Stem Cells and Inner Ear Cell Regeneration. Stefan Heller Stanford University School of Medicine
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1 Stem Cells and Inner Ear Cell Regeneration Stefan Heller Stanford University School of Medicine
2 Embryonic stem cells Induced pluripotent stem cells Somatic stem cells 50 µm Derived from the inner cell mass of the blastocyst, an early stage of embryonic development Artificially derived from a somatic cell, by forcing expression of specific genes Isolated from specific organs: bone marrow, fat, but also: inner ear
3 Embryonic stem cells Induced pluripotent stem cells Somatic stem cells Derived from the inner cell mass of the blastocyst, an early stage of embryonic development Pluripotent, tumorigenic (teratoma), no allografts Artificially derived from a somatic cell, by forcing expression of specific genes Pluripotent, tumorigenic (teratoma and cancer), but allografts are possible (no immunosuppression) Isolated from specific organs: bone marrow, fat, but also: inner ear Tissue regenerative potential, tumorigenic potential is limited
4 Embryonic stem cells Induced pluripotent stem cells Somatic stem cells Derived from the inner cell mass of the blastocyst, an early stage of embryonic development Pluripotent, tumorigenic (teratoma), no allografts Artificially derived from a somatic cell, by forcing expression of specific genes Pluripotent, tumorigenic (teratoma and cancer), but allografts are possible (no immunosuppression) Isolated from specific organs: bone marrow, fat, but also: inner ear Tissue regenerative potential, tumorigenic potential is limited Abundant, can be expanded in the laboratory Abundant, can be expanded in the laboratory Scarce (with respect to the inner ear), expansion in the laboratory very difficult
5 Umbilical cord blood Cord blood contains certain somatic stem cells, mainly hematopoietic stem cells Apart from blood disorders, the use of cord blood for regenerative therapies is highly challenging Claims that cord blood can be used to treat hearing loss are unsubstantiated
6 Embryonic stem cells Induced pluripotent stem cells Somatic stem cells Derived from the inner cell mass of the blastocyst, an early stage of embryonic development Pluripotent, tumorigenic (teratoma), no allografts Artificially derived from a somatic cell, by forcing expression of specific genes Pluripotent, tumorigenic (teratoma and cancer), but allografts are possible (no immunosuppression) Isolated from specific organs: bone marrow, fat, but also: inner ear Tissue regenerative potential, tumorigenic potential is limited Abundant, can be expanded in the laboratory Abundant, can be expanded in the laboratory Scarce (with respect to the inner ear), expansion in the laboratory very difficult
7 Embryonic stem cells Induced pluripotent stem cells Somatic stem cells
8 Embryonic stem cells Induced pluripotent stem cells Somatic stem cells... these are murine cells years!
9 Human stem cells Embryonic stem cells Induced pluripotent stem cells Definitely more challenging, requires lots of funding, very specialized expertise, and patience
10 So, what can we do with stem cells? (and what can we not do)
11
12
13
14 Transplantation
15 Transplantation
16 A serious problem!
17 Existing roadblocks and intensive research
18 So, what can we do with stem cells?...and what can we not do (yet) 1) Transplantation: current roadblock = tumorigenicity, efficacy of progenitor cell production anticipated roadblocks: cell delivery, integration at appropriate sites, long term survival, immunorejection, function, improvement of hearing
19 So, what can we do with stem cells? Hair celland supporting celllike cells
20 A screening tool
21 A screening tool
22 A screening tool
23 A screening tool
24 So, what can we do with stem cells?...and what can we not do (yet) 1) Transplantation: current roadblock = tumorigenicity, efficacy of progenitor cell production anticipated roadblocks: cell delivery, integration at appropriate sites, long term survival, immunorejection, function, improvement of hearing 2) High-throughput / high-content screens: current roadblock = human guidance protocol not ready, efficacy anticipated roadblocks: initial drug candidates need to be validated, FDA and clinical trials
25 Gene therapy
26 So, what can we do with stem cells?...and what can we not do (yet) 1) Transplantation: current roadblock = tumorigenicity, efficacy of progenitor cell production anticipated roadblocks: cell delivery, integration at appropriate sites, long term survival, immunorejection, function, improvement of hearing 2) High-throughput / high-content screens: current roadblock = human guidance protocol not ready, efficacy anticipated roadblocks: initial drug candidates need to be validated, FDA and clinical trials 3) Gene therapy (hair cell regeneration, hereditary hearing loss): current roadblock = safety, efficacy anticipated roadblocks: translation toward human, FDA and clinical trials
27 What else can we do with stem cells? Testing of gene therapy vectors Patient ips cell-derived artificial human sensory epithelia 1) Targeting of the correct cell type 2) Test run in a culture dish. Does the gene therapy really cure a (patient)-specific hearing loss
