- 10. Blood Cell Niche Source ; Stem cell niches,Beyond the dish
- 11. Therapeutic Applications of Hematopoietic Stem Cells Leukemia Sickle Cell Anemia Autoimmune disorders Severe aplastic disease Thalassemia Etc.
- 12. Cartilage and Bone niche Source: Human Bone Marrow Mesenchymal Stem Cells: A Systematic Reappraisal Via the Genostem Experience
- 13. Source: case study at StemRx Bioscience Solutions Pvt. Ltd Fig: Case report of a 45 year old man, treated for AVN- Radiological findings: Restoration of Joint space to near normalcy, articular surface was well defined, subarticular geodes had disappeared with signs of new cartilage formation. Stem cells to treat ; AVN Osteoarthritis Ankylosing Spondylitis Bone fracture Sports injury Etc. Stem Cell Treatment in Orthopedic Conditions
- 14. Neural Stem Cells Niche Stem Cells can treat : Parkinson’s disease Alzheimer's disease Neural disorder syndrome CVA Cord injuries Cerebral palsy And many more.. Traditional thought - Neurons cannot multiply, Modern research – Neurons can be cultured and multiplied Source;Human Bone Marrow Mesenchymal Stem Cells: A Systematic Reappraisal Via the Genostem Experience
- 15. CASE STUDY TESTIMONIAL - AFTER TREATMENT
- 16. Skin and Hair niche Stem Cells to treat : Alopecia Universalis Alopecia areta Hair fall Skin burns Leucoderma Vitiligo Antiaging Source: Nature, epithelial stem cell niches
- 17. Stem cells were taken from the limbus in the patient’s own eye, cultured, and then grafted back on the eye. The grafts had a success rate of 76.6% – leading to restored or improved vision. Stem Cells to cure blindness Stem cells can treat: Diabetic Retinopathy Ocular burns Optic nerve atrophy Corneal injuries Macular Degeneration Retinitis Pigmentosa Etc.
- 18. Diabetes Erectile Dysfunction Cardiac disorders Stem Cell Treatment in Many More as . . .
- 19. Niche Cell Quiescent Stem Cell (Stemness maintained by Mof protein) Signaling Cues with supporting niche Activated Stem Cell Signals Short Lived Progenitor Differentiated Cells CAM Wnt Notch Shh Smad Role of Cyclin Ds proteins and growth regulators Cadherin mediated Integrin mediated Coupled
- 20. Source ; Review Adhesion in the stem cell niche: biological roles and regulation
- 21. Wnt pathway Source : Wnt signaling*David M. Eisenmann§Department of Biological Sciences, University of Maryland Baltimore County HSC-Self renewal Adult Foetal
- 22. Notch Pathway Source ; Notch signaling: mediator and therapeutic target of bone metastasis byNilay Sethi & Yibin Kan Delta/Jagged ligand Differentiation Into T cells Haematopoietic progenitors Osteoblasts and HSCs
- 23. Smad Signaling Pathway Source; Ruhr-Universitat Bochum Department of Molecular Gi-oncology Stephan Hahn, M.D. TGF-inhibitory BMP-promoter Regulation of HSC fate All pathways participate in a cascade synergistically
- 24. PARADIGM SHIFT FROM TRADITIONAL TO CELLULAR MEDICINE Traditional Medicine Cellular Medicine Research
- 25. FUTURE MEDICINE Cells Scaffolds Regenerative Medicine Grafts Bioengineering and repair of the damaged tissue with the help of cells in scaffolds iPSCs CYTOKINES VSELs Endogenous Exogenous
- 26. DRUG DISCOVERY IN A DISH Somatic cells/ Stem Cells Transplanted back iPSC/ Stem Cells Culture Differentiation
- 27. Thank You!! drpvmahajan@gmail.com www.stemrx.in You carry your own repairing kits in your body...!!!
Editor's Notes
- Dear all , Good morning…..First of all I am thankful to the SCS management for inviting me to share the desk and its my pleasure to be here with you.I am doctor Mahajan. Basically I am a surgeon and not a scientist dealing with stem cells therapeutics since last few years. I used get surprised after seeing tiny microscopic cells at laboratory during my studies. I always used to wonder about the functioning of these power-packed cells. Later my passion continued and when I studied stem cells therapeutics in details, I immediately understood stem cells have the great potential and this is the future of the medicine and let me tell you that stem cells look beautiful under the microscope.Imagine that you have been said by a doc that you are suffering from an incurable disease , what will be your status of mind!!!We are entering in the world of stem cells fiction which once upon a time was thought a impossible to treat number of conditions. This is going to be the medicine of 21st century – this is the edge of science and medical revolution.It is the fast and fascinating world- stem cells are known as the building blocks of the body…started your life as the single cell, which autonomously controlled their division by copying and differentiating cells to create your body by organogenesis, but the still the master cell remain as the master keeping its control and managed by niche where it resides.The whole world is interested to know what is happening and how? Inside the body ( in vivo) is a microscopic world busy and complex- maintaining homeostasis of the whole body like the world around us. A miraculous bag of stem cells can create wonders and world is waiting to see what does it consist of… ???Today I am going to open a second wonderful bag of niche where the stem cells resides.
