Scientists have created natural-looking hair that grows through the skin using human induced pluripotent stem cells (iPSCs)


Scientists from Sanford Burnham Prebys have created natural-looking hair that grows through the skin using human induced pluripotent stem cells (iPSCs), a major scientific achievement that could revolutionize the hair growth industry.

The findings were presented today at the annual meeting of the International Society for Stem Cell Research (ISSCR) and received a Merit Award.

A newly formed company, Stemson Therapeutics, has licensed the technology.

More than 80 million men, women and children in the United States experience hair loss. Genetics, aging, childbirth, cancer treatment, burn injuries and medical disorders such as alopecia can cause the condition.

Hair loss is often associated with emotional distress that can reduce quality of life and lead to anxiety and depression.

“Our new protocol described today overcomes key technological challenges that kept our discovery from real-world use,” says Alexey Terskikh, Ph.D., an associate professor in Sanford Burnham Prebys’ Development, Aging and Regeneration Program and the co-founder and chief scientific officer of Stemson Therapeutics.

“Now we have a robust, highly controlled method for generating natural-looking hair that grows through the skin using an unlimited source of human iPSC-derived dermal papilla cells.

Hair growth in nude mice transplanted with human iPSC-derived dermal papilla cells that were combined with mouse epithelial cells inside a biodegradable scaffold. Left insert: enlarged outside view. Right insert: fluorescent microscopy image of hair follicles under the skin; cell nuclei (blue), epithelial cells (green), human dermal papilla cells (red). Credit: Sanford Burnham Preybs

This is a critical breakthrough in the development of cell-based hair-loss therapies and the regenerative medicine field.”

Terskikh studies a type of cell called dermal papilla. .

Residing inside the hair follicle, these cells control hair growth, including hair thickness, length and growth cycle.

In 2015, Terskikh successfully grew hair underneath mouse skin (subcutaneous) by creating dermal papilla derived from human pluripotent stem cells – a tantalizing but uncontrolled process that required further refinement.

“Our new protocol described today overcomes key technological challenges that kept our discovery from real-world use,” says Terskikh.

“Now we have a robust, highly controlled method for generating natural-looking hair that grows through the skin using an unlimited source of human iPSC-derived dermal papilla cells.

This is a critical breakthrough in the development of cell-based hair-loss therapies and the regenerative medicine field.”

The approach detailed in the ISSCR presentation, which was delivered by lead researcher Antonella Pinto, Ph.D., a postdoctoral researcher in the Terskikh lab, features a 3-D biodegradable scaffold made from the same material as dissolvable stitches.

The scaffold controls the direction of hair growth and helps the stem cells integrate into the skin, a naturally tough barrier.

The current protocol relies on mouse epithelial cells combined with human dermal papilla cells.

The experiments were conducted in immunodeficient nude mice, which lack body hair.

The derivation of the epithelial part of a hair follicle from human iPSCs is currently underway in the Terskikh lab.

Combined human iPSC-derived epithelial and dermal papilla cells will enable the generation of entirely human hair follicles, ready for allogenic transplantation in humans.

Distinct from any other approaches to hair follicle regeneration, human iPSCs provide an unlimited supply of cells and can be derived from a simple blood draw.

Hair loss profoundly affects many people’s lives.

A significant part of my practice involves both men and women who are seeking solutions to their hair loss,” says Richard Chaffoo, M.D., F.A.C.S., a triple board-certified plastic surgeon who founded La Jolla Hair MD and is a medical adviser to Stemson Therapeutics.

“I am eager to advance this groundbreaking technology, which could improve the lives of millions of people who struggle with hair loss.”

The hair follicle (HF) is a unique miniorgan, which self-renews for a lifetime. Stem cell populations of multiple lineages reside within human HF and enable its regeneration.

In addition to resident HF stem/progenitor cells (HFSPCs), the cells with similar biological properties can be induced from human-induced pluripotent stem cells (hiPSCs).

As approaches to regenerate HF by combining HF-derived cells have been established in rodents and a huge demand exists to treat hair loss diseases, attempts have been made to bioengineer human HF using HFSPCs or hiPSCs.

Main body of the abstract

The aim of this review is to comprehensively summarize the strategies to regenerate human HF using HFSPCs or hiPSCs. HF morphogenesis and regeneration are enabled by well-orchestrated epithelial-mesenchymal interactions (EMIs).

In rodents, various combinations of keratinocytes with mesenchymal (dermal) cells with trichogenic capacity, which were transplanted into in vivo environment, have successfully generated HF structures.

The regeneration efficiency was higher, when epithelial or dermal HFSPCs were adopted.

The success in HF formation most likely depended on high receptivity to trichogenic dermal signals and/or potent hair inductive capacity of HFSPCs.

In theory, the use of epithelial HFSPCs in the bulge area and dermal papilla cells, their precursor cells in the dermal sheath, or trichogenic neonatal dermal cells should elicit intense EMI sufficient for HF formation.

