Stem Cells and Infec/ous Disease

Transcription

1 Stem Cells and Infec/ous Disease Professor Vassie Ware Bioscience in the 21 st Century December 4,

2 Overview Se4ng the stage for the discussion: historical perspec9ve and prospects in regenera9ve medicine Stem Cell Basics: What are stem cells? Where do stem cells come from? Selected Stem Cell Advances in the News HIV Infec/on and Prospects for Stem Cell Therapy

3 Historical Perspec/ve and Prospects for Regenera/ve Medicine

4 Historical Perspec9ves Major changes in regenera9ve medicine (replacement of damaged or diseased cells and 9ssues with new cells and 9ssues) due to advances in stem cell technologies Some stem cell therapies in existence for over 50 years. First successful bone marrow transplant done in 1956 on leukemia pa9ent. Bone marrow contains adult- derived hematopoie9c stem cells (able to regenerate 9ssues similar to the specialized 9ssues in which they are found. Embryonic stem cells believed to have greater poten9al. This line of stem cell research has been the most controversial.

5 KEY STEM CELL DEVELOPMENTS modified from

6 IMPACT : Understanding birth defects Possibility of genera9ng pa9ent- specific stem cell lines to study the mechanism of different diseases in the laboratory Crea9on of models for drug discovery and tes9ng the toxic effects of drugs Tissue engineering (e.g., use of progenitor cells to make organoids) Prospects for trea9ng individuals with chronic infec9ons and autoimmune diseases (e.g., HIV infec9on, rheumatoid arthri9s, lupus)

7 STEM CELL BASICS I. What are stem cells?

8 Basic Characteris/cs of Stem Cells Stem cells properties: 1. Capable of dividing and renewing for long periods 2. They are unspecialized. 3. They give rise to specialized cells. Adapted from Stem Cells and Cloning by Kelly A. Hogan; h+p://stemcells.nih.gov/info/basics/basics2.asp

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10 All stem cells are not alike! Some stem cells have more poten9al than others. POTENCY describes the cell s ability to differen9ate into other cell types. Unipotent stem cells form only one type of specialized cell type. Mul/potent stem cells can form mul9ple types of cells and 9ssue types. Pluripotent stem cells can form most or all cell types in the adult. To/potent stem cells can form all adult cell types as well as the specialized 9ssues to support development of the embryo (e.g., the placenta)

11 STEM CELL BASICS II. Where do stem cells come from?

12 Different sources of stem cells during development Adapted from Stem Cells and Cloning by K.A. Hogan [T] Teratomas (benign); Teratocarcinomas (malignant). [P] = pluripotent [M] = multipotent [T] = totipotent [P] [P] [P or M] [P or M] [P] ad

13 Isola/on of Human Embryonic Stem Cells First done by Dr. James Thompson and colleagues at the University of Wisconsin (1998). Figure from Stem Cells and Cloning by K.A. Hogan

14 Scien9sts Turn Human Skin Cells into Stem Cells

15 Stem Cell Research in the News!

16 Selected News about Stem Cells Scien9sts Find Way to Track Stem Cells in Brain (Science, November 2007) Stem Cells Restore Memory in Mice (Journal of Neuroscience, October 2007) Stem Cells From Testes Produce Wide Range of Tissue Types (Nature, September 2007) Scien9sts Turn Human Skin Cells into Stem Cells (Science; Cell, November 2007) First Neurons Created from ALS Pa9ent s Skin Cells (Science, July 2008 [online]) Iden9fica9on of small molecules for human hepatocyte expansion and ips differen9a9on (Nature Chemical Biology, June 2013) Photoreceptor precursors derived from three- dimensional embryonic stem cell cultures integrate and mature within adult degenerate re9na (Nature Biotechnology, July 2013) Genera9on of func9onal human pancrea9c beta cells in vitro (Cell, October 2014) HIV- specific Immunity Derived From Chimeric An9gen Receptor- engineered Stem Cells (Molecular Therapy, June 2015)

17 HIV life cycle (expressed on surface of many cells) and CCR5 (expressed on surface of few cell types) are also receptors. Efficient HIV infection requires one of these in addition to CD4. Note that individuals that are genetically lacking the CCR5 protein receptor are normal and remarkably resistant to HIV infection

18 How can stem cells provide therapy for HIV disease? Problems to overcome for therapy to be effective: 1. Must destroy all CD4+ T cells before bone marrow transplant 2. Transplanted bone marrow must be a perfect match Proof of concept: Bone marrow transplant effective in treating HIV disease in patient with HIV and lymphoma (2009). Patient treated with bone marrow from individual who was naturally resistant to HIV infection (lacked the CCR5 receptor). New bone marrow cells did not become infected with HIV.

19 A general strategy for stem cell therapy to treat HIV disease 1. Use patient-derived stem cells from HIV-infected individual 2. Develop bone marrow stem cells from patient derived stem cells 3. Silence CCR5 gene within bone marrow stem cells to render them resistant to HIV infection 4. Transplant genetically modified bone marrow stem cells into HIV-infected patient who may be able to avoid radiation or drug-treatment to remove all HIVinfected cells. 5. Over time new cells may eventually replace the HIV-infected cells

20 Summary: Stem cell therapies offer regenera/ve prospects for numerous human diseases and infec/ons Stem cells are capable of renewal and differen/a/on. Stem cells are derived from numerous sources and have different potency capaci/es. Adult stem cells (ASCs) have been detected in numerous /ssues. Induced pluripotent stem (ips) cells offer great poten/al. Considerable debate surrounds the use of embryonic stem cells. Adult stem cells may offer similar prospects for therapy as do as ESCs, yet a complete understanding of stem cell applica/ons will require a basic understanding of differen/a/on and renewal mechanisms in ASCs and ESCs as well. Additional resources:

21 Ode to a Stem Cell, Part II by VCW There once was stem cell stuck in the hood Dividing endlessly, but only wishing he could Become something else, a skin cell, a hair cell, or some other type But for weeks he sulked and u+ered this gripe Why am I not needed? to his friends he would say Isn t there a call for a specialist somewhere today? Well, if you really want to leave to get a new start, You must change your tune, for surely there is an art To consider what signals you hear and choices you make. Divide once more for the special journey you take. Dare to be different, as you differen9ate!