- Stem Cells: Building blocks of the body. I wont be taking much time in dealing with the introduction.We all know that stem cells represent unspecialized cells, which have the ability to differentiate into different types of adult stem cells. Self-renewal capacity and ability to differentiate into a specific cell type makes stem cells special as they can give rise to particular lineage of the cell.But what makesthem so efficient at their work in their role ???? Where do these master stem cells exist???Ans is ‘Niche’…… An adult human once a tiny cell, is a self assembling machine made up of trillions of microscopic components…..During embryonic development, various niche factors act on embryonic stem cells to alter gene expressions and induce proliferation and differentiation to form fetus. Here is the first niche established in the embryo ( Microenvironment of the stem cells). This niche is the dynamic system where interplay between the stem cells and niche cells play an imp role to sustain the tissue growth.This aspect of dynamic system of niche in vivo if properly studied can be applied in therapeutic applications of stem cells in vitro.
- Niches may be composed of cells, or cells together- extracellular matrix (ECM). These ECM components are very important for communication and passing the information to the stem cells to activate them. They may be sources of secreted or cell surface factors – including members of the Notch, Wnt, fibroblast growth factor (FGF), epidermal growth factor (EGF), transforming growth factor (TGF)-β, stem cell factor (SCF), and chemokine families – that control stem cell renewal, maintenance, or survival.
- Within the human body, stem cell niches maintain adult stem cells in a quiescent state, but after tissue injury, the components of the niche pass signals to these stem cells to activate them to multiply, differentiate and proliferate.Activated stem cell divides. One copy stays in the niche, the other differentiates in the progeny cell. The copied cells may go to the pool of quiescent stem cells – Long Term Stem Cells and the cells which become short term stem cells start differentiating.Further progeny cells give rise to particular lineage because of which Stem cells hold great promise in research and regenerative medicine.
- Niche is important for Self Renewal with the help of VEGF, EGF, IL-6, SCF etc…Proliferation with the help of FGF-2, EGF, BMP, BDNF, collagen, laminin, erythropoietinMigration with the help of BDNF, IGF-1,SCF, SDF-1Differentiation with the help of FGF-2, BDNF, angiopoietin
- Example of a blood cell niche….after activation of stem cells in osteoblastic niche, activated stem cells pass through sinusoid vessel
- Neural stem cell regulation. Neural stem cells in the two adult neurogenic niches, the SVZ and SGZ, can be regulatedby (1) diffusible factors (EGF, FGF, TGF-a, VEGF, PEDF, hormones, BMPs, ATP, Wnts and GABA) and their receptors, (2)cell–cell and cell–extracellular environment interactions via membrane-associated ligands and their receptors (Eph/ephrin andNotch/Jagged) or gap junctions and hemi-channels, (3) ligand inhibition (noggin), (4) release of neurotransmitters and otherfactors from axons (GABA, dopamine (DA), glutamate, acetylcholine (ACh), serotonin (5HT), NO and Shh), (5) basal lamina(sequestration and presentation of diffusible factors, such as growth factors) and ECM proteins (laminin, collagen-1, tenascin-C, LeX, heparansulphate and chondroitinsulphateproteoglycans), and (6) endothelial cell/blood vessel-mediated cues. Thecell types that are able to direct neural stem cell fate choices include cells within the niche (both support cells and stem cells andtheir progeny) (green), neurons (axonal projection; blue) and endothelial cells/blood vessels (red). Structural elements that likelyregulate neural stem cell fate decisions include fractones (in the SVZ) and basal laminae (black lines). In addition, CSF andmeningeal projections (not pictured in this figure) are likely important components of the niche. These elements may work inconcert or independently to promote neural stem cell self-renewal or differentiation. The key to the right lists some of the factorsknown to be present in adult neurogenic niches.
- This slide illustrates the niche of skin and hair. SC resides in bulge and upon activation goes to papilla…
- In this slide, look at the four different pictures which explains the process of stem cell-niche adhesion. The adhesion may be different types as:Cadherin-mediated stem cell-niche adhesion ( Classical cadherin mediated physical cell-cell interaction helps anchor stem cells to their niche. Alpha catenin and beta catenin which associate with the intracellular domain of cadherins, help to cluster cadherin molecules and form adherens junctions. (AJ’s)Integrin-mediated stem cell-niche adhesion ( Integrin mediated cell- extracellular matrix (ECM) interactions help anchor stem cells to the niche, which often contain a number of ECM components. The intracellular domains of integrins interact with the actin cytoskeleton network through talin proteins to cluster integrin molecules together Cadherin+integrin mediated cell-niche adhesion ( Cadherin mediated cell interactions and integrin mediated cell-ECM interactions can work together to anchor stem cells to the niche.In addition to cadherins and integrins, other molecules, such as Delta/Notch, SCF/c-Kit, CD44/hyluronic acid (HA) and gap junction components are also involved in stem cell-niche adhesion.Non cadherin+integrin mediated stem cell niche adhesion
- Till this discussion it has become crystal clear that in vivo niche is indispensable for the proper functioning of the cells. However though the process looks simple it involves lots of signaling pathways which regulates the entire process.In future there is a need to engineer or optimize niche cues for differentiation towards different lineages in vitro and analyzing these homing pathways will definitely provide an understanding insight for the development of some new therapies for the treatment of even chronic diseases where stem cells may prove the only remedy.