28 Realistic expectations!
29 So, what can we do with stem cells?...and what can we not do (yet) 1) Transplantation: current roadblock = tumorigenicity, efficacy of progenitor cell production anticipated roadblocks: cell delivery, integration at appropriate sites, long term survival, immunorejection, function, improvement of hearing 2) High-throughput / high-content screens: current roadblock = human guidance protocol not ready, efficacy anticipated roadblocks: initial drug candidates need to be validated, FDA and clinical trials 3) Gene therapy (hair cell regeneration, hereditary hearing loss): current roadblock = safety, efficacy anticipated roadblocks: translation toward human, FDA and clinical trials
30 So, what can we do with stem cells?...and what can we not do (yet) 1) Transplantation: current roadblock = tumorigenicity, efficacy of progenitor cell production 2) High-throughput / high-content screens: current roadblock = human guidance protocol not ready, efficacy 3) Gene therapy (hair cell regeneration, hereditary hearing loss): current roadblock = safety, efficacy
31 So, what can we do with stem cells?...and what can we not do (yet) 1) Transplantation: current roadblock = tumorigenicity, efficacy of progenitor cell production: 5-10 years 2) High-throughput / high-content screens: current roadblock = human guidance protocol not ready, efficacy: 3-5 years 3) Gene therapy (hair cell regeneration, hereditary hearing loss): current roadblock = safety, efficacy: 5-7 years
32 So, what can we do with stem cells?...and what can we not do (yet) 1) Transplantation: current roadblock = tumorigenicity, efficacy of progenitor cell production: 5-10 years Next step: Animal experiments 2) High-throughput / high-content screens: current roadblock = human guidance protocol not ready, efficacy: 3-5 years 3) Gene therapy (hair cell regeneration, hereditary hearing loss): current roadblock = safety, efficacy: 5-7 years
33 So, what can we do with stem cells?...and what can we not do (yet) 1) Transplantation: current roadblock = tumorigenicity, efficacy of progenitor cell production: 5-10 years Next step: Animal experiments 2) High-throughput / high-content screens: current roadblock = human guidance protocol not ready, efficacy: 3-5 years Next step: drug candidate validation, drug development, FDA approval, clinical trials 3) Gene therapy (hair cell regeneration, hereditary hearing loss): current roadblock = safety, efficacy: 5-7 years
34 So, what can we do with stem cells?...and what can we not do (yet) 1) Transplantation: current roadblock = tumorigenicity, efficacy of progenitor cell production: 5-10 years Next step: Animal experiments 2) High-throughput / high-content screens: current roadblock = human guidance protocol not ready, efficacy: 3-5 years Next step: drug candidate validation, drug development, FDA approval, clinical trials 3) Gene therapy (hair cell regeneration, hereditary hearing loss): current roadblock = safety, efficacy: 5-7 years Next step: FDA approval, clinical trials
35 A drug will not solve the persisting issues
36
37
38 Reprogramming
39 Reprogramming
40 Reprogramming The question is whether we can find a drug or gene therapy that leads to reprograming of damaged epithelia so that they undergo the developmental programs that were active in the embryo This has to be the long term goal. When it will be achievable is impossible to predict
41 Save the date! 9th Molecular Biology of Hearing and Deafness conference: June 22 - June 25, 2013 Stanford University
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