However, technical hurdles, represented by the limitation in starting materials and the loss of intrinsic properties during in vitro expansion, hamper the stable reconstitution of human HFs with this approach.

Several strategies, including the amelioration of culture condition or compartmentalization of cells to strengthen EMI, can be conceived to overcome this obstacle.

Obviously, use of hiPSCs can resolve the shortage of the materials once reliable protocols to induce wanted HFSPC subsets have been developed, which is in progress.

Taking advantage of their pluripotency, hiPSCs may facilitate previously unthinkable approaches to regenerate human HFs, for instance, via bioengineering of 3D integumentary organ system, which can also be applied for the treatment of other diseases.

The hair follicle (HF) is a skin appendage that mainly consists of cylindrical multiple layers of keratinocytes surrounding the hair shaft with a specialized mesenchymal cell aggregate of the dermal papilla (DP) at its proximal end (Fig. 1a, b) [1].

In humans, HF not only provides physical and immunological barrier for external insults [123] but also impacts on one’s appearance.

Thus, a huge demand for the treatment of hair loss conditions exists and numerous approaches with varying levels of evidence have been developed.

With recent advances in regenerative medicine, especially the emergence of human induced pluripotent stem cells (hiPSCs), the possibility of regenerating human HF has been globally discussed [4].

Fig. 1
Fig. 1Normal human scalp hair follicle structure. a A hair follicle microdissected from human scalp (an anagen hair follicle is presented). b Corresponding histopathology image. The bulge area harbors stem cells. Hair matrix cell proliferation in the bulb results in hair shaft elongation. c Hair follicle epithelial stem cells locate in the outermost layer of the outer root sheath. d The dermal papilla (DP) and the dermal sheath (DS) are mesenchymal components demonstrate trichogenic activity

In fact, human HF regeneration for treating non-autoimmune-mediated hair loss diseases, such as androgenetic alopecia or female pattern hair loss, may serve as an ideal model to probe the feasibility of regenerative medicine approaches for several reasons: (1) HF is easily accessible and observable; (2) HF morphogenesis, biology, and physiology have been well understood; (3) in vitro maintenance and cultivation of HF or HF-derived cells have been established; (4) at least in rodents, the methodologies to reconstitute HFs in vivo have been established; and (5) autologous transplantation of HFs in bald area has been widely conducted, etc. [3456].

Of note, HF is a periodically self-renewing miniorgan harboring multiple stem/progenitor cell populations represented by epithelial HF stem cells (HFSCs) at the bulge area (Fig. 1c) and DP or its precursors in the dermal sheath (DS) (Fig. 1d), which serve as ideal cell sources for HF regeneration and, potentially for hiPSC generation [456].

Ultimately, HF-derived hiPSCs can be converted into HFSCs and unlimitedly supply materials for human HF regeneration [7].

HF morphogenesis and regeneration depends on intensive and well-orchestrated interactions between receptive epithelial and inductive mesenchymal components (Fig. 2) [358].

In the past attempts to bioengineer HF, variously prepared epithelial and mesenchymal components were combined and grafted into a permissive in vivo environment to elicit intercompartmental interactions [56].

Theoretically, less-committed and highly proliferative HFSCs or progenitor cells could efficiently yield HFs in those conventional assays.

In line with this hypothesis, HFSCs were shown to be favorable materials for HF regeneration, at least, in rodents [910].

However, the use of human HFSCs or progenitor cells for such application was hampered by the limitation in collectable cells and the loss of their intrinsic properties during in vitro expansion [4]. Improvement of culture condition to maintain/restore their intrinsic property is pivotal.

Fig. 2
Fig. 2Hair follicle morphogenesis and hair cycle Hair follicle morphogenesis and hair cycle are enabled by well-orchestrated epithelial-mesenchymal interactions. In morphogenesis, crosstalk between the placode and the dermal condensate (the precursor of the dermal papilla) initiates epithelial invagination to form the lanugo. In hair cycle, communication between bulge stem cells and the dermal papilla is thought to play key roles in telogen (resting phase)-anagen (growing phase) transition

Recent studies support the usefulness of hiPSCs to experimentally regenerate human HF [11121314].

The cell populations biologically resembling epithelial HFSCs or DP cells can be induced from hiPSCs [121415].

Co-grafting with either component respectively with dermal or epithelial cells into in vivo environment resulted in HF-like structure formation.

Furthermore, hiPSCs may enable previously unthinkable approaches to bioengineer HFs. For instance, taking advantage of their pluripotency, 3D integumentary organ system can be directly generated from hiPSCs [13].

The aim of this review is to summarize the strategies for using human HFSCs and progenitor cells or hiPSCs for HF regeneration with a particular emphasis on the enhancement of epithelial-mesenchymal interactions (EMIs).

Provided by Sanford Burnham Prebys Medical Discovery Institute


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