lec 14 - stem cell therapies

what are some limitations of CRISPR

• difficult to deliver CRISPR/Cas9 material into cells in large numbers (often can only get into a portion of the intended cells)

• not 100% efficient

• not 100% accurate (off-target effects)

  • can cause unintended mutations or edit unintended cells

recap the reasons parents wanted CRISPR editing of embryos when the father had HIV

describe the different ways HIV can be transmitted

• can a father transmit HIV to his child?

what were the issues with designer babies Lulu and Nana?

can stem cell therapy be used to treat HIV infections?

Stem cell therapy is being explored as a potential treatment for HIV infections, but it is not yet a widely available or standard treatment. The approach is based on the idea of replacing an individual's immune cells with HIV-resistant cells, potentially leading to long-term remission or even a functional cure.

Mechanisms of Stem Cell Therapy for HIV

1. CCR5-Δ32 Mutation Approach

   • Some individuals naturally have a mutation in the CCR5 gene (CCR5-Δ32), which makes their immune cells resistant to most strains of HIV.

   • Hematopoietic stem cell transplants (HSCT) from donors with this mutation have led to long-term HIV remission in a few patients, such as the "Berlin Patient" and the "London Patient."

2. Gene Editing of Stem Cells

   • Technologies like CRISPR-Cas9 are being studied to modify a patient's own stem cells to mimic the CCR5-Δ32 mutation or enhance resistance to HIV.

   • This approach could potentially eliminate the need for donor stem cells and reduce the risks of immune rejection.

3. Immune System Reconstitution

   • Stem cell transplantation can help rebuild the immune system after it has been damaged by HIV or treatments like chemotherapy.

   • This could improve immune function and potentially allow the body to control HIV without antiretroviral therapy (ART).

Current Challenges & Limitations

• High Risk & Toxicity: HSCT is a high-risk procedure typically used only in cancer patients or severe cases due to complications like graft-versus-host disease (GVHD).

• Ethical & Practical Concerns: Finding suitable donors with the CCR5-Δ32 mutation is rare, and gene editing raises ethical and safety concerns.

• Not a Universal Cure: The approach may not work for all HIV strains, particularly those using the CXCR4 co-receptor instead of CCR5.

Future Prospects

• Ongoing research aims to make stem cell-based therapies safer and more accessible.

• Advances in gene therapy and immune engineering may offer less invasive alternatives in the future.

In summary, while stem cell therapy shows promise for HIV treatment, it is currently experimental and not a mainstream option.

when is genome editing effective in treating inherited organ diseases? when is it not?

describe the 3D architecture of the matrix cells grow in and how this effects genome editing

what are the criteria of biomaterials and the types

what are the 4 consequences of aging of a stem cell population

what are the two factors that cause adult stem cells to loose functionality with age?

• intrinsic aging: factors affecting the stem cell itself

• extrinsic aging: factors affecting the stem cell’s niche

what has been learned about HPSC aging from older mice studies

describe heterochronic transplantations

combination of transplantations between young or old donors into young or old recipients

describe heterochronic transplantation of skeletal muscle satellite stem cells

describe heterochronic transplantation of hematopoietic stem cells

what stem cells are known to decline in number with age?

• neural stem cells

• melanocyte stem cells in the skin

• germline stem cells

what do we know about mesenchymal stem cells with age?

• show age-related decrease in number in the bone marrow

• shift their differentiation bias from osteogenic lineage to fat cells

what are some properties of adult stem cells that make them vulnerable to aging?

what is the pro and con of stem cell quiescence?

how is cell turnover related to aging?

describe stem cell epigenome and what affects it

explain the epigenetics of the Agouti mice

Agouti gene mutation

• Makes mice obese and yellow and at risk for heart disease and diabetes

• When fed methyl diet, agouti mothers produced healthy offspring

• Methyl silenced agouti gene

2 methods

• DNA methylation

  • Turns genes off because RNA pol cannot access gene

  • Silenced gene

• Histone modification

  • Adding methyl  to histone inhibits unwinding of DNA

    • DNA coils tighter

  • Adding acetyl groups makes DNA uncoil from histones and increases access by RNA pol

how does the stem cell epigenome change with age?

what happens to HPSC methylation with age

• DNA methylation increases in genes associated with differentiation

  • less expression and less differentiation

• DNA methylation decreases in stemness genes

  • more expression of stemness genes = uncontrollable stem cell division → Cancer