干细胞及其治疗学 - zhejiang...
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What is a stem cell?
M t C ll AMature Cell A
B
Mature Cell C
Categories of stem cells?Categories of stem cells?
Adult stem cells: Adult stem cells:
Self-renewal; multipotency; p y
Pluripotent stem cells:
Self renewal; pluripotencySelf-renewal; pluripotency
(1) Embryonic stem cells (ESCs)( ) y ( )
(2) Induced pluripotent stem cells (iPSCs)
Induced pluripotent stem cells
Modified from biochemistry.ucr.edu
www.stemcellresources.org
Adult stem cells
Hematopoietic Stem Cells
www.allthingsstemcell.com
2005 Albert Lasker Basic Medical Research Award
Ernest McCulloch and James Till for ingenious experiments that first identified a stem cell — the blood-forming stem cell — which set theidentified a stem cell the blood forming stem cell which set the stage for all current research on adult and embryonic stem cells
In the early 1960s, McCulloch and Till started a series of experiments that involved injecting bone marrow cells into irradiated mice. Visible nodules were observed in the spleens of the mice, in proportion to the number of bone marrow cells injected. Till and McCulloch called the nodules 'spleen colonies' and speculated that each nodule arose fromnodules spleen colonies , and speculated that each nodule arose from a single marrow cell: perhaps a stem cell.
Colony Forming Unit-Spleen (CFU-S) assayy g p ( ) y
Irving Weissmang
HSCs isolation and assays
2006 Terese Winslow
Ontogeny of the Hematopoietic System
Image from Paterson Institute for Cancer Research
Applications of Hematopoietic Stem Cells
The Nobel Prize in Physiology or Medicine 1990
Bone marrow transplantation
www.scripps.orgE. Donnall ThomasJoseph E. Murray
"for their discoveries concerning organ and cell transplantation in the treatment of human disease"of human disease
Hematopoietic stem cell transplantation is widely in use to treat various hematopoietic malignanciesuse to treat various hematopoietic malignancies
Indications for Hematopoietic Stem Cell Transplants inIndications for Hematopoietic Stem Cell Transplants in the United States, 2009. Center for International Bone Marrow transplant Research (www.cibmtr.org).
World-wide shortage of Bone Marrow Transplantation
More than 17,900 bone marrow or umbilical cord blood transplants were performed in the United States in 2011
据统计，中国等待造血干细胞移植的患者有100多万，仅白血病患者每年新增4万人以上，因白血病死亡的人数达3万人以上。在非血缘关系的人群中造血干细胞相合率很低，较常见的类型是1/5000，较罕见的类型为1/100000。
Additional cell sources for bone marrow transplantation are needed
Mesenchymal Stem Cells
Embryonic Stem Cells
The Nobel Prize in Physiology or Medicine 2009
Mario R. Capecchi Sir Martin J Evans Oliver SmithiesMario R. Capecchi Sir Martin J. Evans Oliver Smithies
"for their discoveries of principles for introducing specific gene modifications in mice by the use of embryonic stem cells".
2006 Terese Winslow
US drug company halts world's first official human embryonic stem cell clinical trial
Photo: AP Photo/Paul Sakuma
Hematopoietic differentiation
Clinical Application
Ontogeny of the Hematopoietic System
Image from Paterson Institute for Cancer Research
Hemangioblast development in mouse ES cells and early mouse embryocells and early mouse embryo
Keller G Genes Dev. 2005;19:1129-1155.
CD45negPFV cells with hemangioblastic propertiesCD45 gPFV cells with hemangioblastic properties
Wang et al. Immunity. 2004. 21: 31-41
H f i l HSC h bHowever, no functional HSCs have been generated from human ES cells so fargenerated from human ES cells so far
Ethi l C ith h ES d i tiEthical Concerns with human ES derivationfacilitate the discovery of iPS technologyy gy
The Nobel Prize in Physiology or Medicine 2012
Sir John B. Gurdon Shinya Yamanakay
"for the discovery that mature cells can be reprogrammedfor the discovery that mature cells can be reprogrammed to become pluripotent"
iPSCs technology for drug screening
Science Translational Medicine 2012
Disease Modeling
Cell. Volume 148, Issue 6, 2012, Pages 1110–1122.
Nature 2012, 481: 295-305.
Nature 2012, 481: 295-305.
Personalized Regenerative Medicine
1. Easy to differentiate human pluripotentstem cells into retinal pigment p gepithelium.
2. The eye can be easily and closelyy y ymonitored for problems.
By JAPAN PRODUCTS | Uploaded 09/12/2014From Nature 2014, Sept
Nature Biotechnology 2015, 9 (33): 890-891.
Quality Issue: iPSCs harbor genomic aberrations
1. Gene deletion
2. Gene duplication
3. Point mutation
Blasco M et al. EMBO J. 2011. 30: 991–993.
Reprogramming-induced mutations make a major contribution to the overall mutational load of iPS Cells
Class I
19 %7 %
:Pre-existing mutations
Class II
ClassIII
:Reprogramming-inducedmutations:Passaging-inducedmutations
Ji et al. Stem Cells 2012; 30:435-440.
74 %
Reason: Presence of copy number variations in the second patient-derived iPSCs, but undetectable in the original fibroblasts.derived iPSCs, but undetectable in the original fibroblasts.
Antioxidants
Reprogramming
Yamanaka S and Blau HM, Nature 2010 456.
Th h i i l f iPSC dThe therapeutic potential of iPSCs and nt‐hESCs needs to be further evaluatednt hESCs needs to be further evaluated
Immunogenicity: Autologous vs allogenic
The End